Artificial Cells, Nanomedicine, and Biotechnology, 2014; Early Online: 1–11

Copyright © 2014 Informa Healthcare USA, Inc.
ISSN: 2169-1401 print / 2169-141X online
DOI: 10.3109/21691401.2014.953633

Application of liposomes in medicine and drug delivery
Hadis Daraee2, Ali Etemadi2, Mohammad Kouhi5, Samira Alimirzalu4 & Abolfazl Akbarzadeh1,3
1Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, 2Department of Medical Biotechnology,
Artificial Cells, Nanomedicine, and Biotechnology Downloaded from by University of Texas at Austin on 09/29/14

Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran, 3Department of Medical
Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran, 4Laboratory of
Polymer, Faculty of Chemistry, Payame Noor University, Tabriz, Iran, and 5Department of Physics, College of Science,
Tabriz Branch, Islamic Azad University, Tabriz, Iran

Abstract (a bilayer). In the presence of water, the heads are attracted
Liposomes provide an established basis for the sustainable to water and line up to form a surface facing the water. The
development of different commercial products for treatment of tails are repelled by water, and line up to form a surface
medical diseases by the smart delivery of drugs. The industrial away from the water. In a cell, one layer of heads faces the
applications include the use of liposomes as drug delivery outside of the cell, attracted to the water in the environment.
vehicles in medicine, adjuvants in vaccination, signal enhancers/ Another layer of heads faces the inside of the cell, attracted
carriers in medical diagnostics and analytical biochemistry, by the water inside the cell. In the case of one bilayer encap-
solubilizers for various ingredients as well as support matrices sulating the aqueous core, one speaks either of small or large
for various ingredients and penetration enhancers in cosmetics. unilamellar vesicles, while in the case of many concentric
For personal use only.

In this review, we summarize the main applications and bilayers, one defines large multilamellar vesicles (Papahad-
liposome-based commercial products that are currently used in jopoulos 1978). The bilayer structures are called liposomes
the medical field. and the monolayer structures are called micelles. Liposomes
are used for drug delivery due to their unique properties.
Keywords: commercial products, liposome, medical field,
In fact, they can contain a wide variety of hydrophilic and
smart delivery
hydrophobic diagnostic or therapeutic agents, providing a
larger drug payload per particle and protecting the encap-
sulated agents from metabolic processes. One of the major
drawbacks of conventional liposomes has been their rapid
The name liposome is derived from two Greek words: ‘Lipos’ clearance from the blood, due to the adsorption of plasma
meaning fat and ‘Soma’ meaning body. A liposome can be proteins in their “second generation form”, which are called
formed in a variety of sizes with unilamellar or multilamellar sterically stabilized liposomes. They have been proved to
construction, and its name relates to its structural building have favorable in vivo pharmacokinetic properties due to
blocks – the phospholipids, and not to its size. Liposomes a surface coating of a hydrophilic carbohydrate or polymer,
were first described by the British hematologist Dr. Alec D usually a lipid derivative of polyethylene glycol (PEG), mak-
Bangham in 1964 (Published 1964), at the Babraham Insti- ing them attractive vehicles for anticancer drug delivery.
tute in Cambridge. They were discovered when Bangham and Also, the composition of the lipid bilayer can be modulated
R. W. Horne were testing the institute’s new electron to obtain other desirable properties, including a prolonged
microscope by adding negative stain to dry phospholipids circulatory half- life (stealth liposomes), the ability to form
(Kumar et  al. 2010, Bangham 1993). A liposome is a tiny a complex with nucleic acids to mediate gene delivery or
bubble (vesicle), made out of the same material as a cell genetic regulation, and the capacity to deliver encapsulated
membrane. Liposomes can be filled with drugs, and used contents to the cytosol through the endosomal/ lysosomal
to deliver drugs for cancer and other diseases. Membranes pathway (Bangham 1993). Liposomes exhibit several prop-
are usually made of phospholipids, which are molecules erties which may be useful in various applications. Sev-
that have a head group and a tail group. The head is attracted eral practical applications, most notably in drug delivery,
to water, and the tail, which is made of a long hydrocar- emerged in the 1970s (Bangham 1993). Liposomes were
bon chain, is repelled by water. In nature, phospholipids first described in 1965 as a model of cellular membranes
are found in stable membranes composed of two layers and quickly were applied to the delivery of substances to

Correspondence: Abolfazl Akbarzadeh and Samira Alimirzalu, Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Tel/Fax:  984113341933. E-mail:; Mohammad Kouhi, Department of Physics, College of Science, Tabriz Branch, Islamic
Azad University, Tabriz, Iran.
