Current Drug Delivery, 2012, 9, 000-000


Polymers and Drug Delivery Systems
Gemma Vilara,b, Judit Tulla-Puchea,b and Fernando Albericioa,b,c,*

Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain; bCIBERBBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain; cDepartment of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, 08028-Barcelona, Spain
Abstract: In the treatment of health related dysfunctions, it is desirable that the drug reaches its site of action at a particular concentration and that this therapeutic dose range remains constant over a sufficiently long period of time to alter the process. However, the action of pharmaceutical agents is limited by various factors, including their degradation, their interaction with other cells, and their incapacity to penetrate tissues as a result of their chemical nature. For these reasons, new formulations are being studied to achieve a greater pharmacological response; among these, polymeric systems of drug carriers are of high interest. These systems are an appropriate tool for time- and distribution-controlled drug delivery. The mechanisms involved in controlled release require polymers with a variety of physicochemical properties. Thus, several types of polymers have been tested as potential drug delivery systems, including nano- and micro-particles, dendrimers, nano- and micro-spheres, capsosomes, and micelles. In all these systems, drugs can be encapsulated or conjugated in polymer matrices. These polymeric systems have been used for a range of treatments for antineoplastic activity, bacterial infections and inflammatory processes, in addition to vaccines.

Keywords: Dendrimers, drug delivery, micelles, nano-micro-particle, nano-micro-spheres, polymers. 1. INTRODUCTION 1.1. Conventional Pharmacotherapy Human health is threatened by autoimmune, neurodegenerative, metabolic and cancer diseases, just to mention a few, which are difficult to treat with systemically, delivered drugs. Conventional pharmacotherapy involves the use of drugs whose absorption and therefore bioavailability depends on many factors, such as solubility, pKa, molecular weight, number of bonds per hydrogen atom of the molecule, and chemical stability, all of which can hinder the achievement of a therapeutic response. In general, the nature of conventional therapeutics, especially their low molecular weight, confers them the capacity to cross various body compartments and access numerous cell types and subcellular organelles. Thus these drugs are suitable for the treatment of diseases. However, this form of indiscriminate distribution leads to the occurrence of side effects and to the need for higher doses of the drug to elicit a satisfactory pharmacological response. Rapid renal clearance as a result of the low molecular weight of these compounds, among other factors such as protein binding, lipophilicity, ionizability etc., implies frequent administration and/or a high dose to achieve a therapeutic effect. Research is being conducted into new formulations that ensure a greater pharmacological response, which in turn would lead to lower doses and therefore the minimization of side effects. Thus, it is necessary to improve the
*Address correspondence to this author at the Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain; Tel:/Fax: ??????????; E-mail: ????????????????????????

bioavailability of drugs. Bioavailability is affected by several factors, including the physical and chemical characteristics of the drug, the dose and concentration, the frequency of dosing, and the administration route. Therefore, research into drug delivery systems seeks to improve the pharmacological activity of drugs by enhancing pharmacokinetics (absorption, distribution, metabolism and excretion) and also by amending pharmacodynamic properties, such as the mechanism of action, pharmacological response, and affinity to the site of action. Active pharmaceutical ingredients (APIs) are almost never administered alone but in dosage forms that generally include other substances called excipients. The latter are added to formulations in order to improve the bioavailability and the acceptance of the drug on the part of patients. Excipients come in numerous forms, such as emulsifiers, dyes, lubricants, diluents, supporters, and chemical stabilizers. These substances were initially considered inert because they do not exert therapeutic action per se nor do they modify the biological action of a drug. However, it is currently upheld that excipients influence the speed and extent of drug absorption, and therefore the pharmaceutical form of these substances affects drug bioavailability. In this regard, recent years have witnessed intense research on the modification of drug release and absorption. The development of new drug delivery systems will offer additional advantages to those mentioned above and may facilitate the launch of poorly soluble drugs. They may also allow an extension of patent protection for an API. And finally, and possibly most importantly, these systems will facilitate more patient-friendly administration, thus resulting in patient increased compliance and satisfaction.
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2 Current Drug Delivery, 2012, Vol. 9, No. 4

Vilar et al.

The integral components of drug delivery systems are usually high molecular weight carriers, such as nano- and micro-particles, nano- and micro-capsules, capsosomes, micelles, and dendrimers, in which the drug is embedded or covalently bound. Hence, the main function of polymeric carriers is to transport drugs to the site of action. Drugs are protected from interacting with other molecules which could cause a change in the chemical structure of the active ingredient causing it to loose its pharmaceutical action. Moreover, polymeric carriers avoid the interaction of the drug with macromolecules such as proteins, which could sequester the active ingredient preventing its arrival at the action place. If a polymeric carrier is to be used, the next step is to design a type of polymeric structure that will permit obtaining the desired release conditions. Therefore, the polymeric structure should be: i) biodegradable, because the chemical bonds that make up its chemical structure break; ii) disassemblable, because the various pieces forming the polymer disassemble but the chemical bonds do not break; and iii) undisassemblable, because the chemical bonds do not disassemble or break, that is, the polymer remains unchanged. .. In the first two cases, micro-sized polymeric carriers could be used. However, if the polymeric structure of the polymer is not biodegradable or disassembable, then nano-sized polymers must be used for renal elimination. A crucial feature of these polymers is the mechanism by which they are removed from the body. They may be excreted directly via kidneys (renal clearance) or biodegraded (metabolic clearance) into smaller molecules, which are then excreted. Passage through the renal glomerular membrane is limited to substances with a molecular weight under 50 KDa, although this value varies depending on the chemical structure of the molecule [1]. Molecular weight is especially relevant for substances that are not biodegradable, and macromolecules with a molecular weight lower than the glomerular limit can be safely removed from the body by preventing their accumulation and therefore their potential toxicity. In the case of biodegradable polymers, another option to consider in their design is the chemical structure of the polymer (degree of hydrophobicity, covalent bonds between monomers, etc.), since the speed and degradation condition, and therefore, the rate and site of drug release, can be modulated depending on the chemical structure of the polymer used. . If the polymer is not biodegradable, the drug can be covalently attached to the polymeric structure by a linker which can be degraded under different conditions such as in an acidic medium or by different enzymes. On the other hand, targets can be bound covalently to the surface which will help the directionality of the vector to the site of action. Another strategy to follow would be to use smart polymers. These are polymers that release drugs when they are induced by a stimulation which causes a change in their structure. Therefore, the drug is released at the appropriate time and place. Therefore, these new formulations seek to improve the pharmaceutical profile and stability of a drug, ensure its correct concentration, achieve maximum biocompatibility,

minimize side effects, stabilize the drug in vivo and in vitro , facilitate the accumulation of the drug at a specific site of action, and increase exposure time in the target cell. 1.2. Controlled Release Methods Controlled release systems aim to improve the effectiveness of drug therapy [2]. These systems modify several parameters of the drug: the release profile and capacity to cross biological carriers (depending on the size of the particle), biodistribution, clearance, and stability (metabolism), among others. In other words, the pharmacokinetics and the pharmacodynamics of the drug are modified by these formulations. Controlled release offers numerous advantages over conventional dosage forms. This approach increases therapeutic activity and decreases side effects, thus reducing the number of drug dosages required during treatment. Controlled release methods offer an appropriate tool for site-specific and time-controlled drug delivery. There are two main situations in which the distribution and time-controlled delivery of a drug can be beneficial. The first is when the natural distribution of the drug causes major side effects due to its interaction with other tissues, while the second is when the natural distribution of the drug does not allow it to reach its molecular site of action due to degradation. Many different kinds of drugs can benefit from distribution or time-controlled delivery, such as anti-inflammatory agents [3], antibiotics [4], chemotherapeutic drugs [5], immunosuppressants [6], anesthetics [7] and vaccines [8]. 1.2.1. Time-Controlled: Modified-Release Formulation This formulation refers to the release of the drug through a system that protects and retains it. Through controlled release over time, this formulation allows the drug to reach a therapeutic concentration in tissues. The usual dose administration of a drug can achieve immediate (short-term) therapeutic concentrations of the active ingredient [9] (Fig. 1.1).

Fig. (1.1). Curve of drug concentration in plasma over time after a single dose [10].

The figure shows that drug absorption [11] does not usually stop abruptly when it reaches the maximum concentration,

this stent can be coated with a drug or polymer which controls the release of the drug. The newest is a polymeric-based drug delivery system that controls the release of carbidopa and levodopa by slowly eroding the polymer´s coating. (1. 1. The time required for a compound that has reached the systemic circulation of the body to reduce the maximum concentration by half is called the half-life. The therapeutic effect is maintained over a long period of time Fig. several DES platforms have been developed and evaluated for clinical use. Nowadays. An example of this formulation is Sinemet CR. The effective (therapeutic) concentration is the minimal drug concentration required to achieve the desired therapeutic effect. Depending on the type of polymer used. which is a device that is inserted into the coronary arteries when they are blocked to keep the arteries open and normal blood flow is resumed. Chronic treatment calls for adherence to a pattern of drug administration because an incorrect number of dosages may exceed the limit of therapeutic concentration and thus result in a toxic response. a stent is a metal support wire whose function is to maintain arteries. a modified-release formulation is designed to deliver the active ingredient at a predetermined speed or at a site other than that of administration. the release of the drug can be modulated depending on the type of polymer used. (1. There are other commercially available products in which the degradation of the polymer coating regulates the release of the drug. different drugrelease kinetics is obtained. These devices control the outflow of drug solutions through osmotic potential gradients across semi-permeable polymer barriers. Generally. Sometimes.2). solid line). [14] functionalized a biocompatible polymer for stent coating for local arterial therapy. The closest pharmaceutical formulations to this type of system are osmotic pumps. Drug concentrations in plasma after delivery by conventional injection in a chronic disease. Therefore. No. 1. respectively. the maximum safe concentration is drug concentration in plasma above which toxic or side effects occur.1. 1. There are two types of extended-release formulations. Finally.Polymers and Drug Delivery Systems Current Drug Delivery. reaching levels that are lower or higher than therapeutic concentrations. 2012. metal stents were coated with a cationized pullulan hydrogel which was loaded with small interfering RNA for gene silencing in vascular cells. in other words. the delivery of which is controlled by diffusion through the polymeric system network. it is important to make a few comments about the Drug-Eluting Stent (DES). forming a reserve deposit. The interval between these two concentrations is the therapeutic window. In contrast. concentrations that are neither effective nor toxic. shown in Figs. doses are administered at regular intervals (multiple doses. blood vessels or other anatomical ducts open. Consequently. The difference between them has to do with the type of stent. One interesting example is the cardiovascular stent. This approach can lead to variations in API concentrations. which .2. (1. Drug absorption ceases with time once the bioavailable dose has been absorbed. The permeability or the degradation of the polymer coating regulates the release of the drug.1. One is a polymeric matrix that contains the active ingredient.2. 4 3 but may continue for some time along the downstream portion of the curve. Sustained-Release Formulation The active substance is steadily released with a kinetic profile of zero-order. respectively (Figs.2. The pressurized chambers contain the aqueous solution Fig. Representation of the therapeutic window between the minimal therapeutic concentration (therapeutic level. Extended-Release Formulation The release of the active ingredient in these formulations is initially produced in a sufficient amount to produce a therapeutic effect and then to continue with a release. the elimination phase of plasma drug concentration depends on the rate of removal by metabolism or excretion. San Juan et al. anti-proliferative drug and polymer used to control drug release. In a chronic treatment. is not necessarily constant but extends the therapeutic action.3 and 1. The concentrations that yield the desired new therapeutic effect in the absence of toxic effects fall within this window. Vol. making the system particularly suitable in the treatment of Parkinson’s disease and syndrome [13]. There are some DES which have been approved for clinical use such as Cypher [15] and Taxus [16] containing sirolimus and paclitaxel.1.and micro-particles. 9. which consists of supports coated with drug-laden polymers. The other type of extended-release formulation comprises API capsules with polymer coatings. Adapted from reference 10. These formulations are presented in the form of hydrogels and nano. Therefore. In general. thus preventing the arteries from reclosing. It was observed that the release of siRNA from the polymer was modulated by the presence of the cationic groups. dotted line) and the maximum therapeutic concentration (toxic level. These formulations can be classified on the basis of the systems that regulate drug release. respectively. in chronic treatments drug doses are separated by two times the half-life of the drug in blood.4). Plenidil or Kapanol tablets provide extended release of felopine or morphine surfate. There are some commercial products such as Plenidil Er or Kapanol. Both tablets are administered orally and the drug is released by diffusion through the system [12].2)). In contrast.5).

Osmotic pumps. The tablet has a rigid water- permeable jacket with one or more laser drilled small holes. Nano.4). Once the active ingredient in the Oros tablet has been released. osmotic pressure. thus causing an increase in pressure. The OROS is a 24-hour controlled release oral drug delivery system in the form of a tablet. Fig.or micro-particles of hydrogels whose swelling structure allows the diffusion of the drug through the pores of the structure. these drug . 2012. The graph shows the therapeutic window between the minimal therapeutic concentration (therapeutic level. the osmotic system is hydrated and swollen. (1. B) Nano.6) 1. size of the delivery orifice and membrane type and characteristics. 4 Vilar et al.5).3. Adapted from reference 10a.3). 1. (1. 9. As the tablet passes through the body. Representation of the concentration of active ingredient versus time for a prolonged release formulation. No. the remnant is excreted in the feces (Fig. In general.or micro-capsules whose degradation allows the release of the drug. the drug is released after a well-defined lag time. Upon immersion in the water. solid line). Adapted from reference 10b. (1. the osmotic pressure of water entering the tablet pushes the active drug through the opening in the tablet.4 Current Drug Delivery. Drug delivery through osmotic systems is affected by a number of factors such as solubility. which acts as an osmotic pump releasing nifedipine [18]. Adapted from reference 10a. An example of this type of product is Adalat OROS. which is relieved by the flow of the solution out of the delivery device through an orifice in the upper part [17]. of the drug and the polymeric osmotic system.1. dotted line) and the maximum therapeutic concentration (toxic level. Thus. Pulsatile-Release Formulation Another form of time.controlled release is a responsive delivery system in which drugs are released in a pulsatile manner only when required by the body. Fig.2. Fig. Vol. A).

Some drugs are unstable in certain environments. Thanks to molecular biology. the identification of these overexpressed targets is used to functionalize polymers with tracking devices.6).2. Adapted from reference 10a. and hence responsive drug delivery systems that release insulin in response to increased blood glucose levels have been designed. Normally. a comprehensive database of molecular targets has been built and it is now known that some specific receptors are overexpressed in malignant tissue.2. such as in plasma or in acidic conditions. Insulin formulations currently require repeated injections daily. Vol. This formulation is constituted by an impermeable anionic polymer called Eudragit S100 which encapsulates theophylline.Polymers and Drug Delivery Systems Current Drug Delivery. thus preventing its delivery to the stomach. One method is to functionalize the surface of nano. 1. and hypertension [19]. Fig. in other words. in these conditions. Delayed-Release Formulation In this case. unpredictable in vitro/in vivo correlation and problems associated with improper handling. Several approaches are currently available to overcome the obstacles posed by non-specific drug delivery. Adapted from reference 10a. the release of the active ingredient does not coincide with the time of administration and its therapeutic action is not extended. 9. modified-release formulations provide alternatives to the routine administration of the drug for improving its management and optimizing its therapeutic action.7). The graph represents the therapeutic window between the minimal therapeutic concentration (therapeutic level. These formulations are also used in pathologies in which the degree of compliance is low because of difficult administration or unpleasant taste of the medicine. It is therefore important to use drug carriers with a controlled distribution system. and a delivery device that releases the drug. 4 5 delivery systems comprise two components. Therefore. asthma. Controlled Distribution The treatment of most diseases requires the distribution of the drug at a specific site. Therefore. such as higher production. lack of reproducibility. . Another example of the above is the formulation developed and studied by Sadaphal et al. Consequentlty. dotted line) and the maximum therapeutic concentration (toxic level. Representation of the concentration of active ingredient versus time for a sustained-release formulation. The pulsatile-release formulation implies the release of the drug only when required by the body.4. glucose oxidase converts glucose to gluconic acid.7). or those with a narrow therapeutic window. which interact with these targets [24]. 1. or simply an electrically charged species. (1. Given that modified-release formulations have a series of drawbacks over standard systems. thereby lowering the pH. carbohydrates [23]. and they are convenient for patients suffering from chronic problems such as diabetes. This decrease in pH causes insulin release because the pH-sensitive polymers (smart polymers) either swell or degrade in acidic environments. The graph shows the therapeutic window between the minimal therapeutic concentration (therapeutic level. This system attempts to mimic the circadian rhythm of the disease by releasing the drug at the appropriate times (Fig. those that are rapidly metabolized and eliminated from the body after administration and thus have a short life. arthritis. Pulsatile drug delivery systems release the drug at the right time and place and in accurate amounts. Fig. these formulations are enteric coatings that protect the active ingredient against adverse physiological media or protect certain parts of the body against the hostile action of the active ingredient. their development for an active ingredient is not justified unless they show a clear advantage over the standard formulation.8). cost. namely a sensor that detects the environmental parameter that stimulates drug release. (1. 1. it is of interest to use a polymer to protect the drug. Thus. a pulsatile-release formulation that uses the enzyme glucose oxidase as a sensor has been proposed [20]. Typically. solid line). For the treatment of diabetes.and micro-particles with receptor recognition elements that are present in diseased tissue. No. 1. such as antibodies [22]. Therefore. 2012. thus preventing it from being continuously in the biophase.1. these coatings are sensitive to pH and allow drug release into the small intestine. these tracking devices help the polymer reach the tissues and regions of the body where the drug is to be released [25] (Fig. dotted line) and the maximum therapeutic concentration (toxic level. When blood sugar levels rise. controlled release is highly beneficial for drugs that show poor bioavailability.2. solid line). [21]. Representation of the concentration of the active ingredient versus time for a sustained-release formulation.

