Nano

2013-10-18
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Nanotechnology in Therapeutics
A Focus on Nanoparticles as a Drug Delivery System
Suwussa Bamrungsap, Zilong Zhao, Tao Chen, Lin Wang, Chunmei Li, Ting Fu, Weihong Tan Nanomedicine. 2012;7(8):1253-1271.
Abstract and Introduction

Abstract
Continuing improvement in the pharmacological and therapeutic properties of drugs is driving the revolution in novel drug delivery systems. In fact, a wide spectrum of therapeutic nanocarriers has been extensively investigated to address this emerging need. Accordingly, this article will review recent developments in the use of nanoparticles as drug delivery systems to treat a wide variety of diseases. Finally, we will introduce challenges and future nanotechnology strategies to overcome limitations in this field.
Introduction
Nanotechnology involves the engineering of functional systems at the molecular scale. Such systems are characterized by unique physical, optical and electronic features that are attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for the prevention, diagnosis and treatment of diseases.[1,2,401] The surge in nanomedicine research during the past few decades is now translating into considerable commercialization efforts around the globe, with many products on the market and a growing number in the pipeline. Currently, nanomedicine is dominated by drug delivery systems, accounting for more than 75% of total sales.[3] Nanomaterials fall into a size range similar to proteins and other macromolecular structures found inside living cells. As such, nanomaterials are poised to take advantage of existing cellular machinery to facilitate the delivery of drugs. Nanoparticles (NPs) containing encapsulated, dispersed, absorbed or conjugated drugs have unique characteristics that can lead to enhanced performance in a variety of dosage forms. When formulated correctly, drug particles are resistant to settling and can have higher saturation solubility, rapid dissolution and enhanced adhesion to biological surfaces, thereby providing rapid onset of therapeutic action and improved bioavailability. In addition, the vast majority of molecules in a nanostructure reside at the particle surface,[4] which maximizes the loading and delivery of cargos, such as therapeutic drugs, proteins and polynucleotides, to targeted cells and tissues. Highly efficient drug delivery, based on nanomaterials, could potentially reduce the drug dose needed to achieve therapeutic benefit, which, in turn, would lower the cost and/or reduce the side effects associated with particular drugs. Furthermore, NP size and surface characteristics can be easily manipulated to achieve both passive and active drug targeting. Site-specific targeting can be achieved by attaching targeting ligands, such as antibodies or aptamers, to the surface of particles, or by using guidance in the form of magnetic NPs. NPs can also control and sustain release of a drug during transport to, or at, the site of localization, altering drug distribution and subsequent clearance of the drug in order to improve therapeutic efficacy and reduce side effects. Nanotechnology could be strategically implemented in new developing drug delivery systems that can expand drug markets. Such a plan would be applied to drugs selected for full-scale development based on their safety and efficacy data, but which fail to reach clinical development because of poor biopharmacological properties, for example, poor solubility or poor permeability across the intestinal epithelium, situations that translate into poor bioavailability and undesirable pharmacokinetic properties.[5] The new drug delivery methods are expected to enable pharmaceutical companies to reformulate existing drugs on the market, thereby extending the lifetime of products and enhancing the performance of drugs by increasing effectiveness, safety and patient adherence, and ultimately reducing healthcare costs.[68] Commercialization of nanotechnology in pharmaceutical and medical science has made great progress. Taking the USA alone as an example, at least 15 new pharmaceuticals approved since 1990 have utilized nanotechnology in their design and drug delivery systems. In each case, both product development and safety data reviews were conducted on a case-by-case basis, using the best available methods and procedures, with an understanding that postmarketing vigilance for safety issues would be ongoing. Some representative examples of therapeutic nanocarriers on the market are briefly described in .
Table 1. Representative examples of nanocarrier-based drugs on the market.
Type of nanostructure
Brand name Active ingredient Rapamune Rapamycin
Indications Immunosuppressive
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Nanocrystalline drugs
Emend Tricor Megace AmBisome Doxil
Aprepitant Fenofibrate Megestrol Amphotericn B Doxorubicin Doxorubicin Cytarabine
Anti-emetic Hypercholesterolemia Anti-anorexia Fungal infections Ovarian cancer, Kaposi's sarcoma and breast cancer Ovarian cancer, Kaposi's sarcoma and breast cancer Lymphomatous meningitis Kaposi's sarcoma Adenosine deaminase enzyme deficiency Acute lymphoblastic leukemia
193 193 193 194 195
Liposomes
Caelyx Depocyt
196 197 198 199 200 201 202
Daunoxome Daunorubicin Adagen Polymerdrug conjugates Onscaspar Pegasys Polymeric micelles Protein (albumin) nanoparticles Lipid colloidal dispersion PEG: Polyethylene glycol. GenexolPM Abraxane Amphotec Adenosine deaminase L-asparaginase
PEGylated IFN--2a Hepatitis C Paclitaxel Paclitaxel Amphotericin B Cancer chemotherapy Metastatic breast cancer Fungal infections
203 204
In this review, we focus mainly on the application of nanotechnology to drug delivery and highlight several areas of opportunity where current and emerging nanotechnologies could enable novel classes of therapeutics. We look at challenges and general trends in pharmaceutical nanotechnology, and we also explore nanotechnology strategies to overcome limitations in drug delivery. However, this article can only serve to provide a glimpse into this rapidly evolving field, both now and what may be expected in the future.
Nanocarriers & Their Applications

Various nanoforms have been attempted as drug delivery systems, varying from biological substances, such as albumin, gelatin and phospholipids for liposomes, to chemical substances, such as various polymers and solid metal-containing NPs (Figure 1). Polymerdrug conjugates, which have high size variation, are normally not considered as NPs. However, since their size can still be controlled within 100 nm, they are also included in these nanodelivery systems. These nanodelivery systems can be designed to have drugs absorbed or conjugated onto the particle surface, encapsulated inside the polymer/lipid or dissolved within the particle matrix. As a consequence, drugs can be protected from a critical environment or their unfavorable biopharmaceutical properties can be masked and replaced with the properties of nanomaterials. In addition, nanocarriers can be accumulated preferentially at tumor, inflammatory and infectious sites by virtue of the enhanced permeability and retention (EPR) effect. The EPR effect involves site-specific characteristics, not associated with normal tissues or organs, thus resulting in increased selective targeting. Based on those properties, nanodrug delivery systems offer many advantages,[911] including:
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Figure 1.
Some nanotechnology-based drug delivery platforms, including a nanocrystal, liposome, polymeric micelle, protein-based nanoparticle, dendrimer, carbon nanotube and polymerdrug conjugate. NP: Nanoparticle. Improving the stability of hydrophobic drugs, rendering them suitable for administration; Improving biodistribution and pharmacokinetics, resulting in improved efficacy; Reducing adverse effects as a consequence of favored accumulation at target sites; Decreasing toxicity by using biocompatible nanomaterials. By adopting nanotechnology, fundamental changes in drug production and delivery are expected to affect approximately half of the worldwide drug production in the next decade, totaling approximately US$380 billion in revenue.[12] Next, several main
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nanocarriers are briefly discussed.