(Received 31 July 2014; revised 7 August 2014; accepted 7 August 2014)


The glycerols. when the liposome and target cell approach each 5. accumulate in the phagocytes. which know them as strange added materials into a target cell. within a van der Waals radius. Particles of phosphatidylcholine are not recognition mechanism. Phosphatidyl ethanolamine (cephalin) – PE are administered to the body. diameter that serve as convenient delivery vehicles for biochemistry. ‘Targeting’ must be classified into two biological coverings. and two sorts of phospholipids exist categories based on the difference in mechanism in vivo . Phosphatidyl Glycerol (PG) other with a very short distance between them. high solubility of cholesterol in the phospholipid liposome Following such binding (irrespective of whether it is specific has been attributed to both hydrophobic and definite head or nonspecific). they are a very useful model. with a bulk (PC) molecule. and nucleotides are encap. are the most commonly used component of nism is ‘active targeting’ which is attained by a molecular liposome formulation and represent greater than 50% of the recognition mechanism. or Phospholipids other cell specific ligands). in which the targeting (recognition soluble in water and in aqueous media. Phosphatidyl choline (Lecithin) – PC cytoplasmic membrane of the target cell. Topical application of of both conventional and stealth liposomes is their natural liposomes has large possibilities in dermatology and in the Artificial Cells. the fluidity the long hydrocarbon fatty series. Another interesting property biologically active compounds.e. Today. such as chemical modification of liposomal mem- For personal use only. chemistry. In order to achieve direct. This is arrangement of cholesterol in the bilayer. a deeper understanding of attackers. they align them- of a specific cell or tissue) is attained by altering the bulk selves closely in planar bilayer sheets in order to minimize structural characteristics of the carrier such as its hydro. antigens (antibodies). Cholesterol positions Nonspecific adsorption is simply an electrostatic and/or a itself in the membrane with its hydroxyl group oriented hydrophobic interaction between the two. through tives of phosphatidic acid. relative to free drugs. The after administration. Phosphatidyl inositol (PI) ever. Another mecha. branes by a cell-specific device (antibodies. and/or the size of the carrier. the localization delivery of anticancer agents in order to reduce the toxic of anticancer drugs to solid tumors.. colloid science. When liposomes 2. Examples of phospholipids are: direct and specific interaction between a specific recogni- tion site on the liposomal surface and a receptor on the 1. For this purpose. an active targeting mechanism Cholesterol becomes dominant. The action between the two surfaces of the cell and the liposome. phospholipids. few of the upcoming applications of liposomes. and Biotechnology Downloaded from informahealthcare. Liposomes have acid fragments such as antibodies or proteins or appropri- been considered to be excellent models of cell membranes ate fragments that target specific receptor sites. Phospholipids are the major structural component of have been proposed. liposomes very high concentrations of up to 1:1 or even 2:1 molar ratio nonspecifically or specifically adhere to the cell surface. saccharides. Liposomes enzymes. Liposomes normal ones is the basis for the increased tumor specificity might be used to target precise cells by attaching amino of liposomal drugs. proteins (peptides). various method. the unfavorable action between the bulk aqueous phase and phobicity or hydrophilicity. Poznansky and Juliano 1984). biophysics. 2  H. accompanied by the intracellular distribution of are positively charged liposomes which interact with the liposomal components to cytosol. active targeting is more Cholesterol does not form a bilayer construction by itself. There are a number of structural and nonstruc- the mechanisms for interaction between the intact cell and tural components of liposomes. of cholesterol to phosphatidylcholine. DNA vac- and have been employed as potent drug carriers in which cination and improved efficiency of gene therapy are just a various materials such as drugs. are especially effective in treating diseases that affect the sulated (Bangham 1993). These are deriva- is attained by recognition at the molecular level. phagosome or aci- liposomes or pH-sensitive liposomes. by ‘passive’ targeting. primary tissue distribution 3.PHOSPHODIGLYCERIDES AND SPHINGOLIPIDS. How. the liposome is internalized into the cell group interaction. or to increase the mulation of liposomal drugs in tumor tissues relative to circulation time and effectiveness of the drugs. Nanomedicine. parallel to the acyl chains in the center of the bilayer. 4. by University of Texas at Austin on 09/29/14 ability to increase. This differential accu. but there is no clear indication for the by the mechanism of endocytosis (or phagocytosis). toxins. while specific towards the aqueous surface and the aliphatic chain aligned adsorption is a receptor-ligand or an antigen-antibody inter. eminent and promising than passive targeting. Daraee et al. and biology. In this mechanism. The main structural parts the liposome is required. One is ‘passive targeting’ (Machy and most common phospholipid is the phosphatidylcholine Leserman 1987. of liposomes are: ologies. Cationic liposomes dosome). including or softness. effective phagocytes of the immune system because they tend to and selective delivery of the liposome itself or liposome. i. or boundary lipids. Phosphatidyl serine (PS) depends mostly on a passive targeting mechanism. . cells. effects of the drugs when given alone. reagent and tool in Structural components of liposome various scientific disciplines. the charge density. fusogens. the targeting weight of lipid in biological membranes. Liposomes entrap DNA by one of two mechanisms followed by the enzymatic digestion of the liposome in the which have resulted in their classification as either cationic intracellular compartment (endosome. but is able to be included into phospholipid membranes in At the first stage of liposome-cell interaction. negatively charged DNA molecules to form a stable complex (Bangham 1993). including mathematics and Liposomes are globular lipid bilayers of 50–1000 nm in theoretical physics.