the behavior of which differs in response to temperature.6 Current Drug Delivery. Some Examples of Smart Polymers Stimulus pH Electric field Glucose concentration Temperature Morphine concentration Urea concentration Polymer Poly(methacrylic-g-ethylene glicol) (p(MMA-g-EG) Poly(methacrylic acid) (PMA) Poly(methacrylic acid-co-butyl methacrylate) Layer of Chitosan Pluronic on PLGA microparticles Methyl vinyl ether-Co-anhydride maleic copolymer Methyl vinyl ehter-Co-anhydride maleic copolymer Drug Released Insulin Pilocarpine and raffinose Insulin Indomethacin Naltrexone Hydrocortisone . the drug is released from the endosome or lysosome by diffusion to the cytosol (Fig. the drug is released from the polymer when the entire system is exposed to either of these two conditions. thus forming what is known as a secondary lysosome. Thus. However. These groups are ionized depending on the pH. urea and morphine. in an endosomal acidic environment. and in a lysosomal environment. in this environment within the lysosome. such as in tumor tissues where the pH is lower than in healthy tissues. Other examples of proteins include Prostate Specific Antigen (PSA). which includes lysosomal endoproteases. these systems do not have Table 1. causing drug release [29]. the proteins carried by the polymer and conjugated in it with an acid-labile linker are released into the endosome because peptide bonds are degraded in the lysosome.8). For example. and therefore an attractive interaction may occur between them through hydrogen bonding. a change in the structure of these groups opens or closes the route through which the drug is released. 2. the drug is encapsulated or absorbed in the hydrogel and released in response to an external stimulus. The introduction of macromolecules into cells by endocytosis [28] involves the invagination of the plasmatic membrane to form a small vesicle called the endosome. these will be discussed further in the section on smart polymers (Table 1. The linkers most frequently used are peptides and oligosaccharides. This stimulus can change features in the structure of the formulation. 4 Vilar et al. and Proline peptidases. Another approach is the use of hydrogels. Thus. Therefore. [26] One interesting model is called the pH-dependent system. However. based on enzyme cleavage specificity of a selected disease. No. Tumor tissues or early endosomes have a slightly acidic pH. Linker libraries have been established by VectraMed. which contains hydrolytic and proteolytic enzymes in an acidic environment. Other systems are controlled by electrical signals. Once the linker has been biodegraded. which is expressed by prostate tumors. One example is the enzyme family of Cathepsin. This early endosome matures and finally fuses with the lysosome. or a repulsive interaction may be induced because of ionic groups with the same charge. POLYMERS USED FOR CONTROLLED-DRUG RELEASE Polymers used for controlled drug release are often called therapeutic polymers. 1. The controlled release of an active ingredient can also be achieved by connecting the drug to the polymer through a specific linker [27] that can be degraded in an acidic environment or by a specific enzyme.9). To this end. It is important to highlight that these linkers are stable in plasma and are degraded only in tumor tissues or in lysosomal or endosomal [30] microenvironments. Vol. Another example of a controlled distribution system is drug release by diffusion through a hydrogel.1. Fig. where labile acid linkers such as cis-aconityl or hydrazone can be degraded [31]. 9. Also of note are those systems that are triggered by external stimuli in the form of variations in the concentration of certain substances. (1.1). Adapted from reference10c. which is characterized by ionizable groups in its structure. which hydrolyze proline sites. and Gupta et al. Polymer functionalized to interact with specific targets. a molecule localized at the invasive edges of human tumors and therefore overexpressed in many types of cancer. 2012. Cathepsin B being among these [32]. These peptidases are overexpressed in pulmonary hypertension and during inflammation. the linkers that are labile to acids or digestive enzymes are cleaved. such as glucose. which contains proteolytic and hydrolytic enzymes. such as pore size and permeability. The stimuli that can be used in various systems to trigger drug release have been reviewed by Qiu et al.

55. 10c. and endosomal or lysosomal escape. surface charge and hydrophobicity in order to overcome physiological barriers. shape. nasal. Depending on the desired application. In contrast. prolonged vascular circulation time. Other features of malignant tissue include poor lymphatic drainage and increased vascularity (angiogenic process). Drug polymer conjugates are of interest when these drugs are attached to the polymer with linkers that are labile to certain digestive enzymes or acidic conditions (see controlled distribution).1. Endocytotic pathway for the cellular uptake of macromolecules and nanocarriers for drug delivery. From a polymer chemistry perspective. because of possible obstruction of veins. However.0) than that of the extracellular matrix (7. nano.10). macromolecules can reach only the latter because the walls of the endothelial cells of these tissues are fenestrated.and micro-formulation is the size. for instance. No. 9. acid-labile linkers can be hydrolyzed. the endosome is absorbed by a lysosome. Vol. Several types of polymers have been tested as potential drug delivery systems. Drug-Polymer Conjugates As mentioned earlier. thus releasing the drug. was first reported by Maeda et al. therapeutic agents can be covalently bound to the polymer backbone. [36] (Fig. resulting in a secondary lysosome that contains hydrolytic and digestive enzymes that are active in acidic environments (lysosome pH: 4). In these applications. (1. it should be noted that distinct mechanisms of controlled release require polymers with a variety of physicochemical properties [33].4). thus compromising therapeutic efficacy. the goal is to improve the mechanism of cellular internalization and cell specificity to achieve optimal release of the drug at the proposed target. and intraocular: however. drugs are embedded or conjugated in polymer matrices. including oral. In these types of drug-polymer conjugates. 2. an active process involves the use of peripherally conjugated targeting moieties for enhanced delivery to a specific site. These biological barriers can be overcome when the nanoparticles show efficient extravasation through the vasculature. some routes cannot be used with microformulations.9). including nano. Nanoformulations can be administered through various routes. they are endocytosed (receptor-mediated endocytosis) or phagocytosed (internalization without the mediation of receptor) by malignant tissues cells to form a vesicle called the endosome. there is an accumulation of nanoparticles in these cells due to the EPR effect. which both lead to the retention of macromolecules. Some studies show overexpression of certain enzymes in .and micro-particles. 1. Once macromolecules reach the malignant tissue.Polymers and Drug Delivery Systems Current Drug Delivery. known as the EPR effect (enhanced permeability and retention effect). which have high mobility in the smallest capillaries. The difference between nano. The size of the former confers this approach a greater capacity to reach the smallest capillary vessels and to penetrate tissues either through paracellular (transport of substances between cells of an epithelium) or transcellular pathways (substances travel through the cell). Therefore. This type of release is used by nanoparticles. resulting in pores that allow macromolecules to cross. improved cellular uptake. Fig.2-7. formulation for drug delivery includes numerous architectural designs in terms of size. 4 7 specific therapeutic activity and are considered excipients in pharmaceutical formulations. In contrast. Given that the pH in these vesicles is lower (6. Adapted from ref. contain hydroxyl groups that allow direct reaction with drugs with carboxylic acid functions. Finally. and materials. small molecules diffuse through the endothelial cell wall to healthy and malignant tissues. 2012. The latter refers to transport through leaky capillary fenestrations into tumor cells by passive diffusion. polymeric carriers of antineoplastic drugs have been extensively studied [35]. Therefore. the systems in which the drugs are embedded or encapsulated in the polymer seek to enhance the distribution and serum stability and to attain a decrease in drug immuno- In recent years. pulmonary. This passive accumulation of macromolecules in tumor tissue. The main interest in polymers for drug delivery purposes is in controlled-release systems. These polymers can accumulate passively in cancerous tissue as a result of certain differences in the biochemical and physiological characteristics of healthy and malignant tissue. In general. thereby producing ester linkages that are biodegradable and thus facilitate the release of the drug in the body. These barriers comprise biological structures or physiological mechanisms that prevent nanoparticles from reaching their targets. nanodelivery systems must have a certain particle size. nanoparticle-mediated drug delivery can be either an active or a passive process. allowing for efficient uptake and selective drug accumulation at the target sites [34]. This type of nanoparticle is common in cancer therapy. genicity through a controlled distribution at the correct site and over time. capsosomes and micelles. such as the intravenous route. parenteral. dendrimers.and micro-spheres. Thus. Polysaccharides.

thus preventing DNA re-ligation. thus causing apoptosis. Schematic representation of the anatomical and physiological characteristics of healthy and tumor tissue with respect to the vascular permeability and retention of small and large molecules (EPR effect). Some of these compounds. Vol. which not only allows its renal clearance but also enables it to reach tumor cells through fenestrated endothelial cells. a cytotoxic quinoline alkaloid that inhibits the DNA enzyme topoisomerase I. Furthermore. have been discontinued or suspended [34-51]. Platinum drugs (carboplatin and cisplatin) are used to treat a wide range of cancers and they react in vivo. Adapted from reference 26. This compound has a similar structure to PK1 but incorporates an additional targeting ligand. HPMA copolymerdoxorubicin (PK1) was the first cancer drug conjugated with a polymer to be tested clinically [39].10). HPMA copolymer platinate (AP 5346) [42] is another drug-polymer conjugate that has progressed into clinical trials. Therefore. Later. (1. HPMA copolymer platinate (AP 5346). malignant tissue. These studies also demonstrated prolonged circulation of the conjugate in plasma. Used in cancer chemotherapy.8 Current Drug Delivery. The drawback is that the receptor of the galactosamine ligand is expressed on both malignant and healthy hepatocytes. namely galactosamine. This conjugate is composed of exatecan (DX-8951) and carboxymethyldextran polyalcohol (CM-Dex-PA) as a carrier. such as HPMA copolymer camptothecin (PNU 166148) and HPMA copolymer paclitaxel (PNU 166945). Moreover. Partial responses in antitumor activity in metastatic melanoma and ovarian cancer to AP 5346 were observed in a Phase I study. Thus. such as HPMA [38] copolymer-doxorubicin galactosamine (PK2). the open form does not inhibit topoisomerase I. Developed by Kopecek and Duncan. the DACH-platinum moiety was bound to HPMA via a pH-sensitive linker. In other words. in this case the drug is released at the extracellular level. The structures of exatecan and camptothecin hold a lactone ring that is highly susceptible to hydrolysis and is inactive in its open form. Therefore. (1. AP 5346 has a longer half-life relative to small platinum drugs that enables it to reach tumor cells by a passive process and then release the drug. thus triggering apoptosis. Another drug-polymer conjugate in clinical trials is DE310. Its structure contains a peptide linker (-Gly-Phe-Leu-) that allows doxorubicin release through the action of lysozyme. which specifically targets liver tissues (controlled distribution). binding to and causing crosslinking of DNA. linear cyclodextrinbound camptothecin (IT-101) and poly(L-glutamic acid)camptothecin (CT-2106) have progressed further to the clinical phase. Fig. This drug causes DNA damage. 2012. DACH has activity against cisplatin-resistant cancer cells. This compound consists of a cytotoxic diaminocyclohexane (DACH)-platinum moiety coupled to a biocompatible hydroxypropylmethacrylamide copolymer (HPMA). 9. this overexpression could be used to obtain a controlled release when a linker labile to these enzymes is used. 25 kDa). 4 Vilar et al. clinical studies for several other polymer conjugates. Clinical studies showed that the toxicity of the conjugate was lower than doxorubicin alone. poly(L-glutamic acid)-paclitaxel (Xyotac). However. this drug has been shown to have a higher therapeutic index in multiple preclinical tumor models and it is entering phase II clinical testing under the new name of Prolindac [43]. the pH of tumor tissue is slightly lower than that of healthy tissue and therefore controlled-drug release can also be obtained when an acid-labile linker is used. carboxymethyldextran polyalcoholbound exatecan (DE-310). No. Another interesting feature of this drug-polymer conjugate is its size (approx. exatecan is camptothecin analog. and consequently released in the extracellular space of tumors and/or the intracellular lysosomal compartment.11) [41]. Several drug-polymer conjugates have entered the clinical development stage [37]. Camptothecin binds to topoisomerase I and DNA. To . Furthermore. HPMA copolymer-doxorubicin galactosamine (PK2) was synthesized Fig. however. resulting in a stable ternary complex. PEG-SN38 (EZN-2208). the results of phase II trials showed antitumor activity for the treatment of breast and non-small cell lung cancer but no response in patients with colorectal cancer [40].

it inhibits the formation of mitotic cell division by blocking mitosis. 9. PG-paclitaxel is a highly promising anticancer drug polymer conjugate because it has the characteristics of an ideal polymeric drug carrier. Vol. The results in animal experiments showed a higher . This drug stimulates the assembly of microtubules from tubulin dimers. the maximum tolerated dose in phase II. Moreover. Those clinical trials determined drug toxicity and pharmacokinetics and therefore. Another interesting drug polymer conjugate that has been studied in numerous clinical trials. stability in circulation. Thus. Exatecan was observed to show a slow release from DE-310. [44]. which has a targeting ligand (R): galactosamine (targeting ligand). In this polymer. The maximum tolerable dose (MTD) and pharmacology of PG-paclitaxel administered weekly to patients with solid tumors were studied [48]. high drug loading. also called XYOTAX (CT-2103) [46]. This spacer is labile to the activity of cathepsin and is thus used to release the drug inside the cell. thus achieving prolonged exposure to this topoisomerase I inhibitor. Thus. and apparent lack of immunogenicity.Polymers and Drug Delivery Systems Current Drug Delivery. including phase III trials. in other words. (1. This enhanced distribution is caused by prolonged tumor exposure and limited systemic exposure compared to the active drug. thus preventing depolymerization. PEG-SN38 (EZN-2208) [50] is currently entering phase II clinical testing. 2012. This conjugate can be administered by short infusion into peripheral veins. SN38 has to be administrated with a formulation. 4 9 HPMA H2 C O NH O C H2 O NH OH C H2 O NH O HN Ph HN Ph Linker O NH O O NH O HN HN O R O NH OH O O OH O Doxorubicine OH O OH O OH Fig. containing a lactone ring. No. SN38 is a camptothecin analog and therefore has the same function as camptothecin (topoisomerase I inhibitor) and a similar structure. PG-TXL shows less toxicity.11). such as biodegradability. clinical trials in patients with advanced solid tumors were studied by Soepenberg et al. breast and lung cancer. [45]. this drug is conjugated to a polymer such as DE-310. This compound is composed by SN38 linked by a covalent bound to poly(ethylene glycol). exatecan is covalently linked via a peptidyl spacer (Gly-Gly-Phe-Gly). protect the closed form (active form). This release was studied by Shiose et al. Results of phase II studies [49] showed that the MTD of PG-TXL was higher than that of other formulations of paclitaxel and that PG-paclitaxel has activity in patients who have not responded to taxol therapy. such as by conjugation to a PEG polymer that protects the lactone ring and prevents its hydrolysis. PG-TXL. Paclitaxel is conjugated via an ester linkage through its 2’hydroxyl group to the carboxylic acid of poly(L-glutamic acid). the area under the curve obtained in the graph on tissue tumor concentration versus time (AUC). Paclitaxel is used in cancer chemotherapy. Consequently. Phase III trials are currently underway to test the efficacy of this compound in patients with advanced non-small-cell lung cancer. is poly(L-glutamic acid)-paclitaxel. who addressed the relationship between cathepsin activity and the release of DE-310 in several types of tumor. In vivo. and preclinical studies have demonstrated that it is well tolerated in this mode. Paclitaxel is used to treat ovarian. the biodistribution [47]. Structure of PK2. is greater when the drug is administered as PG-TXL than when it is administered in other formulations of paclitaxel.