Nanocrystals
One of the most obvious and important nanotechnology tools for product development is the opportunity to convert existing drugs with poor water solubility and dissolution rate into readily water-soluble dispersions by converting them into nanosized drugs.[13,14] In other words, the drug itself may be formulated at a nanoscale such that it can function as its own 'carrier'.[15] Many approaches have been studied, but the most practical strategy involves reducing the drug particle size to nanometer range and stabilizing the drug NP surface with a layer of nonionic surfactants or polymeric macromolecules.[16] By reducing the particle size of the active pharmaceutical ingredient, the drug's surface area is increased considerably, thereby improving its solubility and dissolution and consequently increasing both the maximum plasma concentration and area under the curve. Once the drug is nanosized, it can be formulated into various dosage forms, such as oral, nasal and injectable. These nanocrystal drugs may have advantages over association colloids (micelle solutions) because the level of surfactant per amount of drug can be greatly minimized, using only the amount that is necessary to stabilize the solidfluid interface.[15] Furthermore, recent studies have shown that external agents, such as surfactants, for nanocrystal drug delivery can be eliminated. For example, a method was recently developed for the delivery of a hydrophobic photosensitizing anticancer drug in its pure form using nanocrystals.[17] Synthesized by the reprecipitation method, the resulting drug nanocrystals were stable in aqueous dispersion, without the necessity of any additional stabilizer. These nanocrystals are uniform in size distribution with an average diameter of 110 nm. Such nanocrystals were efficiently taken up by tumor cells in vitro, and irradiation of such cells with visible light (665 nm) resulted in significant cell death. An in vivo study of the nanocrystal drug also showed significant efficacy compared with the conventional surfactant-based delivery system. These results illustrate the potential of pure drug nanocrystals for photodynamic therapy. As shown in , a number of well-known drugs have already been commercialized using the nanocrystal approach.
Brand name Active ingredient Rapamune Rapamycin Aprepitant Fenofibrate Megestrol Amphotericn B Doxorubicin Doxorubicin Cytarabine
Indications Immunosuppressive Anti-emetic Hypercholesterolemia Anti-anorexia Fungal infections Ovarian cancer, Kaposi's sarcoma and breast cancer Ovarian cancer, Kaposi's sarcoma and breast cancer Lymphomatous meningitis Kaposi's sarcoma Adenosine deaminase enzyme deficiency Acute lymphoblastic leukemia
Ref.
193 193 193 193 194 195
Liposomes
Caelyx Depocyt
196 197 198 199 200 201 202
Daunoxome Daunorubicin Adagen Polymerdrug conjugates Onscaspar Pegasys Polymeric micelles Protein (albumin) nanoparticles Lipid colloidal dispersion PEG: Polyethylene glycol.
Organic Nanoplatforms
Adenosine deaminase L-asparaginase
GenexolPM Abraxane Amphotec
203 204
Liposomes Liposomes are self-assembled artificial vesicles developed from amphiphilic phospholipids. These vesicles consist
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of a spherical bilayer structure surrounding an aqueous core domain, and their size can vary from 50 nm to several micrometers. Liposomes have attractive biological properties, including general biocompatibility, biodegradability, isolation of drugs from the surrounding environment and the ability to entrap both hydrophilic and hydrophobic drugs. Through the addition of agents to the lipid membrane, or the alteration of the surface chemistry, liposome properties, such as size, surface charge and functionality, can be easily tuned. Liposomes are the most clinically established nanosystems for drug delivery. Their efficacy has been demonstrated in reducing systemic effects and toxicity, as well as in attenuating drug clearance.[18,19] Modified liposomes at the nanoscale have been shown to have excellent pharmacokinetic profiles for the delivery of DNA, antisense oligonucleotide, siRNA, proteins and chemotherapeutic agents.[20] Examples of marketed liposomal drugs with higher efficacy and lower toxicity than their nonliposomal analogues are listed in . Doxorubicin is an anticancer drug that is widely used for the treatment of various types of tumors. It is a highly toxic compound affecting not only tumor tissue, but also heart and kidney, a fact that limits its therapeutic applications. However, the development of doxorubicin enclosed in liposomes culminated in an approved nanomedical drug delivery system.[21,22] This novel liposomal formulation has resulted in reduced delivery of doxorubicin to the heart and renal system, while elevating the accumulation in tumor tissue[23,24] by the EPR effect. Furthermore, a number of liposomal drugs are currently being investigated, including anticancer agents, such as camptothecin[25] and paclitaxel (PTX), [26] as well as antibiotics, such as vancomycin[27] and amikacin. [28]
Brand name Active ingredient Rapamune Rapamycin Aprepitant Fenofibrate Megestrol Amphotericn B Doxorubicin Doxorubicin Cytarabine
Indications Immunosuppressive Anti-emetic Hypercholesterolemia Anti-anorexia Fungal infections Ovarian cancer, Kaposi's sarcoma and breast cancer Ovarian cancer, Kaposi's sarcoma and breast cancer Lymphomatous meningitis Kaposi's sarcoma Adenosine deaminase enzyme deficiency Acute lymphoblastic leukemia
Ref.
193 193 193 193 194 195
Liposomes
Caelyx Depocyt
196 197 198 199 200 201 202
203 204
Liposomes are also subject to some limitations, including low encapsulation efficiency, fast burst release of drugs, poor storage stability and lack of tunable triggers for drug release.[29] Furthermore, since liposomes cannot usually permeate cells, drugs are released into the extracellular fluid.[30] As such, many efforts have focused on improving their stability and increasing circulation half-life for effective targeting or sustained drug action.[19,31] Surface modification is one method of conferring stability and structural integrity against a harsh bioenvironment after oral or parenteral administration.[32] Surface modification can be achieved by attaching polyethylene glycol (PEG) units, which form a protective layer over the liposome surface (known as stealth liposomes) to slow down liposome recognition, or by attaching other polymers, such as poly(methacrylic acid-cocholesteryl methacrylate)[33] and poly(actylic acid),[34] to improve the circulation time of liposomes in blood. To overcome the fast burst release of the chemotherapeutic drugs from liposomes, drugs such as doxorubicin may be encapsulated in the
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liposomal aqueous phase by an ammonium sulphate gradient.[35] This strategy enables stable drug entrapment with negligible drug leakage during circulation, even after prolonged residence in the blood stream.[36] Further efforts to improve control over the rate of release and drug bioavailability have been made by designing liposomes whose release is environmentally triggered. Accordingly, the drug release from liposome-responsive polymers, or hydrogel, is triggered by a change in pH, temperature, radiofrequency or magnetic field.[37] Liposomes have also been conjugated with active-targeting ligands, such as antibodies [38 40] or folate, for target-specific drug delivery. [41] Polymeric NPs Polymeric NPs are colloidal particles with a size range of 101000 nm, and they can be spherical, branched or coreshell structures. They have been fabricated using biodegradable synthetic polymers, such as polylactidepolyglycolide copolymers, polyacrylates and polycaprolactones, or natural polymers, such as albumin, gelatin, alginate, collagen and chitosan.[42] Various methods, such as solvent evaporation, spontaneous emulsification, solvent diffusion, salting out/emulsification-diffusion, use of supercritical CO2 and polymerization, have been used to prepare the NPs.