The optimistic goals of antibody-sensitized liposomes liposomes or as a lipid helper in cationic liposomes (Wang (immune liposomes as ‘guided missiles’). were extended. The maximum circulation times were achieved Generally. It seems that the median molecular mass. changes ahead of acidification (Litzinger and Huang 1992). 1995). It was recently exposed that the factants have been examined by cryo transmission electron Alexander-de-Gennes model of polymers at interfaces microscopy (TEM). Long circulating liposomes the potentiation of the immune response by acting as an immunological adjuvant. this is a simple procedure requiring the mixing of when using polyethylene glycol covalently bound to the cationic lipids with the DNA and adding them to the cells. efficient lipid for in vitro gene transfection for pH‐sensitive 1984). pH‐insensitive liposomes and their content Long circulating liposomes are delivered to lysosomes and stained. low toxicity. Immune liposomes Another possible function of liposomes in medicine is 5. It of DNA and cationic lipids. It is adhesion and adsorption (or at least adsorption with a presumed that complex formation simply results from ionic conformational change) of blood components such as interactions between the positively charged head group of immunoglobulins. endosomes option in immunoassays and diagnostic tests. but the first considerable improvements pH‐sensitive liposomes were designed based on the were achieved by the incorporation of ganglioside GM1 concept of viruses that fuse with the endosomal membrane. cationic lipids connected with DOPE stabilization is schematically well documented although and with various amounts of three different cationic sur. 1984. tion is capable of being changed. complement components. The best results were obtained by substitut- ing these two lipids with synthetic polymer enclosing Cationic liposomes lipids. fibronectin DOTMA and the negatively charged phosphate groups of and similar molecules which spot strange particles for DNA. complementary proteins. liposomes are internal. antibody production (Alving 1991). 1986). which has often and Huang 1987). in clusters of aggregated multilamellar structures. but predominantly lation in particular cell compartments such as lysosomes. For gene transport. 1990). 2006). pH‐sensitive liposomes have the intrahepatic uptake itself. low antigenicity and their potential to target specific cells in vivo. 1. Cationic liposomes Immune liposomes 4. proteins. Considering a number of addi- After fastening to the cell surface. such as injection in ized into endosomes where they encounter a more acidic different body cavities. 2-distearoryl-sn-glycero. The reconstitution of antigens into Conventional liposomes liposomal membranes or their incorporation into the inte- The conventional liposome-based mechanism is the first rior water core of the liposome would cause the enhance- Artificial Cells. pH sensitive liposomes 3. (Allen and Chonn 1987. not well understood. leoylphosphatidylethanolamine (DOPE) is by far the most (Engelhard et  al. tions (Immordino et  al. tional potential targeting applications. Steele et  al. Conventional. Blood circulation times been proposed. immune liposomes present a viable pH than in the external intermediate. In an effort to determine the physicochemical proper.50 (Mellman et  al. Gabizon and Papahadjopou- ing the lysosomes (Chu et al. In inside the mononuclear phagocytic system including order to avert this deprivation. and Biotechnology Downloaded from informahealthcare. The cationic lipid DOTMA was was suggested that the presence of a steric barrier reduces first synthesized and described by Feigner et al. ability. since the origin of steric ties of the composite. phospholipid. It has been assumed that the function given very encouraging results in in vitro studies – which of phosphatidylethanolamine (PE) is that of a membrane are in general performed in the absence of immunoglobu- synthesis advocate. The differ- the entrapment of the DNA molecules between the lamellae ent types of liposomes are abbreviated below. This results in the configuration of collectives composed between 1500 to 5000 Da is the optimal (Lasic 1994). sphingomyelin. in in vivo applications. Nanomedicine. effective induction of mulations are mainly comprised of natural phospholipids cytotoxic cell (Raphael and Tom 1984) and subsequent or lipids such as 1. because in reality this lipid undergoes lins. Conventional liposome by University of Texas at Austin on 09/29/14 creation of liposomes to be used in pharmaceutical applica. The advantages of lipo- choline (DSPC). The last condition for The experimental results show that liposomal disposi- plasmid liposomes after cell penetration is to avoid accumu. Indeed. Gregoriadis et  al. The results of the cryo TEM analysis (De Gennes 1987) can qualitatively explain the stability of suggest that an excess of lipids in terms of charge leads to liposomes in biological systems (Lasic 1994). following macrophage uptake. (1987).3-phosphatidyl antitumor activity (LeGrue 1984). normally have an inner pH of 6. . The option nism of intracellular