The release of a therapeutic agent depends on the rate of polymer degradation. PNU 166148 [54] is composed by N-(2hydroxypropyl)methacrylamide (HPMA) conjugated with camptothecin. No. homogeneous degradation is a random deterioration that occurs in the entire mass of the polymer matrix. Thus. have been discontinued or suspended.10 Current Drug Delivery. which can be non-covalent (electrostatic and hydrogen bonds) or have covalent bonds (cross-linked polymers).12). Thus. pulsatile. which favors its access to tumor tissues. which in turn consists of -cyclodextrin and poly(ethylene glycol). These favorable results prompted the initiation of a phase II trial designed to determine the side effects of this compound’s profile as maintenance therapy in ovarian cancer patients. this drug showed antitumor activity. In phase I trials. Another polymer conjugate is poly(L-glutamic acid)camptothecin (CT-2106). Results from a phase I clinical trial showed a decrease in the side effects of patients who had been administered this drug and thus an enhancement in their quality of life. solubilization of the polymer and the drug begins. 2. The integrity and the behavior of these structures in physiological conditions allow the controlled release of the therapeutic agent. This system requires two types of polymers. CT. This degradation depends on the stability of the polymer chain linkages in body fluids Fig. the material maintains its original shape and retains the drug.2106 was studied in patients with solid tumor malignancies [52]. The literature describes several mechanisms of drug release [55]. a higher drug exposure to tumor cells. This compound is composed by camptothecin covalently attached to poly(L-glutamic acid) through a glycine linkage. Gombotz. In contrast. This compound is administered by intravenous injection and demonstrates high antitumor activity because of extended circulation times. Hydration of the polymer causes an increase in the volume of the polymeric structure and the resulting increase in pore size allows diffusion of the aqueous medium within the polymeric structure and thus the release of the drug. Vol. 4 Vilar et al. In addition.). clinical development of this compound was abandoned. When the polymer mass is highly degraded and reaches a critical molecular weight. Interactions between the polymer chains. PNU 166945 [53] is a HPMA polymer-conjugated derivative of paclitaxel. PNU 166148 and PNU 166945. such as neurotoxicity. and the other one non-degradable and located inside the external polymer. R. . The latter is modified at the C20 position of hydroxyl group with glycine and was conjugated with GlyC6-Gly. Toxicity associated with paclitaxel. half-life of the drug-polymer conjugate than the free drug. IT-101 is composed by camptothecin covalently attached through a glycine link to a cyclodextrin-based polymer (CDP). the degradation rate is constant and the non-degraded material (material inside the external biodegradable scaffold) maintains its chemical integrity during the process. The dose-limiting toxicity and dosing schedules were determined in phase I clinical trials. was observed in phase I trials. Linkages depicted from highest to lowest lability against hydrolysis in aqueous media. While the molecular weight of the polymer decreases continuously. CT. one degradable and located on the surface of the material to allow it to be in contact with the physiological environment. interactions between chains…) can regulate the release of the therapeutic agent and thus the profile of the final formulation (delayed or immediate release. The results showed toxicity and absence of tumor targeting. The polymers used in the development of drug delivery systems are designed with the capacity to form polymeric supramolecular structures (matrices and capsules). One such mechanism is controlled release by swelling. [56]. Finally. These polymers are fabricated as matrices in which the drug is uniformly distributed. (1. etc. Drug release can also be achieved through polymer degradation. In this case. however. published by W. Carriers in which the Drug is Embedded or Encapsulated Chemists working in synthesis seek to develop polymeric structures with physical and chemical properties that allow the specific release of the therapeutic agent under predetermined conditions. the release occurs through a combination of the three basic mechanisms mentioned previously O N H O O O O O N H O O O O O O O O O O Polyanhydrides > Polycarbonates > Polyesters > Polyurethanes > Polyorthoesters > Polyamides Fig. as mentioned previously. IT-101 [51] is a novel approach to cancer chemotherapy that is currently under study in human trials. et al. PNU 166148 was administered to patients with solid tumors. which are suitable for retaining a therapeutic agent and allow controlled release.12). However. Gradual hydration of the polymeric structure may cause hydrolytic degradation with release of its contents. Heterogeneous degradation occurs when the polymer is not fully degraded. 2012. clinical studies of other polymer conjugates. The drug slowly diffuses through the voids of the polymeric device. the therapeutic agent is released once the material surface has been degraded by diffusion through the non-degradable material. (1. confer stability to these structures. and Springett et. al. another drug release mechanism is through pure diffusion. 9.2106 has entered phase I/II trials and clinical studies have been conducted by Honsi et al.2. Modulation of the chemical architecture of polymers (functional groups. It was studied with the aim to improve drug solubility with the subsequent controlled release of paclitaxel. and an increased solubility.

[57] developed a fluorescent biosensor consisting of seminapthofluorescein conjugated with the enzyme organophosphorus hydrolase (SNALF-1) which is encapsulated in a PEG hydrogel. electrostatic interactions or hydrogen bonding. Among these. dendrimers are polymers with interesting properties as drug carriers because of their specific surface functional groups. The former have a linear structure while the latter are polymeric networks with three-dimensional covalent crosslinking. which is the product obtained from the catalysis reaction of urease enzymes. 2. among these the attack of the nucleophile to an electrophile. gels and hydrogels being among these. This enzyme catalyzes the hydrolysis of neurotoxins. In addition. linear polymer gels are formed by long-chain monomer units linked by covalent bonds such as amides. Therefore. Pishko et al.2. There are several pharmaceutical formulations in which the drug is embedded or encapsulated in the polymer. Hydrogels are the most widely used hydrophilic polymers for this kind of pharmaceutical formulation because they are non-toxic and their three-dimensional structure allows controlled drug release. Therefore. Covalent bonds between chains affect polymer properties and thus make these polymers convenient for use as drug carriers in the form of micro.1.2.2. capsosomes and micelles.and nano-particles.2. and. Vol. 2. The drug carrier consists of hydrophilic polymers. at first the polymer swells. by pure diffusion and by polymer degradation). such as PHEMA (2-hydroxyethyl methacrylate).2. such as biosensors and drug carriers. esters. thereby causing a change in its emission spectrum. Finally. in which the therapeutic agent is embedded in the gel and released when the gel structure swells. depending on the way in which the drug is found within the polymer.and Micro-particles Nano. and glycosidic bonds.2. which consist of a drug carrier with an external core and some liposomes inside. 9. Urea concentration measurement is based on ammonia concentration. thus allowing various compartments inside its structure. seminapthofluorescein. especially regarding their high water content and also soft consistency and elasticity. As an example. These are classified as matrices or capsules. Once the organophosphorus hydrolase enters into contact with toxin.Polymers and Drug Delivery Systems Current Drug Delivery. many studies have been devoted to this type of polymer.or nano-particles. Different types of chemistry have been used to generate cross-linked polymers. A number of synthetic hydrogels have also been studied for drug delivery purposes. resulting in a change in the pH of the me- dium and thus a change in the emission spectrum of the seminapthofluorescein. Given the capacity of hydrogels to absorb large amounts of water and thus their capacity to swell.and micro-particles are formulations in which the drug is trapped or embedded within the polymer.2.1. the fluorescent compound. the drug is encapsulated within these structures and generally its release requires the degradation of the polymeric matrix. which is conjugated to the enzyme. One of the main characteristics of hydrophilic polymers is their capacity to absorb large amounts of water. 2. PMA (poly((metha)acrylic acid)) and copolymers of PVA (Poly(vinyl alcohol)) or PEG (polyethylene glycol) with acrylamides. Furthermore. or radical chemistry. is labile to changes in pH. In contrast. a crosslinking agent is required to obtain the hydrogel structure. The rate of drug release depends on crosslinking density (highly cross-linked systems provide slow drug release because of their small mesh size) and drug solubility. Therefore. Gels and Hydrogels Gels and hydrogels are hydrophilic polymers that vary in their structures. 2. The characteristics of the monomers used and the degree of crosslinking determine hydrogel properties. other types of interactions (hydrogen bonds or Van der Waals interactions) contribute to achieve the three-dimensional structure. such as swelling. Another interesting example is the study carried out by Syu et al. which is attributed to their physical properties that make them similar to living tissue. thus leading to an increase in pH. they have consistently shown excellent characteristics of biocompatibility. Nano. the therapeutic agent is normally absorbed into the particles and the release is caused by diffusion through the pores of the polymer. when the biosensor is incubated in an aqueous medium containing a neurotoxin such as paraoxon. No. either embedded (matrix) or encapsulated (capsules). microand nano-capsules. which allow the attachment of hydrophilic drugs by covalent bonding. its applicability. Synthetic Hydrogels Hydrogels are obtained by simultaneous polymerization and crosslinking of several polyfunctional monomers. in the case of microcapsules. Drug Loading into a Polymer Therapeutic agents can be physically entrapped in the polymeric matrix or covalently bound to the polymer backbone. orthoesters. thus allowing diffusion of the water and toxin inside the polymer. Gels and hydrogels are also used as drug carriers. In contrast. the latter is hydrolyzed. therefore. . 2012.2. Once the linear polymers are formed. hydrogels involve monomers of distinct chains that are covalently linked. 4 11 (release by swelling control. Other interesting carrier polymers are capsosomes. The affinity for water is attributed to the presence of hydrophilic groups in their structure. They immobilized urease enzymes in a core of carbon paper on which a polypyrrole matrix was deposited forming an external layer. Since hydrogels were first introduced into the field of biomedicine. [58] on the design and synthesis of biosensors for urea concentration measurement. micelles are composed of amphipathic linear polymers that are spontaneously formed by selfassembly in water and the drug is encapsulated in the hydrophobic core. In the first case. we find the micro. This interesting property has led to the use of these polymers in several fields of biotechnology. The polymer serves to transport and protect the drug and to allow its controlled release.

The single emulsion method (o/o or o/w) involves mixing a solution of the polymer dissolved in organic solvent with the drug. such as proteins. One instance is the study published by Z. The polymer may show distinct degrees of swelling depending on the pH of the medium or depending on the degree of crosslinking in the structure of the polymer. Solvent evaporation methods have been widely used to prepare polymers loaded with various drugs. Vol. the greater the extent of drug loading. poly(glycolic acid) PGA and their copolymer poly(D. the greater the incorporation of the drug into the polymer.or nano-capsule has been synthesized. The coating material then shrinks around the core material. a drug can be soluble or unsoluble in an aqueous medium.and Micro-Capsules Nano. 2012. No. addressed the behavior and kinetics of budenoside release from microparticles of P(MAA-g-EG). They were loaded with the drug doxorubicin (Dox) to evaluate the anticancer activity of the drug released in vitro . Thus. In general. the ideal is to obtain optimum conditions of polymer swelling and an acceptable degree of drug solubility. micro. Thus. single emulsion or double emulsion.2. Thus. [60] used theophylline as a model drug to be encapsulated in a polymer cross-linked PVA. Solvent evaporation methods can be classified into two types. In this case. Therefore. in these cases. monosaccharides. Encapsulation of the drug was achieved by exposing the polymer previously synthesized with a drug solution in NaOH. This solution is added on a continuous phase (immiscible with the first). This radical reaction required the use of a photoinitiator. Another interesting point concerns drug entrapment. Several tests of drug encapsulation in the polymer were carried out by varying the drug concentration and polymer composition (proportion of glutaraldehyde). Among the former. The optimum incorporation strategy for efficient entrapment should be selected on the basis of the physicochemical characteristics of the drug-carrier pair. Gels are made either from natural or synthetic polymers. studies revealed that the drug release was dependent on the salt concentration of the medium. [59]. a UV lamp. It was observed that the smaller the amount of ethanol used in the solution. The therapeutic agent. microparticles of PEG hydrogels were synthesized by Peppas et al. They studied various methods of absorption because budesonide is soluble in ethanol but this solvent hinders the swelling of the resin and therefore the internalization of the drug within the polymer. all these characteristics may cause a variation in the partition coefficient of the drug between the polymer and the solution. entrapment efficiency depends on drug solubility in the polymeric matrix.and nano-capsules are synthesized with hydrophilic polymers. Furthermore. The latter is a copolymer of polymethacrylic acid and polyethylene glycol. solvent evaporation and spray drying [64]. there are many methods for incorporating drugs during polymer production but the three most commonly used processes are phase separation. drug-polymer interactions. In the first case. Llactic-co-glycolic acid) PLGA are among the most commonly used synthetic polymers. With the loaded microparticles. In this case. As mentioned earlier. joined together by glycosidic bonds. This kind of pharmaceutical formulation is commonly used to transport drugs.12 Current Drug Delivery.and micro-capsules are formed by an outer shell that encapsulates the active agent. An article published by Nakamura et al. Thus the drug is encapsulated in the particle and is released by degradation of the polymer coating. Polysaccharide chitosan has been extensively used in controlled drug delivery. however. Dox was incorporated into the microparticles by incubating these with an aqueous solution at room temperature. In addition. This requires the incubation of a concentrated drug solution with the preformed polymer carrier. are the most widely used. thus forming a crosslinked structure. Nakamura et al. encapsulating it. 4 Vilar et al. These hydrogels were prepared by free radical copolymerization of the macromonomers poly (ethylene glycol) dimethacrylate (PEGDMA) and poly (ethylene glycol) monomethacrylate (PEGMA) in a range of proportions. example of micro. Liu et al. The bibliography cites many examples in which the drug is physically incorporated after the micro. poly(D. which can be mineral oil (o/o) or an aqueous solution (o/w) and that contains an emulsifier whose function is to stabilize the emulsion produced. Nano. diltiazem. Varsohaz et al. the loading of the drug into the polymer was examined using a number of aqueous solutions with varying amounts of ethanol. that are rapidly degraded in body fluids. L-lactic acid) PLA. These microparticles are hydrophilic polymers whose sulfopropyl group confers a net negative charge. The drug can be loaded by in situ polymerization or can be embedded after the polymer has been synthesized. 9. which is in turn related to the composition and molecular weight of the polymer. depending on the number of emulsions produced during the preparation of the drug-polymer. and the presence of functional groups [62].3. Gels are the most widely used hydrophilic polymers for this kind of pharmaceutical formulation. was loaded by adding it to the reaction mixture prior to exposure to the UV light source. the polymer was synthesized by the nucleophilic attack of the alcohol groups in the PVA structure and the aldehyde groups in the glutaraldehyde molecule. and distilled water as a solvent of the reaction. Therefore. [63] who addressed the use of sufopropyl dextran ion-exchange microparticles as carriers for drug delivery.and nano-capsule synthesis with hydrogels can be found. a drug can also be absorbed into preformed polymers. The results showed that the greater the proportion of glutaraldehyde. [61] cites other interesting loaded preformed microparticles. This emulsion is stirred or sonicated and the organic solvent is then removed by solvent evaporation or extraction. Physical drug loading can be performed by incorporating the drug while producing the particles or by incubating a concentrated drug solution with the preformed polymer carrier. We can see from previous articles that absorption conditions used differ because of the distinct physicochemical properties of each polymer and drug. 2. These are polymers composed of repeated monomer units. . thus obtaining several degrees of crosslinking.

surface morphology and internal porosity of the final microspheres. Solvent evaporation is a method used to encapsulate hydrophobic (single emulsion) or hydrophilic (double emulsion) drugs in hydrophilic polymers such as PLA and PLGA.13). The solvent used for the dispersed phase solution was a mixture of acetonitrile and water. in the second step adsorption of the coacervate droplets around the protein phase occurs. the third step involves the hardening of microparticles. this coating technique proceeds through three steps. 9. A burst of drug release was detected with both methods. Phase separation and coacervation is a widely used method for the formation of microcapsules. these droplets of polymer are solidified and stabilized. This technique initially involves dissolving the hydrophobic or hydrolytic polymer in a solvent. forming microcapsules with the drug inside them (Fig. Finally.2. This mixture was spray-dried to achieve microspheres [69]. This new method leads to greater drug loading efficiency into the polymer and to the formation of microparticles with a heterogeneous drug distribution. Dox and insulin were encapsulated in microspheres with an efficiency of 80-90%. 2012.13). the polymer solidifies onto the core particles when the solvent evaporates. The first consists of a phase separation of the coating polyesters (dissolved in CH2 Cl2) induced by silicone oil.15). 2. Vol. Polyesters Polyesters based on PLA. the drug is dispersed in a solution of the coating polymer. etc.Polymers and Drug Delivery Systems Current Drug Delivery. These were obtained by the solvent evaporation method o/o (oil in oil). caused by a change in temperature or by the addition of salt or a non-compatible polymer with the first.. 1. [66] developed a new approach for the preparation of biodegradable lactic acid oligomer microspheres.3. these microparticles were prepared by the o/w solvent evaporation technique. such as those that contain chitosan and gelatin as polymer coating and budesonide as the encapsulated drug. their copolymers PLGA and poly (-caprolactone) (PCL) [70] have been extensively employed because of their biocompatibility and biodegradability (Fig. who mixed a polymeric phase with a drug solution that contained the drug dissolved in methanol and water. PGA. Basically. internal porosity occurs when the coacervate droplets harden so fast that solvent droplets are retained within the polymer matrix. The spray drying technique is used in the pharmaceutical industry to encapsulate active ingredients but it is also used to wrap food. but the microparticles synthesized with this new method showed a larger amount of drug released than corresponding conventional microparticles. Thus. [67] synthesized PLA/PLGA microspheres containing water-soluble drugs.1. 2. in the last step. The organic solvent is then removed by extraction into an external aqueous phase and evaporated. The researchers explained that the viscosity of the coacervate. Consequently. determines the size distribution. 1. [65] who synthesized PLGA microparticles loaded with rhodamine using solvent evaporation techniques for topical drug delivery. this method consists of three steps. [68] who studied the microencapsulation of a protein by coacervation of poly(lactide-co-glycolide). Some drugs cannot be encapsulated with traditional solvent evaporation methods because of their high water solubility. Then. 4 13 In double emulsion (w/o/w). In the first. No. resulting in microspheres that are precipitated into the bottom collector (Fig. Method of coacervation. 1.. and finally. forming w/o/w emulsion. which is in the liquid phase. using a multiple emulsion solvent evaporation technique. in direct connection with the CH2Cl2 content. This research was performed by Naikwade et al. .3. Iwata et al. an aqueous drug solution is first emulsified in a solution of the polymer in organic solvent and this emulsion (w/o) is added to an aqueous phase that contains an emulsifier. a phase separation of the polymer coating. oils.2. while the continuous phase medium was cottonseed oil. Wada et al. This technique is widely used for the synthesis of microspheres. They studied the drug release behavior of the microparticles synthesized with the new method and compared it with that of the microparticles produced with the traditional method. Specifically. One example of the use of this method is the study by Jalón et al. Polymers used in the Formulation of Nano. Specifically.1. As discussed above.14). Core particles are then dispersed in the polymer solution and the mixture is sprayed into a hot chamber through a nozzle of a spray dry. Fig.and Micro-spheres Several polymers have been exploited for the formulation of capsule carrier systems. This method was used by Nihant et al. these solvent droplets will create the pores.1. creates coacervate droplets of the polymer which are absorbed on the surface of the drug. (1.