[43] Advances in polymer science and engineering have resulted in the development of smart polymer (stimuli-sensitive polymer), which can change its physicochemical properties in response to environmental signals. Physical (temperature, ultrasound, light, electricity and mechanical stress), chemical (pH and ionic strength) and biological signals (enzymes and biomolecules) have been used as triggering stimuli. Various monomers having sensitivity to specific stimuli can be tailored to a homopolymer in response to a certain signal or copolymers answering multiple stimuli. The versatility of polymer sources and their easy combination make it possible to tune up polymer sensitivity in response to a given stimulus within a narrow range, leading to more accurate and programmable drug delivery. Polymeric nanocarriers can be categorized based on three drug-incorporation mechanisms. The first includes polymeric carriers that use covalent chemistry for direct drug conjugation (e.g., linear polymers). The second group includes hydrophobic interactions between drugs and nanocarriers (e.g., polymeric micelles from amphiphilic block copolymers). Polymeric nanocarriers in the third group include hydrogels, which offer a water-filled depot for hydrophilic drug encapsulation. PolymerDrug Conjugates (Prodrugs) Many polymerdrug conjugates have been developed since the first combination reported in the 1970s.[44,45] Conjugation of macromolecular polymers to drugs can significantly enhance the blood circulation time of the drugs. Especially, protein or peptide drugs, which can be readily digested inside the human body, can maintain their activity by conjugation of the water-soluble polymer PEG (PEGylation). For example, it was reported that PEGylated Lasparaginase increased its plasma half-life by up to 357 h.[46] Without PEG, the half-life of natural L-asparaginase is only 20 h. In addition to PEGylation of proteins, small molecular anticancer drugs can also be PEGylated to improve their pharmacokinetics for cancer therapy. For instance, PEG-camptothecin (PROTHECAN) has entered clinical trials for cancer therapy.[47] Increasing the otherwise poor solubility of some drugs is another important function of polymerdrug conjugation. Specifically, conjugating water-soluble polymers to functional groups that already exist in the drug structure can significantly enhance the water solubility of the drug. Recently, a new category of polymerdrug conjugates called brush polymerdrug conjugates were prepared by ring-opening metathesis copolymerization.[48] In this report, as PEG was employed as the brush polymer side chains, the conjugates exhibited significant water solubility. However, polymerdrug conjugates require chemical modification of the existing drugs; as a consequence, their production could cost more, and additional purification steps are needed. Moreover, polymers that are chemically conjugated with drugs are often considered new chemical entities owing to a pharmacokinetic profile distinct from that of the parent drugs. As such, additional US FDA approval is required, even though the parent drug has already been approved. Despite the variety of novel drug targets and sophisticated chemistries available, only four drugs (doxorubicin, camptothecin, PTX and platinate) and four polymers (N-[2-hydroxylpropyl]methacrylamide [HPMA] copolymer, poly-L-glutamic acid [PGA], PEG and dextran) have been used to develop polymerdrug conjugates.[4954] In addition to the commercially available polymer drugs listed in , PGA-PTX (Xyotax, CT-2103; Cell Therapeutics Inc./Chugai Pharmaceutical Co. Ltd.),[55] PGA-camptothecin (CT-2106; Cell Therapeutics Inc.)[56] and HPMAdoxorubicin (PK1/FCE28068; Pfizer Inc./Cancer Research Campaign)[57] are now in clinical trials. As an example, PK1 has been evaluated in clinical trials as an anticancer agent, and a Phase I evaluation has been completed in patients with several types of tumors resistant to prior therapy, such as chemotherapy or radiation. However, although the clinical results for HPMAdoxorubicin conjugates look promising, PEG-based conjugation remains the gold-standard in the field of polymeric drug delivery. In addition, polymer drug conjugates are still limited by their nonbiodegradability and the fate of polymers after in vivo administration.[58]
Brand name Active ingredient Rapamune Emend Rapamycin Aprepitant Fenofibrate
Indications Immunosuppressive Anti-emetic Hypercholesterolemia
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Tricor
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Megace AmBisome Doxil Liposomes Caelyx Depocyt
Megestrol Amphotericn B Doxorubicin Doxorubicin Cytarabine
Anti-anorexia Fungal infections Ovarian cancer, Kaposi's sarcoma and breast cancer Ovarian cancer, Kaposi's sarcoma and breast cancer Lymphomatous meningitis Kaposi's sarcoma Adenosine deaminase enzyme deficiency Acute lymphoblastic leukemia
193 194 195
196 197 198 199 200 201 202
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Polymeric Micelles Polymeric micelles are formed when amphiphilic surfactants or polymeric molecules spontaneously associate in aqueous medium to form coreshell structures. The inner core of a micelle, which is hydrophobic, is surrounded by a shell of hydrophilic polymers, such as PEG.[59] Their hydrophobic core serves as a reservoir for poorly water-soluble and amphiphilic drugs; at the same time, their hydrophilic shell stabilizes the core, prolongs circulation time in blood and increases accumulation in tumor tissues.[41] So far, a large variety of drug molecules have been incorporated into polymeric micelles, either by physical encapsulation[60,61] or covalent attachment.[62] Genexol-PM (Samyang, Korea), PEG-poly(D,L-lactide)PTX, employs cremophor-free polymeric micelles loaded with PTX drugs. It was found to have a three-times higher maximum tolerated dose in nude mice and two- to threefold higher levels of biodistribution, compared with those of pristine PTX, in various tissues, including tumors. A Phase I clinical trial has been evaluated in patients, and the results showed that Genexol-PM is superior to conventional PTX for the delivery of higher doses without additional toxicity.[63] Recently, a series of novel dual targeting micellar delivery systems were developed based on the self-assembled hyaluronic acid-octadecyl (HA-C18) copolymer and folic acid-conjugated HA-C18 (FA-HA-C18). PTX was successfully encapsulated by HA-C18 and FA-HA-C18 polymeric micelles, with a high encapsulation efficiency of 97.3%. Since these copolymers are biodegradable, biocompatible and cell-specifically targetable, they become promising nanostructure carriers for hydrophobic anticancer drugs.[64] In addition, stimuli-responsive drug-loaded micelles [6569] and multifunctional polymeric micelles containing imaging as well as therapeutic agents [7072] are now under active investigation with the potential to be the mainstream of the polymeric drug development in the near future. Furthermore, using computer simulation, the experimental preparation of drug-loaded polymeric micelles could be more efficiently guided, by providing insight into the mechanism of mesoscopic structures and serving as a complement to experiments.[73] Hydrogel NPs In recent years, hydrogel NPs have gained considerable attention as one of the most promising nanoparticulate drug delivery systems owing to their unique properties. Hydrogels are cross-linked networks of hydrophilic polymers that can absorb and retain more than 20% of their weight in water, while at the same time, maintaining the distinct 3D structure of the polymer network. Swelling properties, network structure, permeability or mechanical stability of hydrogels can be controlled by external stimuli or physiological parameters.[7478] Hydrogels have been extensively studied for controlled release of therapeutics, stimuli-responsive release and applications in biological implants.[75,7981] However, the hydration response to changes in stimuli in most hydrogel systems is too slow for therapeutic applications. To overcome this limitation, further development of hydrogel structures at the micro- and nano-scale is needed.[82] Recent reports showed some progress in micro- and nanogels of poly-N-isopropylacrylamide with ultrafast responses and attractive rheological properties.[83,84] Ding et al. demonstrated that cisplatin-loaded polyacrylic acid hydrogel NPs could be implanted and plastered on tumor tissue.[85] This hydrogel system exhibited superior efficacy in impeding tumor growth and prolonging lifespan in mice. The in vivo biodistribution assay also demonstrated that the hydrogel implant results in high concentration and retention of the drug. A multifunctional hybrid hydrogel was developed by combining the magnetic properties of NPs and the typical characteristics of the hydrogel. These hybrid hydrogels could be used to load a large number of drugs and transport them to the target site by the application of an external magnetic field.[86] To improve the specificity of the hydrogel drug delivery systems, coreshell