delivery into five types as: of surfactant use does not seem to influence the morphology of the DNA‐lipid‐complexes (Gustafsson et al. Application of liposomes in medicine and drug delivery  3 Liposomes can be classified in terms of work and mecha. and macrophages – failed For personal use only. los 1988). or phosphatidylinositol at 5–10 mol% into the bilayer delivering their genetic material to the cytosol before reach. (gangliosides). Conventional liposomes 2. ment of immune response such as macrophage activation. multiple data indicate pH-sensitive liposomes that liposomes are excellent adjuvants for the enhancement Liposomes of various compositions can extensively bind of immunogenicity to a given antigen involving glycolipids to cell shells. antigens to pathogenic viruses etc. egg phosphatidylcholine somes as immunological adjuvants are their biodegrad- and monosialoganglioside. it was recognized that dio. Usually. 1987.

aerosol. Leakage and fusion of encapsulated drug / molecules. possibly as removed from the circulation by the macrophages which are big as a chromosome. In some cases. Fusion with cell membranes is much liposomal preparation can be discerned: rarer. such as heart. Production cost is high. In vitro and in vivo studies of their interactions 2. ticulate drug carriers only to targeting of the very same cells of 2. Liposomes can be targeted to specific cells or tissues. substances. larger objects cause thrombus 5. Semisynthetic phospholipids in vivo. Phospholipids with non-natural head groups formation and their surface is eventually passivated by coat- ing with bio macromolecules. Low solubility. The body protects itself with a complex defense sys- Artificial Cells. 4. such as creams and 5. Modified natural phospholipids These interactions also determine the fate of liposomes 3. (ii) Inactive objective to the cells of the immune system: Instances are antimonials. while minor particles. Short half-life. and increase the efficacy of the treatment. arabi- liposomes in pharmacology and medicine can be divided nose. liver and bone marrow. Daraee et al. interfaces. liposomes. and of the mechanism of kidneys. and their utilization (iv) Site-avoidance mechanism: as a form. compared to free drug particles. Liposome encapsulation can alter the spatial and temporal distribution of the encapsulated drug molecules in the body. narrowed the spectrum of applications of micro par- positively charged molecules. or reagent in the fundamental studies of cell Liposomes do not dispose in certain organs. on the other 1. and also vaccines. gels. They are quickly 3. The benefits of drug-loaded hydrolysis-like reactions. Fully synthetic phospholipids tem. (i) Enhanced solubility of amphiphilic and lipophilic drugs: Properties of liposomes Furthermore. The benefits and limitations of cardio-. be used to improve the therapeutic effectiveness of the 3. inside the liposome with appropriate substances encapsu- •• Positively charged membranes are impermeable to lated (Lasic et al. into therapeutic and diagnostic applications of liposomes containing drugs or a variety of elements. biological proteins or peptides such as vasopressin. (iii) Maintained free system of systemically or locally which may significantly reduce unwanted toxic side effects administered liposomes. or in (semi) solid structures. liposomes are no exception. Fewer stables. recognition procedures. encapsulated in the liposomal interior at concentrations several fold above their aqueous solubility. and nervous system and this decreases action of certain materials. LUV (Large unilamellar vesicles) liposomes with cells is either simple adsorption or subse- Five groups of phospholipids that can be used for the quent endocytosis. MLV (Multilamellar vesicles) istration. 1992). SUV (Small unilamellar vesicles) with cells have shown that the predominant interaction of 3. immune modulators or (immune) by University of Texas at Austin on 09/29/14 4. There are three types of liposomes: liposomal drug carriers critically depend on the interaction of liposomes with cells and their fate in vivo after admin- 1. Liposomes offer a degree of protection to the DNA the immune system. This is possible •• They are permeable to water. Applications of Cases in points are doxorubicin. this can 2. and Biotechnology Downloaded from informahealthcare. 4  H. Liposomes can complex both with negatively and hand. Although they are composed of natural from degradative processes. ible and non-recognizable surfaces and has also. Amphotericin Applications of liposomes in medicine B. 2. located mainly in the spleen. Liposomes can carry large pieces of DNA. because of the precipitation of the drug or gel configuration •• They are osmotically sensitive. Disadvantages of liposomes The preceding discussion shows that liposomes exhibit different biodistribution and pharmacokinetics when 1. cortisones cytosine. Sometimes phospholipid undergoes oxidation and encapsulated drug molecules. Upon entering the body. bacteria and colloids are eaten up by the cells of the immune system. which can be applied as (colloidal) solution. and neuro-toxicity. hydrophilic