. (1. and therefore the profile of the drug release. Many studies have used combinations of polymers [72] to modify surface properties and to change the speed of polymer degradation and thus the drug release rate. 2012. Vol. mucous membranes. Considerable attention has been given to micro. to reduce the side effects of these drugs. They proposed to reduce the toxicity of cisplatin by loading it onto Fe5 (Fe3+ doped hydroxyapatite at atomic ratio of Feadded/Caadded=5%) and/or encapsulating the latter or cysplatin alone into PLGA microspheres using oil in water single emulsion.14 Current Drug Delivery. 9. Therefore. studies about drug release profile and degradation behaviors were performed and the results demonstrated that Fe5/PLGA composite has a favorable drug release profile with a short initial burst release and a long release time. However. Polyesters have been used for the encapsulation of many types of therapeutic agents. [74]. In the case of PCL polymers. a potent anticancer agent. which have been approved by the FDA for the development of drug delivery systems and other biomedical applications.15). However. thereby allowing a sustained drug release over prolonged periods. which blocks the synthesis and transcription of DNA and PLGA O O O O O O O O Fig. [73] summarized the encapsulation of cisplatin. another interesting work was published by Li et al. Among the most commonly used are PLA and PLGA. • Cancer Cytostatic drugs inhibit the disordered growth of cells. disrupting cell division and destroying the cells that are dividing rapidly. characterization and in vitro and in vivo behavior of these carriers. causing a decrease in local pH. their encapsulation in controlled release polymers is of great interest. (1.and nano-spheres as drug carriers. bone narrow and so on. Once the nanoparticles were obtained. Thus. These polyesters have both advantages and disadvantages when used for the encapsulation of therapeutic macromolecules. Spray drying technique Polyesters are a large group of polymers characterized by the presence of esters bonds in the main chain. these two polyesters are the most widely used because of their non-toxic degradation products and adjustable degradation rate. have been extensively studied. their toxic effect is not confined to malignant cells as they also exert their action on rapidly proliferating tissues such as skin. Polyesters. Huo et al. by using a biodegradable polymer such as PLGA. their biodegradation is slower than that of PLGA. The synthesis. Their interest as biomaterials resides in the fact that the ester groups are hydrolytically degradable.14). half-life of encapsulated molecules. Degradation by non-enzymatic hydrolysis of PLA and PLGA may lead to an accumulation of acidic monomers. 4 Vilar et al. Another relevant intercalating agent is doxorubicin. A solvent evaporation method (commented on earlier) was used to perform this encapsulation. This slowness leads to an increased PGA O O PLA O O n n x y PCL O O PHB O O n n Fig. Recently. No. when the encapsulated therapeutic agent is a protein it may denaturalize [71].

• Peptide Hormones Numerous studies have focused on polymer carriers that carry peptide hormones. Nagarwal et al. which resulted in a rapid pharmacological response followed by an abrupt termination. including tuberculosis and leprosy. Therefore. Pandey et al. considerable efforts have been made towards the encapsulation of proteins and peptides into polymeric particles such as PLGA and PLG because these polymers maintain the integrity and activity of the peptide or protein. an overview of the work on PLGA formulations highlights some studies devoted to enhancing the bioavailability . Therefore. These carriers were synthesized to topical ocular applications. Nutropin Depot® [88] is a polymeric formulation that is available in the market. Once these were administered as an injectable suspension. Another objective is to improve the bioavailability of peptides and proteins that are administered orally. and low absorption of these compounds in the gut. The low bioavailability of peptide compounds has prompted the pharmaceutical industry to introduce new formulations to minimize the problems involved in administration. thereby releasing their drug load. Suarez et al. In classical treatments of mycobacterial diseases. Another study on the treatment of the same disease performed by Nahar et al. For example. This idea is relevant when the target of the transported drug is the pathogen inside the infected phagocytic cell. the hormone maintained a high average life in the body. this feature has been used in various studies such as those performed by Italia et al. have been encapsulated into biodegradable nano. As a result. on the in vitro anti-leishmanial activity of biodegradable nanoparticles. [81] involved encapsulating amphotericin into PLGA particles with anchored mannose. [82] encapsulated the antibiotic streptomycin in nanospheres of poly-lactide-co-glycolide (PLG) using the multiple emulsion technique. on the other hand. it was encapsulated into biodegradable nanoparticles of PLGA [79] and PCL [80] for release at the intracellular level in macrophages. some studies have addressed the treatment of mycobacterial diseases using drug carriers. These types of bacteria include pathogens that cause serious diseases in mammals. such as those caused by mycobacteria. Rafi et al. the in vivo profile is characterized by an initial rapid release followed by a slow decline in GH concentration. encapsulated via the spray drying technique. therefore improving patient quality of life. • Bacterial and Parasitic infections Nanotechnology offers drug delivery systems that are easily endocytosed by phagocytic cells because of the nature of the polymer [78]. [77] synthesized nanospheres of PLA polymer encapsulating 5-flourouracil. which are associated with unwanted side effects. Polymeric nanoparticles are efficient carriers and after their in vivo administration they are endocytosed by phagocytic cells. Other drugs. For example.Polymers and Drug Delivery Systems Current Drug Delivery. was encapsulated into polymeric microspheres. Experiments of these formulations achieved a significant reduction of side effects in mice [75]. have also been encapsulated into this kind of PLGA system. the drug was released by a diffusional mechanism. Therefore. In recent years.and micro-spheres. 9. Thus. another therapeutic agent of interest. such as ciprofloxacin [86] and rifampicin [87]. Ike et al. Nafarelin is a potent hormone responsible for releasing gonadotropin. [76] conducted a study addressing the treatment of malignant pleural effusion with this type of formulation and observed that local administration of microspheres produced an low systemic drug concentration. This formulation consists of micronized particles of rhGH (growth hormone) embedded in biocompatible and biodegradable PLG microspheres. bioactive rhGH is released from the microspheres into the subcutaneous environment initially by diffusion and then by both polymer degradation and diffusion. The study was conducted by Sanders et al. Moreover. such as cefazolin [84] and nafcillin [85]. No. Nafarelin. This system is indicated for the long term treatment of growth failure caused by the lack of adequate endogenous GH secretion and it is administered by subcutaneous injection. almost all drugs of a peptide nature are given frequently via parenteral route because of susceptibility to degradation by enzymes. After administration. multiple injections are required to achieve a desirable therapeutic effect. drastic chemical conditions in parts of the digestive system (such as the stomach). 2012. [90] who encapsulated the therapeutic agent into PLGA microspheres. as a result of the short in vivo half-lives of proteins. the treatment involves prolonged large systemic doses. [89] encapsulated rhGH into PLGA microparticles. as shown by the presence of bioactive rhGH in the serum of animals 30 days after one single injection. and Espuelas et al. Recently. Their activity was evaluated with pathogenic staphylococcus bacteria. [83] synthesized PLGA microspheres with rifampicin. This therapeutic agent has been encapsulated in PLA microspheres in order to obtain lower drug release and sustained action. 4 15 also inhibits the enzyme topoisomerase II. The former was encapsulated into PLGA microspheres and the latter into PLGA nanospheres. Other antibiotics. The researchers studied the release behavior of the therapeutic agent and the results showed that the in vitro release of the hormone in porous particles is quicker than in non-porous particles. These microspheres were administered into the lungs of an animal model and resulted in a reduction of bacteria in the inoculated animals. which is a macrophage target. The administration of peptides and proteins for therapeutic purposes is a challenge because of the enzymatic barriers. Vol. Leishmaniasis is a disease caused by obligate intracellular parasites. the drug reaches the macrophages infected with mycobacteria in low amounts and sometimes it does not persist long enough to develop the desired antimycobacterial effect. Therefore. Nanoparticles have been examined for the treatment of other intracellular bacterial infections. 5-Fluorouracil is a potent anti-metabolite that is used in some cancer therapies. To minimize the adverse effects associated with amphotericin B. This drug acts on DNA synthesis and causes cell death. This formulation was administered orally to mice and an increase in the bioavailability of the encapsulated antibiotic was observed.

Kumar et al.(carboxyphenoxy)propane (CPP).16).bis(p-carboxyphenoxypropane):sebacic acid] in a ratio of 20:80 [P(CPP:SA)] 20:80] for this purpose. to study the release of p-nitroaniline. In general. Depending on their chemical structure. polyanhydrides are hydrolytically unstable polymers.6-bis (p-carboxyphenoxy) hexane] (poly (CHP)). The release profiles shown by the polymers differed. (1. the copolymer is biodegradable and can be used for drug delivery. Polyanhydrides can react with drugs containing nucleophilic functional groups. On the other hand. p . 2012. 9. which are easily removed from the body. and the other co-polymer with [14C]CPP and unlabelled SA implanted in the brain of rats. Many studies have addressed the influence of the physico-chemical characteristics of polyanhydrides on drug release. The degradation of microspheres is pH-sensitive.SA). These studies showed the rate of degradation of the copolymer and the metabolic deposition of the degradation products. such as free amino groups. . Polyanhydrides. poly(sebacic anhydride) (poly(SA)) and the copolymer poly(CHP-co. polyamides. It is important to indicate that this kind of polymer shows high reactivity. thus limiting its application for the encapsulation of nucleophilic drugs. p-nitroaniline and piroxicom. Therefore. Most studies on polyanhydrides are based on sebacic acid (SA). These repeated units. their physical properties can be altered. No. However. the release profile also depends on the polarity of the drug. which will be discussed in the next section. most studies on this hormone are carried out with smart polymers. 4 Vilar et al. which can have the same or a different chemical structure. namely poly[1. called monomers. synthetic methods. [95] who used the co-polymer poly[1. The structure of polymers is characterized by repeated units linked by anhydride groups. Berkland et al. The more hydrophobic the monomer. Vol. p(carboxyphenoxy)hexane (CHP) and their copolymers. especially when a high temperature is required for encapsulation. thus limiting the type of drug that can be successfully incorporated into a polyanhydride matrix. on its different solubility in aqueous solution. Other polymers. [94] reviewed the development. SA O O O O O O n n CHP O O O O n O Fig. by changing the ratio of monomers in the copolymers. Polyanhydrides Polyanhydrides are bioabsorbable [92] materials that are useful in drug delivery because they are biocompatible [93] and degraded in vivo into their non-toxic diacid counterparts. 1.3. These CPP O O authors used two types of radioactive labeling. [97] examined the release of drugs such as rhodamine B. Kipper et al.3.16). such as polyanhydrides. and therefore. being enhanced at high pH and becoming more stable in acidic conditions.16 Current Drug Delivery. Also.2. poly(ortho esters) and natural or modified polysaccharides.2. structures and characterization of polyanhydrides (Fig.1. Researchers observed that each drug exhibited different release mechanisms and therefore distinct release profiles. one with [14C]SA and unlabelled CPP. These differences are attributed to polymer erosion rates and to the different distribution of the drug in the polymer. [96] used microspheres of three bioerodible polyanhydrides. Studies of polyanhydride degradation were carried out by Domb et al. 2. are also used as drug carriers. each of these with different water solubility and encapsulated them into the surface of erodible polymer poly (sebacic anhydride) PSA. in the latter case. resulting in a sustained release as a result of polymer degradation over a period of time depending on the composition of the polymer or co-polymer. thereby affecting their degradation. It has been demonstrated that aliphatic polyanhydrides are degraded within days or weeks while aromatic polyanhydrides take months or even years. the more stable the anhydride bond is to hydrolysis. are diacids. they are referred to as copolymers. of hormones such as insulin [91]. the monomers confer the polymer differing degrees of hydrophilic behavior. thus polymer degradation and drug release behavior can be modified.

these molecules have excellent mechanical properties afforded by the presence of amide groups and hydrogen bonds. dodecanodiol and different ratios of the stereoisomers of L.3. synthesized some biodegradable poly(ester amide) composed of SA. and bovine serum albumin labeled with fluorescein isothiocynate (BSA-FITC) [101] into polyanhydride microspheres. These polymers were achieved by changing the initial acids to neutral products (diketene acetals). which are the degradation products.17). These differ in the type of monomers used and the synthesis of the polymer. the amide bonds are combined in different proportions with other groups that are more susceptible to degradation. POE III and POE IV [108]. For example. POE II. poly (L-lactic acid -co-Laspartate) and poly(L-lactic acid-co-D. the polyamide degradation rate is too slow for their practical use as biodegradable polymers. O O R O n Fig. Capponetti et al. Second. Furthermore.2. Thus. 1. triclosan and clofazimine to study the release rate in vitro [107]. Therefore. and consequently display a highly polar behavior. (1. 2. Carrillo-Conde et al. The copolymer CHP and SA were used for this purpose. in order to modify the physico-chemical properties of the polymer.1. the amino acid lysine of the copolymer poly(lactic acid-co-lysine) (PLAL) provides an amino group that allows modifications of the PLAL systems. to demonstrate the capacity of microparticles to serve as carriers in controlled drug delivery devices. [105] synthesized and characterized biode- gradable microparticles with a PLAL backbone. Polymers that contain ester and amide bonds in the backbone chain are the most interesting class of polyamides for controlled release. No. These polymers have been used to transport drugs encapsulated into a micro. First.3. Hrkach et al. 1. 9. because their main structure is formed by amino acids. POE II.1. They studied the effect of the anhydride monomers. poly(ortho esters) have been developed for drug delivery purposes.2. Furthermore.3. POE I polymers were prepared by transesterification reaction of diols and diethoxy-tetrahydrofuran. POE II polymers were synthesized by addition of diol or polyol to diketene acetal. antigens have been encapsulated. POE II polymers were developed in order to prevent autocatalytic degradation because the degradation products are not acidic and therefore do not react with the ortho ester groups catalyzing their decomposition. Furthermore. Recent studies have addressed the encapsulation of a range of proteins.4. The results showed that the environment provided by the CPTEG monomer was crucial for the preservation of the structure and antigenicity of the protein. on the protein structures (antigen).and D-alanine. Polyamides have some very attractive characteristics with respect to their use as biodegradable materials. [102] encapsulated Yersinia pestis antigen into the co-polymers CHP with SA and co-polymer 1. polyamides are metabolized into non-toxic products. so in general. a low molecular weight drug model. which affect the physico-chemical features of the polymer and thus drug release.6-dioxooctane (CPTEG) with CHP . Vol. Cross-linked structures (hydrogels) can be obtained when the polymer is synthesized from a polyol with diketene acetal (Fig.18). Tetanus Toxoid (TT) [103] has also been used as model antigen for encapsulation into biodegradable polyanhydride microspheres to modulate the immune response mechanism. In contrast. such as insulin [99]. the amide bond is hydrolyzed much more slowly than the ester linkages. O O O O O O R n Fig. pendant groups such as poly (L-lysine). (1.8bis (p-carboxyphenoxy) -3. Polyamides Polyamides are polymers whose repeated units contain amide groups. polyamides have been used to deliver low molecular weight drugs. synthesized other types of copolymers such as poly(L-lactic acid-co-L-lysine). alanine) or poly (L-aspartic acid) were attached to the lysine residues on the backbone. Moreover. L -alanine) [106]. 4 17 A wide variety of proteins [98] have been incorporated into polyanhydride matrices to improve in vivo protein stability. POE I. 2012. the chemical structure of some polyamides is modified to accelerate degradation. 2. these can have a side chain that can provide sites for the attachment of drugs or pendant groups and can thus be used to modify the physico-chemical properties of the polymer or to transport the conjugated drug. These esters comprise four families: POE I. However. They are metabolized to non-toxic products.17). Vera et al. Generally.Polymers and Drug Delivery Systems Current Drug Delivery. The drawback with this family is that degradation products are acids and these catalyze polymer degradation (Fig. L. Thus. human serum albumin (HSA) [100]. In vivo studies in mice demonstrated that microspheres provided a prolonged exposure to antigen for sufficient time to induce primary and secondary immune response.or nano-sphere. Researchers studied the encapsulation and release of rhodamine B. These polymers are generally hydrophilic and their degradation rates depend on the hydrophilicity of the amino acids [104]. The microspheres were loaded with dicofenac sodium salt.18). Poly (Ortho Esters) Over the last 40 years. The problem in this case is that the degra- . poly (D. Acceleration can be achieved through the copolymerization of monomers with other monomers to introduce a hydrolysable bond in the main chain.

which is encapsulated into microspheres of autocatalyzed poly (ortho esters). In many cases. Therefore. polymer degradation can be controlled by these excipients and will take place only when the polymer and excipients are in contact with water. Heller [109] developed a polymeric system which is stable at physiological pH (7. . this family of polymers has been commercialized. Therefore. Finally. this vaccine works by inserting the DNA of bacteria or viruses into human or animal cells. Also. this approach proved only partially successful and POE II polymers were not developed for commercial use. The synthesis of POE IV polymers is straightforward and reproducible and their structure O O CH3 O O O O O O CH C O R' O O O O R O m n Fig. These linkages are rapidly hydrolyzed and their acid reaction products can catalyze autocatalytic degradation (Fig. cells then begin to express proteins of foreign DNA and the immune system recognizes the protein and initiates a response.20). Later on. [111] encapsulated bovine serum albumin into a range of self-catalyzed poly (ortho esters). POE IV polymers are autocatalyzed compounds that contain latent acid in the backbone. 1. Then. The experimental results suggested that drug release rates can vary depending on the composition of the polymer. Heller published a paper on the synthesis and use of various excipients to obtain controlled drug release of therapeutic agents that are physically dispersed in polymers. Therefore. However. Therefore. the transesterificacion reaction was used again. 4 Vilar et al. leading to the suppression of the growth of tumor cells.2. where erosion rates can be adjusted by varying the concentration of this acid.20). 9. it can induce a humoral response (antibody-mediated) and also cellular responses (cytotoxic response mediated by Tc lymphocytes). Therefore. such as fast hydrolysable glycolic or lactic acid. POE IV. the last family studied was POE IV [110]. No. The amount of latent acid is small in order to maintain the hydrophobic nature of the polymer and it allows control over erosion rates. depends on the composition of the polymer (its hydrophobicity). This DNA encodes a protein antigen of interest that induces activation of the immune system. dation of these polymers is very slow due to their hydrophobicity. 2012. (1. However. Therefore. and allows control over the rate of degradation and therefore a regulated drug release rate. its molecular weight and its morphology. which consists of polymers synthesized from polyols and diketene acetals. but unstable at lower pH as a result of the excipients carried in the polymer. Bai et al. [114] described genetic vaccination. [112] proposed that the degradation of the polymer and therefore the release of the drug. latent acid monomers. acid additives were added to the polymer matrix to accelerate degradation. The composite polymer-DNA is phagocytosed by the cells and DNA is released into the cell as a result of the lower pH of the phagosome. Microspheres of poly (ortho esters) have been designed for enhancing the in vivo efficacy of newly developed DNA vaccine. 1. A number of studies have addressed the encapsulation of various drugs in poly (ortho esters) and their release kinetics. but in this case. the DNA is encapsulated into polymers such as polymeric microspheres [113] or liposomes in order to protect it from degradation. have been encapsulated into microspheres of poly(ortho esters). which consists of the encapsulation of a plasmid DNA into poly(ortho esters) microspheres in order to protect DNA from degradation. which had phagocytosed the DNA-polymer system and therefore expressed protein antigen. Chia et al.6 hexanetriol. using trimethylorthoacetate and 1. On the other hand. Their encapsulation and release has been studied. are introduced into the polymer backbone to obtain ester linkages. the development of this family was abandoned due to the difficulty in obtaining polymers with a specific molecular weight (Fig. in this case.19). gives good mechanical and thermal properties. This is because the release occurs through two mechanisms: surface erosion and diffusion of the therapeutic agent. thus obtaining POE III polymers. which causes a decrease in pH. The results of the tests performed in mice indicated an activation of adaptive immunity with humoral and cytotoxic responses. R' O O O R n Fig.4). This DNA vaccine is a plasmid that contains the DNA fragment of interest and an expression vector. As a result of these features. the faster the drug release. if the polymer is highly hydrophobic. such as 5-fluorouracil [115] (antineoplastic agent) and dehydroepiandrosterone [116] (steroid hormone). Other therapeutic agents. (1.18 Current Drug Delivery. only excipients that are on the surface layer will be exposed to water and thus polymer degradation will occur only on the surface layer. Wang et al. the researchers reported that the more hydrophilic the polymer. However. POE III. Vol.19).