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nanogels were developed, which utilize aptamers as the recognition element and near-infrared light as a triggering stimulus for drug delivery. In this system, gold (Au)silver nanorods, which possess intense absorption bands in the near-infrared range, were coated with DNA cross-linked polymeric shells, so that drugs can be rapidly and controllably released upon the nearinfrared irradiation.[87] As the fate of hydrogel NPs after in vivo administration may be a concern for clinical applications, biodegradable hydrogel NPs with diameters of approximately 200 nm have been synthesized via inverse miniemulsion reversible additionfragmentation chain-transfer polymerization of 2-(dimethylamino)ethyl methacrylate. A disulfide cross-linker was used to cross-link the NPs, so that the polymer network could be degraded to its constituent primary chains by exposure to a reductive environment. It is indicated that these biodegradable hydrogel NPs are currently being investigated for encapsulation and controlled release of siRNA.[88] Although hydrogel NPs-based drugs are not commercially available, they have high possibility to be further developed for drug delivery systems in the future, owing to their highly biocompatible and effective drug-loading properties. Protein-based NPs Hydrophobic drugs, such as taxanes, are highly active and widely used in a variety of solid tumor therapies. Both PTX and docetaxel, which are the commercially available taxanes for clinical treatments, are hydrophobic. Because of their solubility problems, they have been formulated as suspensions with nonionic surfactants, such as Cremophor EL (BASF Corp.) for PTX and Tween-80 (ICI Americas, Inc.) for docetaxel. However, these surfactants are associated with hypersensitivity reaction and toxic side effects to tissues. To decrease toxicity, albumin conjugated with PTX has been formulated, yielding NPs approximately 130 nm in size and approved by the FDA for breast cancer treatment.[8991] In addition to reduced toxicity, albuminPTX has been found to bind with the albumin receptor (gp60) on endothelial cells, with further extravascular transport,[9294] resulting in an increase in drug concentration at tumor sites without hypersensitivity reactions. The albuminPTX complex is approved in 38 countries for the treatment of metastatic breast cancer. Furthermore, Abraxane is currently in various stages of investigation for the treatment of other cancers, such as metastatic breast cancer, non-smallcell lung cancer, malignant melanoma, pancreatic and gastric cancer. Dendrimers Dendrimers are synthetic, branched macromolecules that form a tree-like structure. Unlike most linear polymers, the chemical composition and molecular weight of dendrimers can be precisely controlled; hence, it is relatively easy to predict their biocompatibility and pharmacokinetics.[95] Dendrimers are very uniform with extremely low polydispersities, and they are commonly created with dimensions incrementally grown in approximate nanometer steps from 1 to over 10 nm. Their globular structures and the presence of internal cavities enable drugs to be encapsulated within the macromolecule interior and are used to provide controlled release from the inner core.[96] Although the small size (up to 10 nm) of dendrimers limits extensive drug incorporation, their dendritic nature and branching allows drug loading onto the outside surface of the structure[97] via covalent binding or electrostatic interactions. Dendrimers can be synthesized by either divergent or convergent approaches. In the divergent approach, dendrimers are synthesized from the core and further built to other layers called generations. However, this method provides a low yield because the reactions that occur must be conducted on a single molecule processing a large number of equivalent reaction sites.[98] In addition, a large amount of reagents is required for the latter stages of synthesis, resulting in complication of purification. For the convergent method, synthesis begins at the periphery of the dendrimer molecules and stops at the core. In this approach, each synthesized generation can be subsequently purified.[98] Drug molecules associated with dendrimers can be utilized for cancer treatment,[99] the enhancement of drug solubility and permeability (dendrimerdrug conjugates)[100] and intracellular delivery.[101] Some drugs can be physically encapsulated inside the dendrimer network or form linkages (either covalently or noncovalently) on the dendrimer surface.[102] Furthermore, functionalization of the dendrimer surface with specific ligands can enhance potential targeting. For example, Myc et al. reported a polyamidoamine dendrimer conjugate containing FA as the targeting agent and methotroxate as the therapeutic agent.[103] Cytotoxicity and specificity were tested with both FA receptor-expressing and nonexpressing cells. Both in vitro and in vivo results showed that the dendrimer conjugate was preferentially cytotoxic to the target cells. The polyamido amine dendrimer conjugated with an anti-prostate specific membrane antigen antibody was also demonstrated.[104] The antibody dendrimer conjugate specifically bound to anti-prostate specific membrane antigen-positive, but not negative, cell lines. However, dendrimer toxicity and immunogenicity are the main concerns when they are applied for drug delivery. Since the clinical experience with dendrimers has so far been limited, it is hard to tell whether the dendrimers are intrinsically 'safe' or 'toxic'.
Inorganic Platforms
Au NPs Noble metal NPs, such as Au NPs, have emerged as a promising scaffold for drug and gene delivery in that they provide a useful complement to more traditional delivery vehicles. The combination of inertness and low toxicity,[105] easy synthesis, very large surface area, well-established surface functionalization (generally through thiol linkages) and tunable stability provide Au NPs with unique attributes to enable new delivery strategies. Moreover, excess loading of pharmaceuticals on NPs allows 'drug reservoirs' to accumulate for controlled and sustained release, thereby maintaining the drug level within the therapeutic window. An Au NP with 2-nm core diameter could, in principle, be conjugated with 100 molecules to available ligands (n = 108) in the monolayer.[106] Zubarev et al. have recently succeeded in coupling 70 PTX molecules, a chemotherapeutic drug, to an Au NP with a 2-nm core diameter.[107] Efficient release of these therapeutic agents could be