drugs. Phospholipids from natural sources bound molecules with components of cell membranes. Modes of liposome action For personal use only. 4. such as The system is composed of structures of bimolecular sheets the anticancer agent Doxorubicin or Acyclovir. The fourth possible interaction is the exchange of bilayer ingredients. cations and negatively charged ones are relatively permeable to anions. porphyrins. as well Advantages of liposomes as microbes. Characteristic exam- . such as cholesterol and lipid: membrane- 1. nephro-. Nanomedicine. can be intercalated by aqueous space. brain. tool. can be classified into seven categories: 6. in some cases. This response of the immune system has Liposomes offer several advantages in delivering genes to triggered substantial efforts in the development of biocompat- cells.

Blood circulation times liposomes because small molecules with immunogenic were extended but the primary and considerable develop- properties (haptens) cannot induce immune response ments were attained by the incorporation of ganglioside without being attached to a larger particle. liposomes with surface attached ligands Very early studies mostly showed decreased toxicity of can bind to target cells. Such lipo- vehicles for the targeting of drug molecules into these somes were used for analytical studies (Williams et al. and (Allen and Chonn 1987). and tion already since 1988. Unfortunately. For personal use only. their capillaries and basal only in reduced toxicity but also in severely compromised lamina. and differences. malaria are now in clinical trials (Alving 1991). 1989). and Biotechnology Downloaded from informahealthcare. this was also found to be true for anti-provocative drugs. including selective targeting of cancer be implemented in antibacterial and antiviral therapy and other diseased cells. particularly in the drug molecules towards those tissues. however. but for the majority of or pulmonary (by inhalation) administration are also being other applications the fast clearance represents a major considered. 1994). but in most of the by University of Texas at Austin on 09/29/14 such as antibiotics. Many different lipo- (vi) Improved transfer of hydrophilic. liposome encapsulation is done carefully when tolerability of administration but with not too much hope the drugs are very potent. which is useful in the use of some liposomes as localized drug often force liposomes to float as a creamy layer on the top of reservoirs in some topical applications. chelators. rely on liposomes with (Svenson et al. (v) Precise targeting of Location: Liposomes in anticancer therapy In certain cases. into to be less toxic than the free drug (Weiner et al. Other applications Liposomes in infections and parasitic diseases Tiny liposomes composed of lipids with long and saturated While usually liposomes are digested by phagocytic cells hydrocarbon chains in mixtures with cholesterol were in the body after intravenous administration. plasmids and genes. this GM1 or phosphatidylinositol at 5–10 mol% into the bilayer is done by administration of alum or killed bacteria. or tinc- delivery vehicle (New et al. The preparation of antibiotic-loaded changed surface properties which. 1993). they are ideal shown to build up at the sites of inflammations. ing lipids. electric molecules some formulations of various anticancer agents were shown Artificial Cells. resulting not badly formed blood vessels. macrophages. suffer from liposomes at reasonably high drug to lipid ratios may not their quick clearance from the blood by the immune system. The automatic targeting of liposomes to macrophages can be exploited in several other ways. Several other routes. Numerous different formulations are in times in the blood circulation or at the sites of diverse stages of clinical studies and show mixed results local (subcutaneous. i. The best known examples of this ‘Trojan Liposomes can also be used to deliver drugs targeted at the horse-like’ mechanism are several parasitic diseases which lung (McCalden 1990). of free or liposome-encapsulated drug usually exhibits no lated with the size of the drug molecule or its complex. Normally. leave the blood stream. 1988). Applications in case of dermally functional liposomal dosage forms: humans generally showed reduced toxicity and better Usually. The longest circulation times were achieved when . while human vaccinations against reduced cardiotoxicity of Doxorubicin liposomes. The usual nature of liposomes to normally reside in the cells of the mononuclear phagocytic collect in the liver and spleen was used in the treatment of system. the administration in antifungal therapy. These formulations mostly ture.. Some usual toxins persuade tough The results showed that liposome disposition can be changed. Similar approaches can New strategies. Instances include anti-cancer. toxic and have very short life of usefulness. Oral applications of liposomes are at present rather use the ionophore amphotericin B and are relocated from limited due to the very liposomicidal surroundings in the very thriving and prolific areas of liposome formulations stomach