2. the combination of molecular interactions such as van der Waals forces. Its relevance is due to its cationic nature. in their structures. a way to decrease the repulsion between charges is to ensure polymer swelling. such as carboxylic acids or sulfonic acids. Once out of the endosome. Generally. when the pH of the medium rises. or also basic groups. the degree of polymer ionization increases. the degree of polymer ionization decreases. [121] studied the use of a hydrogel that responds to a change in pH for the transport of orally administered insulin. the researchers examined a drug carrier that would protect the peptide in this organ and allow its release in the intestine where the pH is slightly alkaline. in the case of polymers that have amino groups in their structure. 2012. They conducted studies on the in vitro and in vivo release of the plasmid. thereby maintaining the charges as far apart as possible. the drug is released through a diffusion mechanism. Therefore. But once the microparticles reached alkaline and neutral environments. in the same microsphere structure as chitosan. [117] studied the encapsulation of DNA into chitosan. observing continuous drug release. After transfections. Cationic polymers condense DNA into a nanosized polymer by a self-assembly process. the carriers are located in the endosomes. These drug carriers may interact with the negatively charged cellular membrane. Hydrogels are a good choice for their use in controlled drug release because they are biocompatible and display satisfactory swelling properties in aqueous media. Double plasmid-loaded chitosan microspheres were prepared by complex coacervation to obtain high encapsulation efficiency. Thus distinct configurational and constitutional isomers are obtained respectively. obtaining nanoparticles of a definite size and shape. These gene carriers have to leave the endosome before it fuses with lysosomes and before exogenous DNA is degraded by lysosomal enzymes. In the case of polymers [120] that contain acidic groups. in vivo release was determined by the expression of the galactosidase and luciferase proteins. which is part of the O-glycoside bond. Lowman et al. Therefore. hydrogen bonds. electrical signals. once this stimulus causes polymer swelling. Smart Polymers Recent years have witnessed increasing attention to smart polymers as drug carriers because their properties can be tailored to fit the requirements required for drug delivery. Özbas-Turan et al. the interactions that occurred previously were lost and the pore size of the hydrogel increased. Chitosan is an interesting polymeric carrier. No. namely the intestine. leading to ionization variations in their structure. containing -galactosidase and luciferase as reporter genes. DNA was released constantly up to 72 hours. 2. The release of DNA from nanoparticles showed an initial burst release within 3 hours of incubation and then. pMK3 and pPGL2. The main interest in studying these materials is to control the swelling by specific stimuli that will allow the controlled release of bioactive molecules. determine the degree of hydrogel swelling at equilibrium. This change in the degree of ionization causes an alteration in the swelling as a result of electrostatic repulsion forces between the charges present. and temperature can change the features of the system. 4 19 2. Thus this pH-responsive carrier protected insulin in the acidic environment of the stomach as a result of the intermolecular interaction that prevented the hydrogel from swelling. The in vitro release of the plasmid was studied spectrophotometrically. such as pore size and permeability. Masotti et al. Natural or Modified Polysaccharides Natural and modified polysaccharides are biodegradable and biocompatible polymers.4. Therefore. In the intracellular environment.  or  isomers. Properties such as biodegradability. low toxicity and good biocompatibility make it suitable for use in biomedical and pharmaceutical formulations. In contrast. Researchers modify these structural properties to design these intelligent polymers. these microspheres showed a high production of these proteins. Vol. pH-Sensitive Hydrogels These polymers are characterized by the presence of acid groups.1. In contrast. Polysaccharide polymers differ in their structure and conformation. it has been studied as a drug carrier in the pulmonary route [119]. 9. thus allowing insulin release. pH-sensitive hydrogels have been used to develop controlled release formulations for oral administration. the gene carrier will be translocated to the nucleus if the free DNA is located near this structure. [118] discussed the possibility of encapsulating two plasmids.Polymers and Drug Delivery Systems Current Drug Delivery. Another key property of the polysaccharide chitosan is its mucoadhesivity.2.3. which favors the encapsulation of compounds with opposite charge. therefore making it a good candidate as a gene carrier. there are polymers with the same monosaccharide that differ in their O-glycoside bond configuration. pH-sensitive hydrogels have also been used to produce biosensors. hydrogels are loaded with enzymes that change the local pH of the microenvironment inside the . On the other hand. while others differ in the hydroxyl. These polymers also differ in the length of the chain and the number of branches in it. which consists of the electrostatic interaction of the positively charged polymer with the negatively charged DNA. when the pH of the medium rises. Stimuli such as pH. The polymers can be formed by several monomers or by various types of Oglycoside bonds. hydrophobic interactions and electrostatic interactions.1. This drug is a peptide labile to proteolytic degradation in the acidic stomach. This drug carrier was poly(methacrylic-g-ethylene glycol) (P(MMA-g-EG)) and the peptide was absorbed in the preformed polymer.2. The volume of the hydrogel or the degree of swelling depends on the balance between the attractive and repulsive interactions present in the network. Therefore. These groups can accept or donate protons depending on the pH of the medium. The smart polymers that received most attention are those that respond to stimuli of temperature and pH because these are inherent variables of physiological systems. for this reason. such as amines. 2.4. Thus.5. being internalized via endocytosis.

N-dietylacrylamide) (PDEAAm) and poly(Nvinylcaprolactam) (PVCL). [124] described the synthesis of a thermosensitive polymer based on hydrolyzed gelatin. a non-steroidal anti-inflammatory. and thus the pores. leading to the release of the drug. 9. Na et al. a structure called the core is required. the polymer structure. positive temperature-sensitive hydrogels have an upper critical solution temperature (UCST) and swell as a result of increased temperature. leading to a collapse of the polymer and polymer shrinkage (negatively thermosensitive). The morphology of the microparticles was examined by field emission scanning electron microscopy. 2. thereby allowing small molecules to cross by passive diffusion. which compartmentalize the interior of the capsule polymer. Therefore. a second layer of liposomes is added again. Recent work by Curcio et al. therefore. These observations lead to the conclusion that if the proportion of hydrophobic groups on the structure of the polymer rises. These phase transitions are manifested in significant changes in the volume of hydrogels. change. The formation of gluconic acid leads to a decrease in local pH. Once the microparticles were synthesized. a polymer at room temperature in water forms hydrogen bonds. the hydrogel swells. they studied the changes in porosity on the surface of elastin polypeptide (ELP) microspheres. a temperaturesensitive hydrogel. When the temperature increases. Another example of this application is found in a study by Yoon Ki Joung et al. For example. No. Some polymers increase their hydrophilicity as the temperature increases. the temperature of transition between the shrunken to the swollen state increases. Once the temperature decreases to normal values. Specifically. was encapsulated and used as a model drug to study the behavior of these microspheres. 2012. in drug delivery studies. Finally. whose function is to reduce the patient’s temperature. there is an enzyme that catalyzes the conversion of glucose to gluconic acid. one of the most important one being as drug carriers. who encapsulated indomethacin into temperature-sensitive polymers. Other temperature sensitive hydrogels are thermoreversible. To obtain thermosensitivity properties. Capsosome synthesis is complex. positively thermosensitive and thermally reversible gels. Other polymers which can be used by delivery of therapeutic molecules are poly(N. One example of these hydrogels are copolymers of Nisopropylacrylamide (PNIAAm) whose value of LCST is around 32 °C.2. while the other was to control this release by the stimulus of temperature. When the body temperature increases and exceeds a certain value. which were prepared by the oil-in water (O/W) emulsion method. The researchers encapsulated the therapeutic agent into PLGA microparticles. the polymer is swollen because its structure is hydrated. After add- . on which the capsosome will be synthesized. these encapsulated molecules can be hydrophobic. Some examples of these are poly(acrylic acid) (PAA). and therefore an adjustment of the LCST of PNIPAAm can be achieved by copolymerizing with other monomers which will change the degree of hydrophobicity and consequently the LCST value of the resulting polymer. leading to an expansion in their structure (positively thermosensitive) while others decrease their hydrophilicity when there is a temperature increase. thus allowing pulsatile drug release.5. Some of these are Pluronics. hydrogen bonds are weakened. they were embedded into a chitosan-pluronic hydrogel matrix. 4 Vilar et al. Tetronics and poloxamer). and therefore will bind to the liposome membrane. First. In contrast. This drug reduces fever. Temperature-sensitive hydrogel systems are widely studied for use in body-temperature control. the output of the drug from the polymer matrix decreases dramatically as a result of the shrinkage of the polymer structure. This mechanism is widely used for the release of insulin [122]. a second polymeric layer called the separation layer is added. pain and swelling. Temperature-Sensitive Hydrogels In the last decade. This type of polymer lends itself to many applications. The transition temperature (Tt) of the polymer was deter- mined by differential scanning calorimetry (DSC) and this coincided with a change in volume of the polymer. At the same time. while hydrophobic interactions are intensified and the polymer network shrinks. drug release was much faster. or hydrophilic. the liposomes in these systems divide the interior of the capsule into compartments. has been studied. Moreover. One objective of introducing a layer of chitosan-pluronic hydrogel into PLGA microparticles was to reduce the drug-release rate of microparticles synthesized exclusively with PLGA. These systems depend on the patient’s temperature when the polymer is introduced. Diclofenac sodium salt.20 Current Drug Delivery. polyacrylamide (PAAm) and poly(acrylamode-co-butyl methacrylate). These systems show permeability of the outer membrane.4. phase transition in temperaturedependent hydrophilic hydrogels. Capsosomes Capsosomes are polymeric structures that have a biodegradable outer layer and contain liposomes. when the temperature is higher than the transition temperature. [123] conducted a study on the changes in the structure of a hydrogel versus temperature and how this change affects drug release.2. After adding this first layer of liposomes. [125].2. One of the interesting features of this polymer is its transition temperature. which can contain the same molecule or different ones. However. the polymer must have a correct balance of hydrophilic and hydrophobic chains in its structure. A layer of a polymer called the precursor is added onto this core and the first layer of liposomes is immobilized on it. which is slightly above body temperature. Negative temperature-sensitive hydrogels have a lower critical solution temperature (LCST) and they show an on/off drug release with on at a low temperature and off at a high temperature. gels. a very useful temperature for biomedical applications is close to that of body temperature. thereby resulting in a change in the swelling of the hydrogel. which will be located in the aqueous core of liposomes. Temperature sensitive hydrogels are classified into negatively thermosensitive. For instance. and onto this. resulting in drug release. 2. it was observed that when the temperature was increased above the transition temperature. Vol.

2. is in equilibrium with free-form linear ones. Therefore. The copolymer emulsion stabilized o/w is stirred until the chloroform is evaporated and the micelles are loaded with the drug. and an o/w emulsion is formed by adding the drug solution in chloroform. Finally. Moreover. Therefore. together with the polarity of the micellar core. One of the most studied subjects in capsosomes is the enzyme catalysis reaction. This is the first candidate of an antitumor drug on polymer micelles to have progressed to phase I clinical trials in Japan. 9. the polymer can be removed as an individual linear polymer from the micelle structure by the kidney because the polymer chain molecular weight is lower than the critical value for kidney filtration. catalase [128] and urease [129] have been encapsulated into capsosomes and these systems have been reported to show catalytic activity. the enzymes were encapsulated into the different compartments (liposomes). chymotrypsin [127]. Polymer micelles have been studied for the delivery of poorly soluble and toxic chemotherapeutic agents to treat cancer. Micelles These copolymers are composed of individual linear polymers that contain a hydrophobic and hydrophilic segment. Thus. First. Finally. 4 21 ing the last layer of liposomes. a model peptide (thiocoraline) was introduced into the membrane of liposomes. in vivo drug release is controlled by the segments of the outer layer. thereby allowing circulation through the blood as a result of the high solubility and stability of the complex in physiological medium. 2012. The block-copolymer micelles form spontaneously by self-assembly in water when the concentration of the amphiphilic block copolymer is above the critical micellar concentration (CMC) [132]. which controls the drug release rate. PEO is believed to form the outer shell of the micelles and the doxoru- . Micellar systems have several advantages as drug carriers. Vol. The semi-permeable nature of the outermost layer of the capsosomes allows small substrates and products to diffuse inside these capsules. Another advantage of micelles is their long half-life in the body because they cannot be removed via kidney filtration cause of their large size.6. Among these is their capacity to encapsulate hydrophobic drugs. however. The catalyst system was composed of glucose oxidase and horseradish peroxidase. the development of systems with compartments and the success in the encapsulation of various enzymes or proteins with diverse functions illustrate the potential of these systems as drug carriers and also as microreactors. such as proteins and cells. The outer layer often consists of a polar poly(ethylene oxide) (PEO) that forms the shell of the carriers and protects its core. Finally. thereby improving therapeutic efficacy. the drug activity continues for a long period after a single injection. they cannot leave the liposomes because they are high molecular weight molecules and cannot diffuse through membranes. It is responsible for interactions with biostructures. while the hydrophilic part is located outside. Enzymes such as glucose oxidase [126]. the drug is protected from metabolization by enzymes or other bioactive species of the physiological medium. Kataoka’s group developed a micelle carrier (NK 911) [135] for anticancer therapy. depending on the degree of hydrophobicity polymer core. One approach is to add the drug and the copolymer in a solvent miscible with water. in a study by Hosta [131] and colleagues. Another method is to introduce the drug into the polymer by a method of oil in water emulsion (o/w). Micelles are used as drug carriers. and the links or interactions used to attach the drug to the polymer backbone. These polymeric structures are slowly excreted by the renal route as a result of their composition and structure. the lipidic membrane of the liposomes has a transition temperature phase that is normally moderately higher than the physiological temperature. so the structure of the lipidic membrane changes slightly at this temperature and facilitates the entry and exit of compounds into and from the liposome respectively. and this interaction determines the pharmacokinetics and biodistribution of the drug. The micellar structure. the hydrophobic micellar core.2. the release rate is controlled by the stability of the micelles. For this purpose. NK911 is based on poly(ethylene oxide)-b-poly(aspartic acid) (PEO-b-PAsp) block copolymers conjugated with doxorubicin. in contact with the aqueous medium. This was the first step towards the possibility of incorporating transmembrane proteins that can act as specific transport proteins or as enzymes that must be attached to the membrane to retain their function. the structure around which the core was synthesized is removed by degradation to obtain the capsosome structure. Therefore. the outermost layer of the capsosomes is built. in which the two enzymes were found in separate compartments. which confers them the capacity to form micellar structures in aqueous media. the hydrophobic core of polymeric micelles facilitates the incorporation of hydrophobic drugs either through covalent or non-covalent interactions. As a result of long-term circulation. which consists of biodegradable polymers. Therefore.Polymers and Drug Delivery Systems Current Drug Delivery. peroxidase. These amphipathic polymers are arranged so that the hydrophobic part is located inside the structure. Kreft and colleagues [130] published a paper about the synthesis of a capsosome with two coupled enzymatic reactions. No. These micelles can reach tumors by a passive mechanism (EPR effect) or they can be have targeting moieties conjugated to reach tumors by an active mechanism for enhanced delivery to a specific site [134]. an aqueous solution of copolymer micelles is prepared. Furthermore. The drug-loaded polymeric micelles are formed as the solvent is replaced by water. The outer layer plays a crucial role in polymeric micelles. which can improve the interaction with cells. encapsulated enzymes are accessible to their substrates. and then to dialyze the mixture in aqueous medium. in which low molecular weight drugs are incorporated inside them. which is formed by noncovalent intermolecular interactions between individual linear polymers. Some polymer micelle formulations of anticancer drugs have been reported to reach clinical trials. Drug loading into micelles can be achieved several ways [133].