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triggered by internal (e.g., glutathione[108] or pH[109]) or external (e.g., light[110,111]) stimuli. In addition to serving as the carrier for drug delivery, Au NPs can also be imaged using contrast imaging techniques. Once the Au NPs are targeted to the diseased site, such as a tumor, hyperthermia treatment can be used for tumor destruction. For example, a recent study demonstrated that PEGylated Au NPs were employed for highly efficient drug delivery and in vivo photodynamic therapy of cancer.[112] Compared with conventional photodynamic therapy drug delivery in vivo, PEGylated Au NPs accelerated the silicon phthalocyanine 4 administration by approximately two orders of magnitude without side effects in treated mice. The key issue that needs to be addressed with Au NPs is the engineering of the particle surface for optimized properties, such as bioavailability and nonimmunogenicity. Superparamagnetic NPs Magnetic NPs have been proposed as drug carriers with a push towards clinical trials.[113] The superparamagnetic properties of iron (II) oxide particles can be used to guide microcapsules in place for delivery by external magnetic fields. Another advantage of using magnetic NPs is the ability to heat the particles after internalization, which is known as the hyperthermia effect. For example, Brazel et al. developed a grafted thermosensitive polymeric system by embedding FePt NPs in poly(N-isopropylacrylamide)-based hydrogels, which can be triggered to release the loaded drug by inducing an increase in temperature based on a magnetic thermal heating event.[114] The grafted hydrogel system is also shown to exhibit a desirable positive thermal response with an increased drug diffusion coefficient for temperatures higher than physiological temperature.[115] Besides being utilized for targeting and raising temperature, magnetic NPs can also affect the permeability of microcapsules by applying external oscillating magnetic fields and releasing encapsulated materials.[116] For example, ferromagnetic Aucoated cobalt NPs (3 nm in diameter) were incorporated into the polymer walls of microcapsules. Subsequently, application of external alternating magnetic fields of 100300 Hz and 1200 Oe strength disturbed the capsule wall structures and dramatically increased their permeability to macromolecules. This work supports the hypothesis that magnetic NPs embedded in polyelectrolyte capsules can be used for the controlled release of substances by applying an external magnetic field. The main benefits of superparamagnetic NPs over classical cancer therapies are minimal invasiveness, accessibility of hidden tumors and minimal side effects. Conventional heating of a tissue by, for example, microwaves or laser light results in the destruction of healthy tissue surrounding the tumor. However, targeted paramagnetic particles provide a powerful strategy for localized heating of cancerous cells. Ceramic NPs Ceramic NPs are particles fabricated from inorganic compounds with porous characteristics, such as silica, alumina and titania.[117119] Among these, silica NPs have attracted much research attention as a result of their biocompatibility and ease of synthesis, as well as surface modification.[120122,301] Furthermore, the well-established silane chemistry facilitates the cross-linking of drugs to silica particles.[123,124] For example, recent breakthroughs in mesoporous silica NPs (MSNs) have brought new possibilities to this burgeoning area of research. MSNs contain hundreds of empty channels (mesopores) arranged in a 2D network of a honeycomb-like porous structure. In contrast to the low biocompatibility of other amorphous silica materials, recent studies have shown that MSNs exhibit superior biocompatibility at concentrations adequate for pharmacological applications.[125,126] Once the vehicle is localized in the cytoplasm, it is desirable to have effective control over the release of drug molecules in order to reach pharmacologically effective levels. The ability to selectively functionalize the external particle and/or the interior nanochannel surface of MSNs is advantageous in achieving this goal. [127,128] Different functional groups can be added by using this methodology, including, for example, functionalization with stimuli-responsive tethers that could be further attached to NPs (Au and iron [II] oxide). These NPs could work as gatekeepers and be removed by either intracellular or external triggers, such as changes in pH, reducing environment, enzymatic activity, light, electromagnetic field or ultrasound.[128] The surface of MSNs can be engineered with cell-specific moieties, such as organic molecules, peptides, aptamers and antibodies, to achieve cell type or tissue specificity. Moreover, optical and magnetic contrast agents can be introduced to develop multipurpose drug delivery systems. These strategies demonstrated that the application of target-specific MSN vehicles in vitro is promising; however, the application in vivo has not yet been reported. These particles are not biodegradable; consequently, there is a concern that they may accumulate in the human body and cause harmful effects.[117] For further in vivo applications, the biocompatibility, biodistribution, retention, degradation and clearance of MSNs must be systematically investigated. Carbon-based Nanomaterials Carbon-based nanomaterials have attracted particular interest because they can be surface functionalized for the grafting of nucleic acids, peptides and proteins. Carbon nanotubes (CNTs), fullerene, and nanodiamonds [129] have been extensively studied for drug delivery applications.[130] The size, geometry and surface characteristics of single-wall nanotubes (SWNTs), multiwall nanotubes and C60 fullerenes make them appealing for drug carrier usage. For example, PTX-conjugated SWNTs have shown promise for in vivo cancer treatment. SWNT delivery of PTX affords markedly improved treatment efficacy over clinical Taxol (Bristol-Myers Squibb Co.), as evidenced by its ability to slow down tumor growth at a low PTX dose.[131] However, the primary drawback of carbon-based nanomaterials appears to be their toxicity. Experiments have shown that
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CNTs can lead to cell proliferation inhibition and apoptosis. Although they are less toxic than carbon fibers and NPs, the toxicity of CNTs increases significantly when carbonyl, carboxyl and/or hydroxyl functional groups are present on their surface. [132] Because of the reported toxicity of CNTs, [133137] studies involving their application for drug delivery are still being conducted.[138140] In order to promote the application of CNTs for drug delivery, researchers have functionalized their surface, rendering them benign.[136] Unfortunately, concerns that functionalized CNTs may revert back to a toxic state if the functional group detaches has limited the pursuit of using these modified CNTs for biomedical applications. The toxicity of other forms of nanocarbons has also been reported.[132,140,141] One study of human lung tumor cells showed that carbon NPs are even more toxic than multiwall nanotubes and carbon nanofibers.[132] Given the mounting evidence demonstrating the toxicity of carbon NPs, the enthusiasm to develop carbon NPs for drug delivery has decreased significantly in recent years.
Integrated Nanocomposite Particles
A variety of nanoplatforms have been developed for a wide spectrum of applications, and each of these applications has unique advantages and limitations. By combining the specific function of each material, new hybrid nanocomposite materials can be fabricated. For instance, liposomes and polymeric NPs are the two most widely studied drug delivery platforms, and attempts have been made to combine the advantages of both systems. A recent study reported the use of nanocells consisting of nuclear poly(lactic-co-glycolic acid) NPs within an extranuclear PEGylated phospholipid envelope for temporal targeting of tumor cells and neovasculature.[142] Moreover, liposomes are routinely coated with a hydrophilic polymer, such as PEG or poly(ethylene oxide), to improve the circulation time in vivo, which is another example of a liposomepolymer composite.[143] Similarly, liposomal locked-in dendrimers, the combination of liposomes and dendrimers in one formulation, has resulted in higher drug loading and slower drug release from the composite, as compared with pure liposomes.[144] Another LipoMag formulation, which consists of an oleic acid-coated magnetic nanocrystal core and a cationic lipid shell, was magnetically guided to deliver and silence genes in cells and tumors in mice.[145]
Targeting Strategies
Two basic requirements should be realized in the design of nanocarriers to achieve effective drug delivery (Figure 2). First, drugs should be able to reach the desired tumor sites after administration with minimal loss to their volume and activity in blood circulation. Second, drugs should only kill tumor cells without harmful effects to healthy tissue.[146] These requirements may be enabled using two strategies: passive and active targeting of drugs.[147]
Figure 2.
Passive and active targeting.