and duodenum. or in pulmonary the tube. anti-disease and efficacy. Liposomes with altered surface properties ity (Lopez-Berestein et  al. tissue by local anatomical conditions such as leaky and the drug molecules were not bioavailable.e. gel. administration. primary and secondary liver tumors. however. such as topical application applications of liposomal aerosols. liposomes are being used in animal vaccina. liposome encapsulation obviously prevents the accumula- tion of drug in these organs and drastically reduces toxic. be easy because of the interactions of these molecules with Their inability to extravasate. lation which is infected and therefore offer an ideal drug Liposomes can also be applied as a thick cream. including by macrophage Sterically stabilized liposomes activation and injection. Liposomes accumulate in the very same cell popu. and in general. This can be duplicated and improved by the use of well as the intrahepatic uptake itself. 1986). Application of liposomes in medicine and drug delivery  5 ples are reduced nephrotoxicity of Amphotericin B. These toxicities are normally corre. 1985). but mostly inside the mononuclear phagocytic system as vation. or can be delivered into the target the liposome-encapsulated drug. The best results were obtained by liposomes evidently offer an elegant alternative (Gregoriadis substituting these two lipids with synthetic polymer contain- 1990). intramuscular or intrapulmonary) (Bakker-Woudenberg et al. macrophage response which results in macrophage acti. This cells. Indeed. 1978). neonatal jaundice in an animal model (Hamori et al. includes both short term and chronic toxicities because liposome encapsulation reduces the distribution of the (vii) Improved penetration into tissues. Nanomedicine. bilayers and high densities of their aqueous solutions. obstacle.

ment of these drugs into liposomes resulted in increased tion of the drug in tumors was 4–10 times superior to that flow life span. it seems that marrow) and decreased uptake in the kidney. too stable in the intestine to deliver the encapsulated drug via spleen and bone marrow. prostaglandins. transfect certain cells in vivo upon localized (mostly lung- tained release system was demonstrated by the action of the epithelial cells upon intratracheal instillation) or systemic polypeptide vasopressin (Woodle et al. as it is well known that various (Lasic 1993). 1992). from 1500 to 5000 Da. such as protect macromolecules against enzymatic degradation in the in tumors. This eliminates the the normal absorption process. 6  H. and infections. and such complexes were able to transfect cells in leave the blood circulation. such as studied for the treatment of other diseases and for vaccination immunoglobulins. in leaving the blood and accessing the tumor. and in antiviral therapy. DNA-carrier Medical applications of stealth liposomes systems include several colloidal particles: cationic liposomes The former application requires larger liposomes (0. but are consequently distribution of stealth liposomes is shifted from the liver. Furthermore. The absorp. mixed micelles and vesicles help to transport hydro- studies when liposomes loaded with potent drugs are used. and defense from the drug metabolic deprivation. Although in vitro stability of liposomes in biological systems (Lasic 1994). In the intact vasculature. Obviously. Daraee et al. The origin of steric stabilization is drugs. body. well documented although not well understood. it requires careful toxicology and tolerability micelles. Alternatively. inflammations. In summary. Mechanically and sterically stabilized numerous other applications. the liposomes can survive these conditions. fibronectin and applications. with its improved uptake in organs higher drug concentration in lesions as compared to the rich in mononuclear phagocytic cells (liver. degradation formed from commonly available lipids to enzymatic deg- and/or deactivation in the body. insulin and many others. A significant barrier to the becoming more and more important with the introduction development of liposomes for oral or mucosal delivery of of genetically engineered polypeptides and proteins which macromolecules has been the susceptibility of liposomes are hampered by the rapid blood acceptance. Common liposomes thus fail to sites characterized with porous blood capillaries. in vivo delivery is preferred. The therapy (the treatment of diseases at the molecular level by first example is provided by improved therapeutic efficacy switching genes on or off). polyethylene glycol covalently bound to the phospholipid successful in the treatments of inflammations. for gene long circulating micro-reservoir or localized drug depot. thereby giving rise to a variety of side effects. The prolonged up to a month as compared to few days for a free liposomes act as an adjuvant and carrier of co-adjuvants (viral For personal use only. while the subcutaneous/intramuscular sus. indicating cells. it Recombinant-DNA technology and studies of gene was shown that the Alexander-de-Gennes model of polymers function and gene therapy all depend on the delivery of Artificial Cells. techniques can rely on a number of physical and chemical methods. 