Dendrimers are used for many treatments. In 2008. In the convergent synthesis. etc. they can be conjugated or interacted with the multivalent surface of the dendrimer. This is because FA is an essential ingredient for the replication of DNA and therefore. bicin conjugated poly(aspartic acid) chain is hydrophobic and forms the hydrophobic core of the micelles in aqueous media. The copolymer residue increases the water-solubility of paclitaxel and allows the delivery of higher doses than free paclitaxel. SP1049C was evaluated in phase II studies in patients with metastatic adenocarcinoma of the esophagus and esophageal junction. these new dendrimers showed a more relaxed structure than G5-FITC-FA. The hydrophobic core enables NK911 to entrap a sufficient amount of doxorubicin. and with fluorescein isothiocynate (FITC). and had not been conjugated by FA or FITC were capped with chemical groups such as carboxy or 2. This agent showed a better response than when single drugs such as cisplatin. The PAMAM dendrimer was conjugated with FA to obtain a specific focus. the interior of a dendrimer is an ideal place to encapsulate guest molecules. maximum tolerated dose and pharmacokinetic profile were determined in phase I. which have precise chemical characteristics and allow the encapsulation of drugs with hydrophobic properties. alternatively. 4 Vilar et al. The toxicity profile. The literature cites a variety of polymer configurations (lipid. that is. Supratek Pharma obtained FDA clearance for an investigative application for SP1049C for the treatment of metastatic adenocarcinoma. Once the dendrimer had been synthesized and conjugated.L-lactide) copolymer that contains paclitaxel in the core. These dendrimers can have distinct functional groups. Another important feature of the dendrimer is that it contains specific surface functional groups that allow attachment of hydrophilic drugs by covalent bonds. a drug that inhibits FA metabolism. Dendritic structures can be synthesized by two strategies. Finally. polysaccharide. Amino groups that are on the surface of a structure of the generation 5 PAMAM. Given the absence of repulsive forces from the charged amines. its cytotoxic activity occurs during the Sphase of the cell cycle. which corresponds to human epidermoid carcinoma. They may even hold more hydrophobic subunits such as poly(aryl ethers). (1. [140] synthesized a generation 5 polyamidoamine dendrimer. These controlled release drugs allow the administration of lower concentration doses and a therefore achieve a decrease in toxicity to healthy cells. another biodegradable micelle. And finally. which is used as an imaging agent to track the localization of the dendrimer.3. a mixture of amines and polyamides (dendrimer PAMAM) Fig. as mentioned above. which contains a high number of functional groups. a cell line that over-expresses folate receptors. 2012. divergent or convergent synthesis. dose limiting toxicities. electrostatic interactions or hydrogen bonds. paclitaxel and docetaxel were used. which in turn branch off. This formulation has been assigned to a pivotal phase III study protocol under the Special Protocol Assessment process. The efficacy and safety of Genexol-PM and cisplatin were evaluated in phase II for the treatment of advanced nonsmall-cell lung cancer [138]. Genexol is a micellar formulation characterized by a poly(ethylene glycol)-poly(D. a structure is obtained which is formed by a nucleus surrounded by a protective shell. and the recommended dose for phase II were determined. they are coupled to the core. In preclinical studies. Parameters such as the maximum tolerated dose. The nucleus is called generation zero because it does not have a focal point. Synthetic nanoscale dendrimers are multifunctional molecules capable of interacting specifically with tumor cells and they cause apoptosis. SP1049C demonstrated increased efficacy compared to free doxorubicin. Quintana et al. namely fluorescein and folic acid (G5-FITC-FA). peptide. One way of carrying dendrimers into malignant cells is through their conjugation with folic acid (FA) because the FA receptor is over-expressed in tumor cells. G5-FITC-FA dendrimers bound poorly to KB . This is an anticancer agent that contains doxorubicin and two nonionic pluronic block copolymers. a generation 4 dendrimer is a system that has 4 focal points between the core and the surface. The former consists of synthesizing the dendrimer from the nucleus. it was also conjugated to methotrexate. Doxorubicin is mixed with these systems. the segments of the dendrimer are synthesized separately. 2. and once obtained. is required in large amounts for the rapid cell division feature of cancer. and carboxylic acids. bacterial infection. resulting in a spontaneous incorporation of the drug into micelles. vaccine and gene therapy. Genexol-PM. Finally. such as polyamines (dendrimer PPI). Therefore. leading to a three-dimensional globular structure of concentric layers. The dendrimeric structure contains two key features that make them of interest as drug carriers. This drug specifically acts during DNA and RNA synthesis. 9. Therefore. The conjugation of dendrimers with FA also facilitates their internalization via receptor-mediated endocytosis. in vitro studies were performed with the KB cell line. Another micelle formulation in clinical trials is SP1049C [136]. the starting point on which the first layer will be joined. Drug Carriers in which the Drug can be Embedded or Linked Covalently: Dendrimers The chemical structure of a dendrimer consists of a core or central structure that contains several branches. This results in a first-generation polymer that will be joined by the next layer and so the dendrimer will grow successively generation to generation. One is its interior hollows. The convergent synthesis starts building the dendrimer from the surface and ends up in the nucleus.21). the dendrimeric structure is characterized by layers between each focal point (or cascade point) called generations. Vol. No. dose limiting toxicity. antiviral. In contrast.). since it forms a multivalent surface with a high number of reactive sites. including tumor [139]. These tests were performed with various dendrimer models.3dihydroxypropyl or acetamide groups. NK911 expresses higher in vivo antitumor activity than free doxorubicin because of the enhanced permeability and retention (EPR) effect. is in clinical trials [137].22 Current Drug Delivery.

PAMAM dendrimer. 4 23 NH O NH O O NH2 N H N H2N N H N O NH O NH O N N O HN HN O O NH2 N H N H2 N N H N O O HN O HN NH2 NH2 Fig. FITC and methotrexate. A partial acetylation of the amino groups of the dendrimer surface was carried out to neutralize the structure and to prevent undesired reactions with molecules present in the body. Dendrimer biocides that contain quaternary ammonium salts as functional end groups are an example. Quaternary ammonium compounds [146] are antimicrobial agents that disrupt bacterial membranes. Furthermore. [141] explained the synthesis. which make the dendrimer more reactive to antimicrobial conjugation. and 5-fluoro-uracil [145].21). A wide range of bacteria and yeast that cause human diseases are mediated by polyvalent interaction of carbohydrate and protein components with human cells. BH3 peptides [144] (which induce apoptosis). No. the latter conjugated by an acid-labile linker to the surface of the dendrimer. the characterization and in vitro and in vivo studies of PAMAM dendrimers conjugated with FA. cells. acetamide. The results of this study showed that dendrimers conjugated with FA inhibited the growth of KB cells carried out and showed a decrease in toxicity. The main advantage of dendrimers as drugs is the number of potential sites for the attachment of functional surface groups that can grow exponentially generation to generation.G5-FITC-FA and 2. Vol. Kono et al. these results demonstrated that the modification of the surface is crucial for improving the interaction of the dendrimer with the target cell. This finding is explained by the fact that some FA moieties are hidden inside the dendrimer. dendrimers have been used as carriers for other anticancer drugs. [142] synthesized a polyether dendritic compound containing hydrazide groups on the surface which were conjugated with folate residues to carry methotrexate to tumor cells. In contrast. showing minimal uptake. 9. (1. PAMAM dendrimers have demonstrated significant antimicrobial activity because of their higher density of functional groups. nadifloxacin and prulifloxacin . thereby indicating the lack of specific interaction with the receptor. The incorporation of antibacterial agents. such as sulfamethoxazole [147].Polymers and Drug Delivery Systems H2N NH2 Current Drug Delivery. resulting in a reduced interaction with the receptor. Therefore. Majoros et al.3dihydroxypropyl. such as cisplatin [143]. 2012.G5-FITC-FA showed high interaction and internalization in these cells. The multiple surface groups on a single entity (multivalency or polyvalency) allow their association with pathogens. silver salts [148].

was developed. Ota et al. which are exposed on the surface of tumor cells. is repelled by the cell surface. 2012. which are dendrimers that present multiple copies of carbohydrates on their surface. The action of the drugs is limited by their degradation. MAPs have been developed as vaccines against cancer. so they are designed with surface anionic groups such as sulfonate residues or sialic acid. present a high degree of mutation. which is also negatively charged. Haptens are low molecular weight molecules that induce a weak immune response unless their molecular weight is increased by polymerization or they are coupled to a high molecular weight carrier. has demonstrated significant antimicrobial activity. The capacity of dendrimers to transfect cells depends on their size. are widely used to address carbohydrate-protein interaction. Therefore. administration of relatively high doses is required to obtain the desired concentration at the site of action. Kukowska-Latallo [157] synthesized several types of PAMAM dendrimers that differed in their core and number of generations. [155] showed that MAP structures are internalized by dendritic cells. Moreover. lysine-based peptide dendrimers [151] have shown antimicrobial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria as well as against fungal pathogens (Candida albicans). These were studied to improve transport and DNA transfection in a variety of mammalian cell lines. They also suppressed the early stages of viral replication. which is negatively charged. thus inducing an immune response. in theory. the dendrimer had the CD4+ T cell epitope to activate immune responses (lymphocytes T and B) specific for some types of carcinomas [154]. 9. Amino-terminated PAMAM or PPI are the dendrimers most commonly used as non-viral transfection agents of DNA to the nucleus. In other experiments. 3. Thus. This feature explains why it is so difficult to develop a vaccine against these viruses. thus leading to undesirable toxicological and immunological processes. are potent targets for anticancer vaccines. and it can be used with a broad range of cell types. Vol. Thus the dendrimers are taken up into the cell by non-specific endocytosis. Therefore. many viruses. a multiple antigenic-linked dendrimer (MAG) that was synthesized carrying the Tn antigen linking to the carbohydrate tumor target. However. which are antigen-presenting cells. Dendrimers are an excellent tool for vaccines because of their high capacity to combine a large number of haptens on the cell surface. To this end. Finally. acidic carbohydrates that are present on the cell surface. and inability to penetrate tissues due to their chemical nature. and niclosmide [150]. These sialic acids interact with glycoproteins localized on the surface of the influenza A virus. another interesting application of dendrimers is in gene therapy. The structure of the dendrimer is formed by a central core and charged amino groups on the surface. the results showed a highly efficient transfection in several cell lines with minimal cytotoxicity in eukaryotic cells. being of particular interest polymeric . MAP is the most widely used dendrimer for this purpose. PAMAM is used to protect DNA from degradation by nucleases and to deliver genetic material to tumor cells. conferring high selectivity to interact with the fusion protein of viruses. CONCLUSION In the treatment of a pathophysiological process. Their results showed that MAP structures are processed in the same way as an intracellular pathogen (cross presentation). Furthermore. In general. leading to less likelihood of infection by the virus to the cell. [149]. the anionic dendrimer and/or the glycodendrimer compete with the cell surface by binding to the virus. which causes malaria in humans. leading to a peptide presented by a major histocompatibility complex (MHC) class I. thus giving the complex an overall positive charge and thereby support adherence of the complex to the negatively charged cell surface. inhibited HIV attachment and fusion by binding on the surface of the virus. it is desirable that the drug reaches its site of action at a particular concentration. shape and number of primary amine groups on the polymer surface.24 Current Drug Delivery. Therefore. thus preventing its binding to healthy cells. [158] have studied PAMAM dendrimers as carriers for cancer gene therapy. epitopes of the major surface protein in this parasite were conjugated to the dendrimer. Transfection is higher in dendrimers with an excess of primary amines on their surface than with DNA phosphate groups. Navarro et al. glycodendrimers. Hence. such as influenza A virus and HIV. thus preventing viral adhesion to the sialic acid healthy cell surfaces. This therapeutic dose range must be constant over a sufficiently long period of time to alter the process. Carbohydrate antigens. interaction with other cells. PAMAM dendrimers [152] with a surface that had been modified covalently with naphthyl-sulfonate residues. This molecule has a multi-branched lysine core onto which haptens can be conjugated. this new technology for gene transfer offers significant advantages. research efforts are devoted to designing new formulations. Therefore. Antiviral dendrimers attempt to mimic the anionic cell surface. Various reporter genes were used to test the efficiency of transfection. aminoterminated dendrimers carry DNA to the membrane and contribute to the transfection process by inducing the disruption of the membrane because. The results of experiments in mice showed an immune response. These features allow the interaction of these charged groups with the negatively charged phosphate groups of nucleic acids and enhance their adherence to the cell surface. naked DNA. MAP structures have also been used to transport protein antigens against microorganisms such as Plasmodium falciparum [156]. Dendrimers are also used in vaccines. One example is the PAMAM dendrimer [153] conjugated with sialic acid. Superfect [159] is a commercial transfection reagent consisting of activated dendrimer molecules that can carry larger amounts of genetic material than modified viruses for gene therapy. which leads to major changes in envelope protein glycosylation patterns when comparing different strains. 4 Vilar et al. such as high gene transfer efficiencies and minimal toxicity. For these reasons. No.

dendrimers. The dendrimeric structure allows the encapsulation of drugs with hydrophobic properties in its interior cavities while functional groups found on their surface can attach hydrophilic drugs by covalent bonds. These polymeric systems are suitable for site-specific and time-controlled delivery of drugs. such as polyesters. are the most widely used. trapped. including nano. thus allowing drug release within them. The treatment of most diseases requires drug distribution at a specific site. or by linking the drug to the polymer through a specific linker that is degraded under certain conditions.and micro-particles. a pulsatile-release formulation. Finally. Thus the drug is encapsulated inside the particle and it is released by the degradation of the polymer coating. Time-controlled drug delivery can be achieved depending on the features of the polymer. which are endocytosed by macrophages. the treatment of the diseases caused by these bacteria call for drug carriers such as dendrimers. Micelles are composed of individual linear polymers that contain a hydrophobic and a hydrophilic segment. in which drugs are released only when required by the body. treatments for intracellular bacterial infection are hindered because most antibiotics have poor intracellular diffusion and some have a reduced activity in the acidic conditions of lysosomes. In summary.and micro-particles are formulations in which the drug can be conjugated. and copolymers of PVA or PEG with acrylamides. namely proteins and nucleic acids. which compartmentalize the interior of the capsule polymer. which allows small molecules to cross the membrane by passive diffusion. the chemical nature of the many types of polymeric drug carriers available facilitates the distribution and interaction of drugs with their target tissue. to achieve a higher desired pharmacological response. The DNA in this vaccine system encodes a protein antigen of interest that induces activation of the immune system. 9. Polymeric carriers of antineoplastic drugs can passively accumulate in cancerous tissues because of differences in the biochemical and physiological features of healthy and malignant tissues (EPR effect) while they can actively accumulate in the same tissues because they have been conjugated to targeting moieties. Other controlled-distribution systems use polymers. The three-dimensional structure of these hydrogels allows a controlled drug release. a sustained-release formulation. in which the active ingredient is released at a time other than at the time of administration (polymers sensitive to stimuli). Nano. drugs can be encapsulated or conjugated into polymer matrices. Vol. leading to a three-dimensional globular structure with concentric layers. there is another promising formulation for drug delivery. Several polymers have been exploited for this kind of formulation. The DNA vaccine is a newly developed system. In both cases they require polymeric carriers because they are susceptible to degradation by peptidases or nucleases. another relevant application of drug delivery systems is vaccines. Finally. Hydrogels such as PHEMA. These formulations are also used against bacterial infections. bacterial infection and inflammatory process as well as for vaccines. and a delayed-release formulation. such as in an acidic environment or by a specific enzyme. this kind of pharmaceutical formulation is used to transport drugs that are rapidly degraded in body fluids. poly(orthoesters) and polysaccharides. From a polymer chemistry perspective. capsosomes and micelles. Thus. Therefore. This DNA can be encapsulated into polymeric carriers. Another formulation is capsosomes. Vaccines are classified into two groups.and micro-capsules are comprised of an outer shell that encapsulates the active agent. .Polymers and Drug Delivery Systems Current Drug Delivery. Moroever. whose properties. polyamides. It is then released into the phagosome. Usually. it is important to appreciate that the mechanisms of controlled-release require polymers with a variety of physico-chemical properties. These polymeric systems have been used for various purposes including treatments for antineoplastic activity. 4 25 systems of drug carriers. 2012. This can be achieved by functionalizing the surface of polymeric particles with receptor recognition elements . dendrimers. electrostatic interactions and hydrogen bonds. The hydrophobic core of polymeric micelles facilitates the incorporation of hydrophobic drugs either through covalent or non-covalent interactions. or embedded within the polymer. These carriers also protect their drug cargo from degradation and prevent their side effects. ACKNOWLEDGEMENT None declared. Furthermore. CONFLICT OF INTEREST None declared. such as swelling. thus obtaining the following: an extended release formulation (swelling of polymeric matrix or degradation of polymeric capsules). In these systems. Nano. which have the capacity to form micellar structures in aqueous me- dia. which in turn branch off. antineoplastic drugs are highly toxic and these delivery systems can prevent their degradation and interaction with other tissues. Modulation of the chemical architecture of the polymer can regulate the release of the therapeutic agent and thus the profile of the final formulation. These polymeric structures have a biodegradable outer layer and contain liposomes. No. thus allowing it to reach the cell nucleus and express the foreign protein. thereby protecting it from degradation. such as antibodies and carbohydrates. nano. in which the active substance is released with a kinetic profile of order 0 (osmotic pumps). change in response to an external stimulus such as pH. These systems show interesting features such as outer membrane permeability. Most intracellular infections are difficult to eradicate because bacteria inside phagosomes are protected from antibiotics. polyanhydrides. the division of the capsule into compartments by liposomes allows them to hold the same or distinct molecules. Several types of polymers have been tested as potential drug delivery systems.and micro-spheres. The chemical structure of the dendrimer consists of a core or central structure that contains several branches.