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By the enhanced permeability and retention effect, nanoparticles (NPs) can be passively extravasated through leaky vascularization, allowing their accumulation at the tumor region (A). In this case, drugs may be released in the extracellular matrix and then diffuse through the tissue. Active targeting (B) can enhance the therapeutic efficacy of drugs by the increased accumulation and cellular uptake of NPs through receptor-mediated endocytosis. NPs can be engineered to incorporate ligands that bind to endothelial cell surface receptors. In this case, the enhanced permeability and retention effect does not pertain, and the presence of leaky vasculature is not required.
Passive Targeting
Passive targeting takes advantage of the unique pathophysiological characteristics of tumor vessels, enabling nanodrugs to accumulate in tumor tissues. Typically, tumor vessels are highly disorganized and dilated with a high number of pores, resulting in enlarged gap junctions between endothelial cells and compromised lymphatic drainage. The 'leaky' vascularization, which refers to the EPR effect, allows migration of macromolecules up to 400 nm in diameter into the surrounding tumor region.[147149] One of the earliest nanoscale technologies for passive targeting of drugs was based on the use of liposomes. More advanced liposomes are coated with a synthetic polymer that protects the agents from immune destruction.[150] Moreover, the EPR effect, the microenvironment surrounding tumor tissue, is different from that of healthy cells, a physiological phenomenon that also supports passive targeting. Based on the high metabolic rate of fast-growing tumor cells, they require more oxygen and nutrients. Consequently, glycolysis is stimulated to obtain extra energy, resulting in an acidic environment. [151] Taking advantage of this, pH-sensitive liposomes have been designed to be stable at physiological pH 7.4, but degraded to release drug molecules at the acidic pH.[152] Although passive targeting approaches form the basis of clinical therapy, they suffer from several limitations. Ubiquitously targeting cells within a tumor is not always feasible because some drugs cannot diffuse efficiently, and the random nature of the approach makes it difficult to control the process. The passive strategy is further limited because certain tumors do not exhibit an EPR effect, and the permeability of vessels may not be the same throughout a single tumor.[153]
Active Targeting
One way to overcome the limitations of passive targeting is to attach affinity ligands (antibodies,[154] peptides,[155] aptamers [156] or small molecules [157] that only bind to specific receptors on the cell surface) to the surface of the nanocarriers by a variety of conjugation chemistries. Nanocarriers will recognize and bind to target cells through ligandreceptor interactions by the expression of receptors or epitopes on the cell surface. In order to achieve high specificity, those receptors should be highly expressed on tumor cells, but not on normal cells. Furthermore, the receptors should homogeneously express and should not be shed into the blood circulation. Internalization of targeting conjugates can also occur by receptor-mediated endocytosis after binding to target cells, facilitating drug release inside the cells. Based on the receptor-mediated endocytosis mechanism, targeting conjugates bind with their receptors first, followed by plasma membrane enclosure around the ligand receptor complex to form an endosome. The newly formed endosome is transferred to specific organelles, and drugs could be released by acidic pH or enzymes. Although the active targeting strategy looks intriguing, nanodrugs currently approved for clinical use are relatively simple and generally lack active targeting or triggered drug release components. Moreover, nanodrugs currently under clinical development lack specific targeting. To fully explore the application of targeted drug delivery, we need to investigate whether the specific diseases are the correct application for targeting, whether the properties of the therapeutic drugs, as well as their site and mode of action, are suited for targeting and whether the delivery vehicles are optimal for product development.[158]
Key Factors Impacting Drug Delivery