1992). and a week for the peptide encapsulated in conven. improved deposition in the infected tissues in the control group which was treated with free drug. liposomes (or chance to transport antivirals and dermatological agents to their precursors) can be delivered directly into the intestine in these sites. might profit gastrointestinal tract. drug. The entrap- that they had been released by the liposomes. It was of cytosine arabinose in the treatment of lymphoma (Allen discovered that cationic lipid-based DNA complexes can et  al. lipids may inactivate some enzymes Applications of stealth liposomes in humans that would take in or pump out drugs. Sterically stabilized liposomes vitro. Its action was (through endothelial cells in the lung) administration. resulting in the expression of the protein encoded may also act as a sustained drug release system either as a in the DNA plasmid in the target by University of Texas at Austin on 09/29/14 at interfaces (De Gennes 1987) can qualitatively explain the nucleic acids into cells in vitro and in vivo. steroid and non-steroid anti-inflammatory quent macrophage uptake. Liposomal ety of tumors. It is possible that the mere presence of lipids administration of empty stealth liposomes is well tolerated increases absorption in the gut. The encouraging results of Doxorubicin encapsulated in stealth liposomes in preclinical studies were also observed Cancer therapy in clinical trials in humans. while it was shown that the various capsules. liposomes must be competent substantial improvements in the treatments of a vari. Nanomedicine. On the other hand. similar molecules. phobic molecules across the epithelial membranes in the intestine. was used. It was suggested that the presence of a steric barrier reduces Vaccination. in addition to the accumulation at the dissolution in the intestine. To target tumors. we trust that they will be also entrapment of these drugs showed reduced cardiotoxicity. The altered biodistribution radation and to the low pH in the stomach and the bile-salt of stealth liposomes. antivirals. gene therapy and diagnostics adhesion and adsorption (or at least adsorption with a As a result of their special properties. complement proteins. liposomes are being conformational change) of blood components. and Biotechnology Downloaded from informahealthcare. myocardium stealth liposomes loaded with anticancer drugs will achieve and brain. Examples are liposomal antibiotics. infections. It is significant to note that these ideas are response to the vaccine antigen. is the optimum (Lasic 1994). Recently. spleen and bone administration of free drug. to the skin. glycolipids and glycoprotein) and potentiate an immune tional liposomes. The drug remained encapsulated Cytotoxic drugs can distribute non-specifically all over the in circulating liposomes for up to one week after injection. which mark foreign particles for subse. It seems that the mid-range molecular mass. altered The high efficacy was due to the approximately 10-fold tissue release of the drug. . and cause the death of normal as well as malignant while drug metabolites were found at tumor sites.2mm) have been shown to form complexes (negatively charged) while the latter one is due to the ability of small vesicles to DNA. In addition. in vivo delivery is more demanding.

Furthermore. Targeted liposomes must survive in the systemic circulation tamicin when given by the intravenous route to rabbits. Strategies to increase the antitubercular action of rifampin was significantly increased circulation time of liposomes. with both teniposide and paclitaxel. Lipid composition therapy. In a simple in vitro culture. liposomal drug delivery structure for the lung is antigens expressed on malignant cells could improve the dependent on the following parameters: therapeutic effectiveness of liposomal preparations as well as reduce the adverse side effects associated with chemo. CHP-coated lipo- is the incorporation of a fusogenic molecule. 2. The survival of 9L-glioma-implanted rats was investigated OCH3. The pendant type immune liposomes can Liposomes for brain-targeted drug delivery flee from the gaps between adjacent endothelial cells and Yagi et al. the so-called 4. Photodynamic therapy (PDT) as a cancer treatment is nota. octadecylphosphocholine and ET-18. liver. the ligands at the liposomal surface. much higher than ligand. ing to the target cells or their internalization by endocytosis. Sustained release compared to the controls receiving free by University of Texas at Austin on 09/29/14 i. Furthermore. The benefit of the by the use of liposomes in which an antitumor drug (CDDP. The ability to selectively market including AmBisome.05) com- Treatment of mycobacterial infections differs from that pared with the case of the untreated group (20.1 times in the ipsilateral brain. They employed sulfatide and a monoclonal antibody as the directed targeting. and Biotechnology Downloaded from informahealthcare. while the liposome trap clearly Procedures for the formation of targeted restricted the antimicrobial motion of chloramphenicol. Charge antibodies at the distal end of PEG series. 