48. Cassidy. T.. Today. Duncan...cordislabeling.. [2a] [3a] [33] [34] [35] [36] [37a] [4] [5] [6] [7] [8] [9] [10a] [38] [39] [40a] [41a] [11] [12a] [42a] [13] [14] [15] [43] [44] [45] [16] [17] [18] [19] [20] [21] [22a] [46a] [47] [48] [49a] [23] [24] [25a] [50a] [51a] [52] [26a] [53] [27] [28] [29] [54a] . Adv. Kuga.. Drug Dev. 1117-1133. 2007. R. Rihova. P.M. Donath. Samyn. N. Pharm. Frigerio. 1629-1636.M. 63. T. Rochetti. 2012. 2005. J. 750-763.P. I... Thera.. Young. Caliceti. J. M. S. R. Rev. A. 203-230. Cancer Res. 1995. P. 19. J. Cheng. R... 2009. Tripathi. P.. W. K. 6. S. K. Burton. A. K. Lovegren. G.. 289-310. M. Müller.. S. Garzone.. M. K.. Brocchini. Clin. Nature 1998. A.. Mita. c) Cho. Cancer Res..Wiley-VCH Verlag. Macromol. K. R. Chem. Bioconjug. Nanomed. B. Subr. Ulbrich. 5. T. 347-360. 2.. 2002. Cheng.. Robson. 31.: Romero. R...W. Giles. P. de Heus.. Seymour. D.. Shiose. Mater. 31A.. J.. H. Bolton. Kratz.. Wedge. C.. T.pdf (Accesed December 2011) http://www.. B. Bargar. Cancer Res. S. Tong. Trends Biotechnol. Rademaker-Lakhai J. B. J. Cancer Ther. Madhu C.R... Chipman. Pharm.. 1341-1358.enzon..A. H. Adv. Prabha. Garrett. 49-54.. Duggan. Duncan. Chakrabarti. Garg. A. M. R. Takimoto. www.. McNamara. F. 2001. I. 1987. 1129-1145.. Engl... 1606-1614 Homsi. Res. T. Control. D. Seymour. P. Chem. R.. 16. Int. M. Rea. 187-195. S. H. 392-395. S. Baker. 83-94. C. De Conti. B.. Nienstedt.. Rump.. W. Anticancer Drugs.. L. Hesslewood. Eur. Jodrell. 871). J. J. M. J. Biomacromolecules... Beijnen. J.. Singer. S. Walter. R. O’Hagan. M. Tanaka. Rev. 99. Hopewel. R. J.. Panyam. 2002. Ulbrich. M. 4 Vilar et al. Fraier. 7. J. 2008. 1997. (b) Rice. Siahaan. S... G. 332-355. B. R. Grigolini. J. P. Horak. Pharm. Shin.. Chem. K. P.. J. http://www. G. 332-351. Lussignoli.J. Qiu... Drug Deliv. P.. (Accessed November 2011) (b) http://www. H. Brendel.. G. M.. Wanders. 428. 468-473.. L.. Michael E. 46. 272-282.M. Fraier. Pharmacol.J. Ed.. 2004. Kost. Wiley. C. Int. Pharm. C. 609-636. Clin. Schellens... A. M.. Vermani. R. R. J. Br. Inc. J. Feldman. J. Simon. X. Ind. P. Veera. (b) Seymour. Olivi. M. Pharm. 315-323. P. Drug Deliv. D.... P. B. Cassidy... J... 2000. Whitlock. N. T. 2003. H. J. 1985. 87-103.. S. R. T.. G. Pimm.. (b) Julyan. 59-73. Allen. M. 1. Ribatti. Mita. Boivin. (c) Kelland. Main. Bisset. Singer. D. H. Shaffer. 2005.A.. Shaffer. 61.. R. Int. 321-339 (b)Gupta. Allievi. Pharm. De Vries.. 1009-1021. V. Mezo. 10. Chem.. W. J. R. D. W. S. B. T. (abst. Drugs. Howell. Koopman. D.. Twelves. A... Cancer Chemother. F. Hwang. 2010.. Biomaterials 1994. J. 24. Y. A. P. Doran. International Journal of Drug Delivery. S.. O’Flaherty. 81-99. Cancer. Hashida.. Takada.. V. Sadaphal... L. S. Haffer.. D. S. Chen. 345-381. Aghajanian.. Expert Opin... 3127. Biol. 2006. Eisenfeld. 14. Eisenfeld. S. 45. Sci.. Chiappori... M. Stromatt. Drug Res. Langer. M. Rev. Int. Strohalm. N. Chandira.. 1990. Matsumura.. 523-33.racgp.. Duncan. 55-60. 21. GmbH & Co. W. M. A... J.. Warner.. Rowinsky. J. Spriggs. A.. E. Cancer Res. Pontius. Angiuli. Twelves.. W. Schatzlein. V. 2010. Pezulli. J. Am. Clin.. D.. 243-254.. 61. Greenberger. 786-816. Ferry. Singh.. M. J. Schierholz.. A.. Yamashita.... Ohno. Angulo. 99-107... Sullivan. M. Release 1994. K. 47. No.J. 1996. Bernareggi... Kopecek. 2e. (b) Vasey. G. 561-566. 62. A. Cancer Res. P. Brerton. J. & Res.. Kumar. (b) Schluep.. J.pdf (Accessed November 2011) http://packageinserts. (b) Brumlik. F. Inc. 1991. 13. R. Wagenaar. Shah. 1995. de Bruin. Oncol. Letourneur.. H. Cheverton.. Ponzoni. Thakare. KgaA. E.. REFERENCES [1a] Seymour. B. Magnè. A. Blackie.. O. 2005. D... R. Park. Murray. 2007. NY.. 153-162. D. C.. 546-549 Clegg...Cilli. Duncan. Rev. Neurosurgery. L. G. Pharmacol.. 87-93.. 57. D. 139. Kerr. L. 2009. 425-430. Cancer. Clin.. S. 1996. C. 47.. C.. Bala. Hernáez. S. Singer. M. Drug Deliv. J. L. R. M. Domb. Garg. Van den Mooter. Duncan. 695-708. 2002. Burger.. Y. J.. 2002. (c) Miller. Christodoulou.. Rev. Baker. 2.. Brown. F..J.. Takimoto.cypherstent. P. 2007. B. D. Muirhead... Clin. J. Duncan. Mathiowitz E (Ed. Brem. Soepenberg. Mitchell. G. Horbett. Nowotnik. Sampath Kumar. Kopeckova. R.. Biomed. C. H. Oldham. Kerr. A. 2010. 48. A... Clin. D. Davis. Hlawaty. Wallace. Sparreboom. Clin. D. Biomed. 2. 39-47. J. Besman. 1214-1219.. J. Angew. R. R. Strohalm. J. Int..... 20. Mandjes. 2365-2370.. R. Daryani.. K.. P. Duncan. Nie.. 1999.. USA.. Wang. Meyers. Rev. Springett.. Kopecek. (b) Conforti.. Boivin. Ratner. Rev. B. Pharm.. Beijnen.. L.. 158-170. http://pharmacycode.ptca. D.. Pezzoni. Cancer. Control. Bhowmik. Portes. 1995. 109-115. A.. 3074-80.. J. Adv. J.. P. Munster.. Chem. Adv. Al-Shamkhani. 5. 1991.. L. M. Daniel.. Cassidy..R. A. Yu. 2009. Control. 569-579. Revista Iberoamericana de Polí J. J. In: Encyclopedia of controlled release. Schot. Pharm. 57. Y. M.html (Accesed December 2011) Verma. L. 38.. Miyamoto. Oncol.. Pharmacol. E. 2006. L. J.. M.. Mater. T. F. Y. L. Becherini. S. Res. J. Y. (c) Li.. M. Kopecek. R. Ed... Cancer Res.. Pellizzoni. 2004. Cancer. Pharm. Ulbrich.. S. M. E. 2009. S. A.. Sahooo. 1198-1215.. Cancer Chemother.. K. Drug Discov. A. Anticancer Drugs 2005. M. J. 5.. Lind. 766-770. Rosing. P. R. M. Stromatt. Wang. E. R. (b) Seymour.. Release. Bull. Davis. Rev.26 Current Drug Delivery. S. C. Eskens. Res. A. 9. (c) Duncan. M. Cancer. 37. Hunter.J. Vicent.. 3.A. (b) Shaffer.). Loi. Nowotnik. 64. Ducharme. Enzon Pharmaceuticals. 1999. 16. X. Porro. 2006.. D. 26.B. J. Charnsangavej.. R... Vranckx. Burtles.. Rev.. Campone.. Drug Discov. A.. Thomson. S.. H... H. D. S. Waehler. 21. Daud. M. Hudecz.. Soc. F. G.... P. Singer. Sel.. C. B.. M. J. E. V. Maeda. K. J. (c) Gombotz. R. V. E.. (b) Brouwers. 461-470. J. R. Adv.. Flanagan. 15.. Med.. 163-204. W. M... 70-74. A.M.. R. 4809-4821. Pulverer. F. 1. J. E. Cancer Res. Vol. Sapra.. Schug. 233-239. M. 2001. Nori. P. 1995.. Segal..... B. In: Polymer-drug conjugates: drug release from pendent linkers. Eur. R. Vasey.. J. O. F.. A. Pharmacol. Soltero. Marchisio. Lora. E. 2003. C. R.. R... Marsilio. Baldwin.I. M.. Ferry.. 16. In: Targeting and intracellular delivery of drugs. D.. Expert Opin. 23.A.. K. D. 1985.S. Chem.A... M. Hensley.. V.D. Cvitkovic. Morrison. L. 287-295. 1986. [30] [31] [32] Ferruti. C. 2006. M. J. J... 2009. 3181-3198.. 375-383... Shakesheff. C. S. C.. 2. 891-897. Duncan. Drugs Fut.. M. Calvert. Ke. M. Rapid Comm. Drug Deliv. E. M.W. (Accessed May 2011) (b) Pastorino. Exp. A. 1999. 2949-2954. D. Chiranjib. Angew. Int. M.A. M. Investig. 3.. S. Wilding.. J. C. 53.. R. Pauli.. K. 2005. W. W. Oncol. Rev..P....K. Wiley.. J. C. M. Bertani. Drug Deliv. S. Lammers. 12.. J.. W. W. Adv. C.. (b)Haag. 81. Terzi. M. J. W. J. K. K. Mishra.. Kinget.. 23. Duncan. F. Weinheim. ten Bokkel Huinink. K. Gandhi....D. P. G.. Duncan. Hesslewood. J. Shabat.. R. P. 29... D. Subr. Cassidy. Wonnemann.. Toxicol. K. J. 1999. Tekade. F. Maniar.... Drug Deliv. P. B. A.. Hum. A. J.. McGee. 2011. Blume. de Bono.... Satchi-Fainaro. S.. L. J. Cancer Res. 519.. Angiuli. M.. J. Verweij. J. B. Vawter. 6387-6392.. M. 2007. S. R. Bisset. Anschütz. Pettit.. 2003. (c) Kalala. Nat. 1999. R. A.. Szerkerke. J. J. Bioconjug. Polymer reviews. Langer. Adv. Controlled Release. David. Y. 62. Germany. b) Sáez. Ravikumar Reddy J.W. Z. 48. R. Kaye. Veronese. 1999. 7. 2002. Robbins. 1310-1316.. J. Sarantopoulos.R. S.. Proc. H. J. H. Ueda. 60. 1996. Labhasetwar. F. 1189-92. 2009. de Jone. Int. (b) Springett.K. 1-11. J.. 11. A.Exp.. 348-356.... S.aspx (Accesed December 2011) http://www.. Allievi. 2004. M.. 30. D. P. Schellens. K. H. (b) Sabattini. J. 2002. G. J. 1.. Erez. 30.. Vicent. 349-360.. In: Drug Delivery: principles and applications. D... Howell... International J. D.. Poyner. M. D. Verschraegen. M. B. K. F. L. Release 1994.. L... Duncan. M... D. L. M.. P. S. Milas. 22. 5855-5861. 1023-1050. S.T.. S. P. Toal. Ed. In: Encyclopedia of Molecular Cell Biology and Molecular Medicine. Botton.. Drug Deliv.W. Clin.pdf (Accessed November 2011) San Juan. 18. S. Uhrich. Emionite. 2009.. 12. 2008. A. Houjou. M. 2010. In: Translation of Pharmaceutics: The Science of Dosage Form Design. Funt. M. Curiel. 2001. 34. 2010. 703-711. S. C. Cannizzarro. Drug Deliv. World Sci. Adv. J.. 115. S.B. G. Mohamed T. Tamargo. C. Clin. Zurlo. H. C. M. Kumar. Bennouna. Ochi. Ed. Meerum Terwogt.. Biol. Baker Lee. Anderson. R. D. 2002. 262.. W.A. A. Br. Curiel. M. K. Price. J. Katayama. 281-290.