In order to achieve effective drug delivery, nanocarriers must have suitable circulation time to prevent the elimination of drugs before reaching their target. Based on previous investigations, size, shape and surface characteristics are key factors that impact the efficiency of drug delivery systems.
Size & Shape
Particle size plays a key role in particle functions, such as degradation, vascular dynamics, targeting, clearance and uptake mechanisms.[159] Particles have been shown to have different velocities, diffusion characteristics and adhesion properties, depending on their size,[160] resulting in different uptake efficiencies.[161164] The size of nanodrugs should be large enough to prevent rapid leakage in blood capillaries, but, at the same time, small enough to escape the capture of macrophages in the reticuloendothelial system, such as the liver and spleen. Some of the main outcomes reported in these studies are that the size limits for internalization of NPs through endocytosis are clearly cell dependent; particles less than 200 nm in size will mainly follow endocytic pathways; particles above this size can be either engulfed through endocytosis or not internalized at all and microsized particles have to be internalized by phagocytic pathways.[165] Interestingly, in the case of spherical Au NPs, it was found that the maximum uptake occurred with Au NPs 50 nm in diameter.[166,167] Coincidently, in a separate study, it
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was reported that a diameter of 50 nm is the optimal size to achieve the most efficient endocytosis of MNSs.[168] Apart from size, recent studies have shown that the shape of particles can also have an intriguing effect on particle functions, especially in biological processes, including internalization, transport through the blood vessels and targeting diseased sites. [169171] Varying toxicities of materials having identical chemical composition (silica), but different shape (nanowire vs NP), was also reported.[172] Recent advances with particular focus on the importance of particle shape, as well as the challenges yet to be overcome, are reviewed elsewhere.[173]
Surface Characteristics
Besides size and shape, surface characteristics of NPs can also determine their lifespan during circulation in the blood stream. One of the major breakthroughs in this area was the finding that particles coated with hydrophilic polymer molecules, such as PEG, can resist serum protein adsorption, prolonging the systemic circulation of the particle.[174] Since then, numerous variations of PEG and other hydrophilic polymers have been tested for improved circulation.[175] The surface charge on the particle also affects other functions, such as internalization by macrophages. Positively charged particles have been shown to exhibit higher internalization by macrophages and dendritic cells compared with neutral or negatively charged particles,[176] although surface charge effect could also be cell-type dependent.[177] The effects of particle size and surface chemistry on particle function have been reviewed elsewhere.[174,175,178]
Challenges of Nanotechnology for Drug Delivery

Although progress in the application of nanotechnology to drug delivery has been dramatic and successful, as evidenced by some nanodrugs now on the market, several main challenges remain in this field (Figure 3).
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Figure 3.
Remaining challenges in the field of nanomedicine.

Biological Understanding
In order for bionanotechnologies to progress toward human applications, a better understanding of the mechanisms underlying intracellular uptake, trafficking and the fate of nanomaterials in complex biological networks is needed. Current delivery systems suffer from some major hindrances (e.g., rapid clearance by the immune system, low targeting efficiency and difficulty in crossing biological barriers).[179] In view of these obstacles, a full understanding of the basic science of NP transport will result in achieving the ability to control and manipulate drug delivery.
Safety Concern
Paralleling the development of nanomedicine, a field known as nanotoxicology has also emerged. Nanotoxicology refers to the study of the potential negative impact of the interactions between nanomaterials and biological systems.[180] Some preliminary nanotoxicity investigations have led to the speculation that nanomaterials may contribute to the formation of free radicals,[181] damage of brain cells [182] and undesirable penetration through the epidermis or other physiological barriers into areas of the body that are more susceptible to toxic effects.[183] Several mechanisms have been proposed to affect the toxicity of nanomaterials, depending on multiple factors derived from physiochemical properties, physical characteristics and environmental conditions. For example, naked quantum dots show cytotoxicity by induction of reactive oxygen species,
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resulting in damage to the nucleus, mitochondria and plasma membranes.[184] Also, cadmium (Cd)-containing quantum dots have been reported to be toxic by the release of free Cd2+ ions.[185] However, their toxicity was reduced after surface modification, such as attaching N-acetylcystein.[186] Au solution has not been considered to present a hazard, and Au NPs have been taken up by cells without cytotoxic effects. By contrast, Au nanorod cytotoxicity could be attributed to the presence of the stabilizer cetyltrimethylammonium bromide.[187] For silica NPs, only concentrations above 0.1 mg/ml were found to be toxic, as shown in a reduction of cell availability and proliferation.[188] CNTs also cause reactive oxygen species generation, mytochondria dysfunction, lipid peroxidation and changes in cell morphology,[189] while graphite and fullerene produce no significant adverse effects.[190] In addition, it was reported that most cationic NPs can cause hemolysis and blood clotting, while neutral and anionic NPs are quite nontoxic.[191] NPs can be inhaled, ingested or absorbed through the skin, and they can penetrate cells, even into the cell nucleus, where, if sufficiently small, they can come into close contact with genetic material. Thus, nanomaterial toxicity should be considered relative to the patient population, as well as the entire manufacturing and disposal processes. Based on safety concerns, the establishment of standards or reference materials and consensus testing protocols that can provide benchmarks for the development of novel classes of materials are needed.
Manufacturing Issue
Another challenge facing nanodrug delivery is the large-scale production of nanomaterials in terms of scaling up laboratory or pilot technologies for consistent and reproducible production and commercialization. A number of nanodrug delivery technologies may not be compatible with large-scale production owing to the nature of the preparation method and high cost of materials employed. The challenges of scaling up include a low concentration of nanomaterials, agglomeration and the chemistry process. It is much easier to modify or maintain the size or composition of nanomaterials at the laboratory scale for improved performance than at a large scale. The biomedical community should rethink the level of control needed when working with nanomaterials. Rather than requiring perfect control of the physical dimensions of nanomaterials, a statistical approach may be adopted in order to establish a metric for classifying nanomaterials by material type, average size, aspect ratio and standard deviation. This would fit well with the formation of a toxicology database, since it is unrealistic to establish the toxicology of every size or aspect ratio of a nanomaterial.
Economic & Financial Barriers
Economic and financial barriers can also stand in the way of implementing nanomedicine. The limited availability of reimbursement by public and private health insurers for relatively expensive new diagnostic tests has emerged as a major impediment to the deployment of personalized medicine in general, and nanoproducts are likely to encounter even greater hurdles because of their costs and complexity.[192] Despite the number of patents for nanodrug delivery technologies, commercialization is still in its early stage. Because of the high development costs of nanodrugs and medical devices, startup companies have little chance of bringing products to the market without support from 'Big Pharma', which is able to provide the financial resources and expertise needed to achieve regulatory and commercial success.
Future Perspective
The marriage of nanotechnology and medicine has yielded an offspring that is set to bring momentous advances in the fight against a range of diseases. Nanomedicine is actually a child well past its infancy, with two families of therapeutic nanocarriers liposomes and albumin NPs already firmly in clinical practice worldwide, and still more in the preclinical phases of development. In order to transform nanotechnologies from basic research into clinical products, it is important to understand how the biodistribution of NPs, which is primarily governed by their ability to negotiate biological barriers, affects the body's complex biological network, as well as mass transport across compartmental boundaries in the body. Moreover, the healthy growth of this field depends on establishing a toxicology database to support safety determinations and risk assessments. The database should include toxicity as a function of material, size, shape, cell type or animal, duration of exposure and the methods used to assay toxicity. In addition, the ability to scale up the production of drug particles is required. The manufacturing complexity of nanodrug delivery may be an obstacle confronting generic drug companies. Lastly, storage and handling protocols must be considered. With such a database, the translation of biomedical nanotechnology from the laboratory to the general public will be significantly accelerated. Realizing such a goal requires harmonized efforts among scientists in various disciplines, including medicine, materials science, engineering, physics and biotechnology. Better cross training would produce better proposals with a greater likelihood of success. Experts from different disciplines need to work together to translate novel laboratory innovation into commercially viable medical products. In addition, continuous cooperation between federal agencies and the pharmaceutical industry is necessary.
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The ultimate goal of nanodrug delivery systems is to develop clinically useful formulations for treating diseases. As nanomedical applications for personalized medicine become more advanced and multifunctional, they may increasingly challenge, and perhaps eventually invalidate, traditional regulatory categories and criteria. Therefore, it will be critical for regulatory systems to provide oversight and well-defined evaluation pathways for nanomedicine products, while remaining adaptive to rapidly emerging nanomedical technologies and products.
Summary
Nanotechnology is an emerging field with the potential to revolutionize drug delivery. Advances in this area have allowed some nanomedicines in the market to achieve desirable pharmacokinetic properties, reduce toxicity and improve patient compliance, as well as clinical outcomes. Integration of nanoparticulate drug delivery technologies in preformulation work not only accelerates the development of new therapeutic moieties, but also helps in the reduction of attrition of new molecular entities caused by undesirable biopharmaceutical and pharmacokinetic properties. Optimizing the integration of nanomaterials into drug delivery systems will require standardized metrics for their classification, as well as protocols for their handling. This will, in turn, result in a better understanding of the interactions of nanomaterials with biological systems, which will facilitate better engineering of their properties specific to biomedical applications. The development of such drug carriers will require a greater understanding of both the surface chemistry of nanomaterials and the interaction chemistry of these nanomaterials with biological systems. This can only be achieved through collaborative efforts among scientists in different disciplines. Those who work in this emerging field should have up-to-date information on related toxicology issues, potential health and safety risks and the regulatory environment that will impact patient use. Understanding both the benefits and the risks of these new nanotechnology applications will be essential to good decision-making for drug developers, regulators and ultimately the consumers and patients who will be the beneficiaries of new drug delivery technologies.
Sidebar
Executive Summary
The emergence of nanotechnology is revolutionizing drug delivery with considerable commercialization efforts around the world. A multitude of nanoforms have been attempted as drug delivery systems with the ultimate goal of synthesizing a multifunctional vehicle optimized to perform desired tasks in a defined order. Several challenges remain in the field of nanodrug delivery. Addressing the challenges of nanomedicine with harmonized efforts among scientists in different disciplines will accelerate the commercialization of this field.
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Abstract and Introduction

Brand name Active ingredient Rapamune Rapamycin

Emend Tricor Megace AmBisome Doxil

Aprepitant Fenofibrate Megestrol Amphotericn B Doxorubicin Doxorubicin Cytarabine

193 193 193 194 195

196 197 198 199 200 201 202

Nanocarriers & Their Applications

nanocarriers are briefly discussed.

Emend Tricor Megace AmBisome Doxil

196 197 198 199 200 201 202

Adenosine deaminase L-asparaginase

GenexolPM Abraxane Amphotec

Emend Tricor Megace AmBisome Doxil

196 197 198 199 200 201 202

Brand name Active ingredient Rapamune Emend Rapamycin Aprepitant Fenofibrate

Indications Immunosuppressive Anti-emetic Hypercholesterolemia

Megace AmBisome Doxil Liposomes Caelyx Depocyt

Megestrol Amphotericn B Doxorubicin Doxorubicin Cytarabine

193 194 195

196 197 198 199 200 201 202

Passive and active targeting.

Key Factors Impacting Drug Delivery

Challenges of Nanotechnology for Drug Delivery

Remaining challenges in the field of nanomedicine.

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