Su. 6.. R. Ng. 1990. 1995. 5. Williams. C. A... 2000. J. J. M.. Blanco-Príeto. 62.. 1219-1227. Bioconjug. J.. Y.. 637-651.S. B. Release. Eur. Langer.. Ikada. E. H. J.. Schwartz. S. Somayaji. G. Release 1999. A. Mc Murray. S. 408-412.. Lange N.. Narasimhan.E. L.. 54(7). O. Chem.. Control. Shimizu. R. Xu. K. Biomed. K. J.. M. Berckland. S. Biomaterials 2008. H.. Wang. Jansen.. A. Drug Target.... O. M. Drug Deliv. 1324-1331. X. J. Y. M. J...M. L. 77. S.. H.. J. J.... B. J. Na. 53-62. L. Biomed. Chest. A. J. S.. Roh.. T.H... 41. Ortaggi. Wannemuehler. M.. Zheng.. Lee. Feijen.. (b) Bai. J. G.. Ygartua. Carrillo-Conde. Sederel. R. Pharm. 2007.. S. D. 644-649. Biomaterials 1991. Y. H. 187-195. L.. Bantjes. Biosci.. D.. Mc Rae. Vera. Wada. 2010. C. Watanabe. Y. C.. Int. A.. 23. Narasimhan. M.S.. E.. N. W. D. Lakshmi.. H. Chem. Domb. 29-43.. Kim. S-H. S. Bordi. O. J. 1997. (c) Duncan. A. Y. 2009. F. M. 1999. M. Pharm. T. 77. Al-Quadi. N. Lowman. 2001. Rock. M. Kissel. Microencapsulation 2003.. S. L..D. Lieverst. 51-66. Puiggalí. R. S.. 2005. Mitragotri... Remunan-Lopez. Bioprocess Eng. A... Pharm. Anal... Z.. R. 1994.. Mela. C. 421-427. P. M. P. Marino.. 2012. Wang. Lee. V. Adv. S. J... Syu. W. Atyabi.. Hosseini-Nasr. 648-657. Díaz J. Ooi. Gonsalves. Ike.M. J. McConnell. 95-110. T... Li. Ji. 226.. A. A. Hrkach. Kazantseva. Palocci. 4405-4412. McGinity. A. F. Langer. M. N. 552-560. Mater. Torres-Lugo. 1057-1065. X. 3110-3119. Br. Hitomi.. J. Eds. (b) Parajó. Petersen. 2004. Res. 2671-2677 Peppas.. M. B.html . Loiseau. J.. J. P. M. N. M... 96. Mater.. S.. K. 94..N. J. 97-109. Stolnik. Sharma. Res. L. (b) Panyam.K. Anderson. Chen... Wada. Laurencin. Uhrich. R.. J.. Garcia-Fuentes. V. Biomed. I. 2. Y. W. 2004. Wang... Horváth. Pharm. Drug Deliv. 437-441. N. Colombo. T....C. Wada. Tech.H. M. S. L.. R. C. 88. 99. K..Narasimhan. Govender. C. Masotti. 1804-1814. 933-961. Schiltz. S. Kell. Pellizzoni.. 81-87. Nah. S. N.. G. B.. Trewyn.. Yan.C... 2008. Li. Mater. 2002. (b) Heller. In: Modern Research and Educational Topics in Microscopy. Biomacromolecules. Cancer. Chen. 147. 61. R. Ballinger. Garnett. Barr. Res.. Valenta. Wilson. G. Keul. 419-441. J.. Yang Y. A. M. S. Maiti. C. K. Chemotherapy. Chung. L. C. R. Int. 2008. S. Pharm. J. D. Pharm. K.. I. 495-514. Pack.. Revista Iberoamericana de Polímeros. Park. 2004. R.. No. 99. Grandfils. R. 177-184. Chang.. 2003. Sci. 6.Polymers and Drug Delivery Systems Spinelli. G. K... 2002. Naikwade. Web page: http://www. C. Bai. Processing and fabrication of advanced materials.. J. Hitomi. S. S. R. M... Rev. Samadi. 6. Zhou. ten Bokkel Huinink.. R. 431-434.. Hyron S. Speed. Hitomi.K. Y. Microencapsul. S. 2010. J. M.. H. Control. P. Z. S... C.. J.. K. 2004... György. A. N. Lin. 681-688. P. 33-43. Iranian Polymer Journal. Keys. 71.. Abdellavoi.. R. M. J.. 1971. 352. Katti.. Jain. Barr. K. J. 26. Heller. Sci.. M.. Chung. Nilsen-Hamilton... Lin. 2007. M. J. Kipper. Fredette.. Singh.. B. R.. Aral. J.. (b) Ike. W.. Narasimhan. S. Altman. Ikada.. Ike. D. 54. Cun.. Schellens. (b) Yeo. D. Kipper.... Sackett. Angulo. S. J. G. Pharmazie. 2001. 129-41. Deng. J.. Smith.. M. A. J. 798-810 Marck. Annals of the New York Academy of Sciences. VIII. Xu. Hyon. F. Seo.. S. Sci. J... K. Nat. Pharm. Wu. Kumar N. Espuelas. N. Santoyo. Simonian.. 2007. J. Gao. Suarez. Yahya. 2010. Cheung. M. Sci. 2001. P. Sci. Özbas-Turan. 332-351. R. Wild. Lowman. Pharm... Shi. Br. S. M.W. R. 317-323.. J. Pharm. Palocci. Drug Deliv. Mater. D. T. Chem. Fraier... Ronneberger. J. 91. Sternberg.. Leslie-Pelecky. M.. C. 2002. 17. Dinarvand.. 20. Li.. R.H. Vantus. 911-915. Singh.. Shen. 6.. J. R. Biomaterials 2002. Y... 213-224. Newcomer. Labthasetwar. Raghavan.. H.. C. J. J. Ng. Cancer. J. C. S.. J. A. 23-27. Domb. R. H. J. Peppas. 2010.. 1985..... Volland. Nihant. S. 686-697. G. Release. F.. G. Y. W. M. Y.drugs. M. A. K.. B. Bordi. 5. R. 2004. J. Watanabe. J. J. G. P. C. Pishko. 289-299. W. Chem. 4909-4912. S.. Pharm. 100. Chem. 17. T.. Polymer International.. R. Drug Deliv.. J. Ravi Kumar. S. Rabinovich. R. Yang. 289. Park. Control... S. 2009.... Nagai. Sci. 20... J. Iwata. R. S... Mater. 593-599. Narasimhan. 2009. A.. K. W. J. 199. Y.. Y. J. S. Pillai. 51-56. Takayama. Nagarwal. M. Van Kesteren. Tashima. Na.. B. K. Kabasakal.. Singh.. Biomed.. M.. Poh. Nahar. 2009. 2010. Shimizu... 329-335. D. H. 190-196. H. Determan.K. Control. Control. M. 93. [88] Current Drug Delivery.. 4 27 [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104a] [55] [56] [57] [58] [59] [60] [61] [62a] [63] [64a] [65] [66] [67] [68] [69] [70] [71a] [105] [106] [107] [108a] [109] [72a] [73] [74] [75] [76a] [110] [111a] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [112] [113] [114] [115] [116] [117a] [118] [119] [120] [87] Drugs information on line. F. C.... B. A.S. Xiao. J. 54.. 1999.. ..M. Sanders.. Mater. J. Pandey.. C. 10. 123-131.. Chia. J.... 75.. Ou. Chemother. Nanomedicine. Adv. D. S. . Natsume. Nguyen. Biomaterials 1994. S. Kim. Caponetti. N. Z. Heller. Li.. F.. Heller.. 76. Tao. E.. N. Determan. 6. Kipper. 26. Q.. A.. J. 1998. B. Y. R. C. S. L. S. Chris Minion. A... 2002. 2001.. Spinelli. L. H. T. Y. C. Pharm. (b) Schoemaker. Res.. A. H.. K.Marino. 1990. M. Y. d’Angelo. 213-230. T. J. J. Cui. Twelves. Sci. J.. 446... M.. N.E.. Barratt. M.. Ng. Mendez-Vilas A. A.. N . 1015-1039. Esmaeili. Nanomedicine. J. J.. 284-286. Rad-Malekshahi. M. Rosing. Heller. Biomed. 1993... J. 8. Wildevuur.R. T. E. Langer. J. S. Macromol. Manoharan. G. Langer. 2010.. S.. B.. 87.. L. Control Release.. Chaumonz. J.. D. Cannizzaro. Wannemuehler. D. J. K.I. R... 10.. Microencapsul. B. C..M.M.. Maitani. D.. 2010.. J. 24. 11-25. J. M. (b) Uhrich. W. Dash. Ortaggi. 11.. J. K. D. Anish. Illum.. J. 27-32. C. S. Rev. 055302/1-055302/6. Barr. S. A.. 15... 34. 1630-42. Zange. Int. J. Grenha. I.. N. 2009.. Q. J. W. 11. Int. Stassen.. Sáez. Zeng. 12. Jeong.. G. Y. Liu. J. K. (b) Martin E... M. Pharm. 919-924. Cannizzaro. D. M.. M. 2002. Applied Polymer Science. S. B. Coudane. H. J... Res.. Nguyen. Hickey. C. Lim.. L. Z. Control. 53. 12. S. G. Panda. Gurny.. 2010. A. K. Shakesheff. Langer.. . Hernáez. Varshosaz. V. C. B. J... M. E. J. Kim. M. W. M. T. R. Lotan. Release. 1999.. 2588-2598. Release. 64... Q.. Welle. E. W. 23. Kriwet. 1999. Drug Delivery Systems. X. 27.. 2009. B. J. T. Kanchan. 29. 1985. Heller. Rauth. Rev. J. J. Huo. C. 4237-4250. Vasavada.. 2001. 3181-3198. E.. Lin. J..... X. Ikada. K. Nakamura. Control. J. D. H. Legrand. 161-167. C. Yu. V. 10. Drug Deliv. P. J.. 034114. Choi. 2004. Yipchuck... Sci. H. Sun. Res. Langer. F.. 573-580. R. 2002. Biotechnol.. K. 5. Koopaie.. Pharm. Mater Sci: Mater Med. 80.. R. J.. D. 2001. Seijo.. Singh.. A. K. 5. Zydowicz. Y.. Bouchemal. 608-14. H..S. de Jalón. L. 98(11). Jang.. Langer. 5. Chasin. C... J. J. Beijnen. 925-933.. C. K.... 2006. Wada. J. Biosens Bioelectron. Hudson. Nanotechnology 2008. Harvey. Ge. M. 15.. Teyssié... Heller. P. K.. 136-141. J. G. Eisen. D...... C. 3181-3198. Langer. L.. Vitale.. 181-184. J. Polymeric Drug Delivery II. Vaida. Rev. Irache. 61.. 19. R. Wang. P. 1999. C. Shakesheff. Akbuga. 87-101. 2009. A.. J. P.. O’Hara. Grazia Porro. K.. 3. 9. Microencapsul. N. Res. Comb.. Riley.. Wang.. 3. Russell. D. 2006. Hopfer. 1991..I.. Liu. F. J. Weng. Domb... S. J. Shen. 1-11. Katime..63-67. 1625-1632.. Drugs. (Accessed May 2011) Rafi. Bittner. Hydrogels and Biodegradable Polymers for Bioapplications.. J. 2004. Laurencin.. Langer. 2035-2042. 2000. Macromolecules as Drug and as Carriers for Biologically Active Materials. . Bendayan. Y. Jérome. H. Keyer-Uysal. Baek. Bajaj. M. (b) Masotti.. M. S. K. Putman. Microencapsul. S. S. 1996.. Khuller. Goffinet. C. J. N. B.. 10. 2006. 2007. L. J.G. Pharm.. Release 2001. Phillips. 1463-1481. J. Adv. Narasimhan. Vol. Ng. J. Q. M. F. B. J. Nanotechnol. Ting.. Möller. 2010. Davis. V.K.. G. Pharm.. Hrkach. J. X. May. R. 757-762. . Res. Rev. D. 405-22. T. 1990. Y. Briançon.. Y.1007/s11095011-0600-9). Zhang. 889-910. Zhou. Antimicrob. 93-102. Swart. Chung. S. Y. 2011 (DOI 10. Alonso. 99. F. He. Breda. L. Gombotz. S.. J.. Lee. 27832793. 79.. Broxup. Yang Y. Pandit. Pharm. S. S. Lotan.. V. 3. K..50-55... B. 48. Biomed. . W. N. Pharm.J. Brown.. Int. 2009. Sci. Perkin.. 2010. Zhang. Xie. Kim. Ehtezazi. Kunna. Release. 24. R. C. Morris. S. Acta Biomater. R.. J. J. A. Fessi. Heller. Rev. Pettit. R. Italia. Bories. W. 3. J... E. Kant. E. Villemure.. M.. Drug Deliv.. M. C. 1131-1148. G. Kim.

Pharm. Y.. Watanabe. Chowdhury.. Langmuir. T.. I. Y-J. J. Chem. G. C.. J.. Nanobiotechnol. Cheng.. J. (b) Mak.. 429-434. 1999.Szoka. Bang. Baker. 2007. F. 5. Cancer Res. Ono. 2006. Ferry. J. M... M. Nardin. Res. Kwon. A. Annals of Oncology. 2. B. S-Y. Peppas. M. Park. Mol. De Clercq. J. F. C. S. Volodkin. Hagnauer. M. Y. Lvov.. 2007. M.. 2009.. Eur. Y. 2000. 26. Kim. Lee. D. Jr.. H. Y. J. 9.. Prevot. Boddu. Calvo-Calle. (b) Tiourina. Lee. A. R. 1115-1121. D. U. T. Schols. (b) Bay. J. 5605-5608.. S.. Sacci. 918-925. Chen C. 1.. G. V. 147-149.. T. AAPS. A. LoMan. 195-203. A. Nakada.. H. 2012. H. T. Nakhasi... Hoffman. Cancer 2004. Iemma. P. Y. T. Jr. Shinohara. 703-714.. 717-27. M. J. 186. Pannecouque. Raczka. Moya Castro... Shchukin. D-W. Epand. Nanomed. Piehler. Br. 1984. (b) Joshi. Chem.. 1528-1529. Mardel. S. E. 2002. T.... R. Landers. S... P.. I.. 229-256. N. Tomalia.. J.. J.. M. R.. K.... Leclerc. B. H. Heath. N. McShane. D.... Chung.. G. Mitra. R. S. Lee. Jowle.. D.T. M. Redemann.. I. 502-510. B.. Med. 767-776. Klajnert.. A. I. 37083716. S. O. M. V. de Villiers. Evagorou. E. S. Infect Immun. E.. 26. 778-783. 1999. 2412. 459-468.. Commun. 2005. M. Lu. 16. 21. Myc. N. Acad. Lo-Man. Biosci. J. M. D. Puoci. I. H. A. 1. N. 1996. R.. Z. J. D. 2004. Y. Parisi... Du. B. 18-21. 2000. R. J. W. Z. Macromol.. M.. I. V. No. Zhu. Biomacromolecules. (b) Klajnert. K. D.. A. K. B. D. 88. C. Raff.. A... A.... Baker. Farm.... Caruso.. Petrov. G. Kono. Bay.. Albericio. G. Hill. A. M. Liebenberg. K.D. M... 11... 1471-1476. G. Res. Weigold. Y.. A.. T-Y. 2001. Baker.. 49. H. T. M. Picci. K. Pharmacol. Shin. 274-277. UrbanczykLipkowska. Danson. Macromol.. Nice. Z. Commun. 2. Klechkovskaya. 249257.. Int. E. Patri. J. Morita. Jr. 1032-1038. K. 46. 58.. L.. 8. T. Caruso. S-W.. Galecki. U.. B... 269-273 . F. J. O.. Kerr. Ito. H. G. Yokoyama. Lu.. Biotechnol. Cooper. 192-195. Caruso. F. Casolaro... Control.28 Current Drug Delivery. [123] [124] [125] [126a] [127a] [128a] [129a] [152a] [130a] [131] [132] [133] [134] [135] [153] [154a] [155] [156a] [136] [137] [157] [158] [159] [138] [139] [140] Received: ??????????? Revised: ??????????? Accepted: ??????????? . 193-209. D. Yamada. An. 208-217. G.. Janiszewska.. C. Park. Dis. 10. E. Sukhorukov. Rodriguez. 2010. W... K. J. Fang.Myc P. A. Renneberg.. M. K. 89-99. 23. Ueno. Debyser. Colloids Surf... Pharm.. I. Srivastava.. V.. R. R.. Ma. 2006.. 59. 1995. W. Res. R. M. H. Kim D-W. 61. R. Shin. D. 209-214. Hamouda. J... M. Q. R. Biomed. N. Commun. H-K... L. Na. M. Morishita. Okusaka. L. C. M. Sukhorukov.. Mater. A... J. Mulé.. Piehler. L. Zhi. 10.. Control. B.. M. J. S. Hyun. 42. Acad. S. Chem. Kim. N. Xu. 1222-1230. Tang. Ed. Swanson. D. Natl. 2002. Sci. Brown... Möhwald. Z.. Nagai. 652-662. 57. Tomalia. C. 769-775. Navarro... 2004. Heo... J. Chem. Ocul.. M. 2002. Bioconjug. Kenney.. J. L.. 20. S. 1116511169. 2008. Patri. A. G. M.. Gam.. 2006. Park.. R... 19. Int... D. D.. 2009. Bioconjug. Yan. M. Janiszewska. Moreno. J. Angew. 16. H. Y.. G. F. G.. R. Yokohama. T.(Camb). 91. D. Larionova. Caruso. O. Chem. K. Naito. T. Y.... J.. M.. 304. H.. 2007. PharmSciTech.. S-C. Johnson.. I. 2009. 4884-4890. Balogh. S.. Pharm. 2010. J. 327. Kumar. Lee. J. Hamaguchi. Med.. G. X. S.. Liu. Heo. L. Uenaka. Prog. Matsumura. Proc.. 2006. 12. T.. Pharmacol.X. Sakurai.. Kim. Lim. Int. Mater. Chang. Ferreira. I. F.. C. S. Kreft.. 2150-2152. Jr... Y. Antipov.. Kobayashi. 2001. M. Oliveira. M. Baker.. C. Release. A. Chem. J. Z.. Jr... Trau. Kukowska-Latallo. Zanaveskina. Myc.. 1999. S. J. K. S.. Spindler... K. Choi. Muro. A. T.. K.. Ther. A. J-Y. 4 [121] [122a] Lowman. Chem. Mohwald. X. 43. M.. G. De Clercq. D. A. C.. A. D. J.. Langmuir 2010. 1485-1488. M.. K. Kim. Pluymers. H. M.. 24. Funct. Bioorg. J. 2005. Cao. D. G.. G. R. Jr. Z.. L.. Chem. Fikkert. K.. P. R. B. R. Pharm. Shcharbin. Leclerc. Pannecouque. Pharm. Dériaud. B. 708-719. I. Myc. Release. Dickey.. G. Kajita. Rapid Commun.... Alakhov. Br. 59-66.. Curcio. 1997.. Brits. Abeylath. J. Labieniec. I. 2000. 2008. M. D. J. Joung.. 18.. Devarakonda. Bryszewska.. Zhuo.2418. T. A. Vaccine.. Chem. Kataoka. Kataoka. Xu. [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151a] Vilar et al. 18.. J. S.. S. R. Mohwald. Duncan. R.. Y. Y. Vol. Mohwald. 74.. Int. 1999. S. E. 2002. Ikeda. J.. J. 1100-1108. 7. 1999. R. G. Bai. Vichier-Guerre. Nano Lett.. A. 10.. K. R. Biomaterials.. E... Jung. Wiley Interdiscip Rev. Fedutik. K. R. Xu.. Jwala. Y. Williams.-l. J. Sci. M. (Camb). 93. 933-937. Polymer J. 62. 2003. F. Biosci. 2009-2014. V. 145-152. C. Nussenzweig. K.. L.. R.. Malik. Naito.. T. J. Bryszewska.. Med.. Okano. Bielinska. Nakayama. S..... Cantacuzène. Ota.. Boykins.... Macromol. Clin. Städler.. 1989..... Ranson. R.. H.. Kim. 620-625. A. Holan.. J. B. Halbert.U. Mahoros. Cirillo. Y. 7. 16. M. 1310-1316. Shirao. McManus. 3359-3368. Osinaga. 25. R. A. Cancer Res. 2005.. Cantacuzène. 1994. K. Fréchet. Sukhorukov. 90.. Haynie.. Thomas. D. Spizzirri. 2986-2989... Y. Kono. J.C. Hematololy Am Soc Hematol Educ Program. A. A. Z.. Sukhoroukov. Kim. W. Sajurai... 2085-2091. Kim. Adv.. Quintana. Majoros. Urbanczyk-Lipkowska. Engl. 1775-1781.(b) Z.. (b) Ishihara. Becker. Kim. J. Shimada. Langmuir. 1.. Matthews. (b)Wang.. F. Pept. Brampton. Anticancer Drugs. Z. M.. Okano. Trau. 309. E. Baker. J. (b) Yu. Margison.. Turos.. 4897-4902. Cancer Res. J. Antipov. 1.. Ura.. A.. (b) Witvrouw.. 1520-1524. Schols.. M.S. A. Kwon. 1999. Gentle. E. 20. Hosta. Z... R. Tros de Ilarduya. Harada.. A... 625-631. 2007. E. Pharm.. J... I. 1996. A. Infect. Baker.. Qu..A. 10. D. F. Witvrouw. Yukio. 2010. 2007. B. Holan. 2001.. Cancer 2004. T.. V.

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