2. Drug and Lipid ratio accessory form of immune liposomes.5 times in the tumor sitive agents is useful for PDT. by passive convective transport.e.g. 1990). Reduced toxicity was observed when TNF-alpha was coadministered. e. liposomal neomycin and penicillin were found to be active beside bacteria. possessed by the mycobacteria and the host. which would somes labeled with [14C]-DPPC were injected by the carotid persuade liposomal combinations subsequent to their bind. by the fact that their hemolytic activity was much reduced 7. In all runs. 1990). Liposomal aerosol has several advantages over dylinositol (Allen 1994) or lipid derivatives of polymers like ordinary aerosol.5/∼g/kg of CDDP was administered via the carotid route when they were incorporated into liposomes. liposomal formulation form for ether lipids was supported c/s-platinum diamino dichloride) was loaded. The ultimate goal of the pendant type immune liposome in brain tumors of the rat (Ochi et al. somes coated with CHP also were significantly accumulated apy. Size Artificial Cells. The long enough to reach and bind to their target. To target liposomal anticancer drugs via specific ligands against be efficient. 1. A new type of long-circulating immune liposomes.. Distribution of the that a long-circulating liposomal formulation of photosen. CHP-coated liposome increased by 4. Tissue distribution of the liposome with of chemotherapy and radiotherapy. 1990). poly(vinyl . GMi. Average survival was 35. This was statistically significant (P  0. into rats. Application of liposomes in medicine and drug delivery  7 dermal toxicity and better survival of experimental animals 1. spleen. route into Fisher-344 rats implanted with 9L-gliosarcoma.3 days) (Ochi of other bacterial diseases because of several properties et al. showed much 5. Prevention of local irritation a significant increase of the liposomal drug in tumor tissue 3. like a reduction in liposomal when encapsulated in egg phosphatidylcholine liposomes. These results suggest or without CHP-coating was investigated. as follows (Fendler and Romero 1977): PEG (Klibanov et  al.. Nanomedicine. and phosphati- disorders. More Liposome for respiratory drug delivery system success came from the tactic of including a hydrophilic Liposomes are widely used in several types of respiratory molecule at the liposomal surface. For personal use only. The 4. and a critical incorporation of rifabutin in liposomes resulted in a step to achieving this was the development of liposomes significant enhancement of activity against Mycobacterium which remained long-circulating following the coupling of avium infection compared to free rifabutin. kidney and blood) was collected 30 min after injec- ble for its relatively low side effects in comparison with those tion of the liposome. Method of delivery superior target ability than the usual immune liposomes on collectively targeting sites of lung endothelial cells and solid tumor tissue. Lipo. Improved stability in the large aqueous core antitumor effects of liposomes against solid tumors were Several injectable liposome-based products are now in the superior to those of TNF solution. Each tissue (tumor.3 days for the group treated with the CHP-coated Antimicrobial therapy liposomes. of the ether lipids. polyethylene glycol (PEG) immune liposome-attached 3. and decreased by activity against leukemic cells was found for combinations 4 times in the spleen compared with that of control liposome. Active targeting of tumor tissue with the sensory device in order to increase the target ability of the pendant type immune liposomes is particularly important liposome (Lasic and Papahadjopoulos 1998). Enhanced in vitro cytotoxic and by 2. ipsilateral and contralateral brain. size (Juliano and Stamp 1975) or the inclusion of cholesterol and/or high phase transition lipids (Senior 1986) provided a modest decrease in the clearance rate of liposomes. have developed a liposome that can pass through openings at the vessel termini during tumor angiogenesis the blood-brain barrier (BBB) and reach human glioma. long-circulating liposomes some encapsulation changes the tissue distribution of gen. 5 days after tumor inoculation. fungisome and mycoses. poly(acrylamide). Egg PC lipo- for many highly toxic anticancer drugs in cancer chemother.

PEG was covalently coupled onto the liposomal surface after an antibody) and a spacer molecule (e. In another method. compared to the control. While not all of the above polymers have been sterically interfere with the accessibility of the antibody to investigated for their ability to prolong the circulation time the liposomal surf ace.g. hinders the interaction of the conjugates in detergent followed by dialysis or by hydrat- proteins. Immuno to the liposomal surface. which may conjugate into the lipid bilayer of a liposome. thiol groups can then be coupled through thioether bonds to maleimide groups on proteins (introduced onto exposed Non-covalent coupling methods amino groups) through the use of a hetero bifunctional The non-covalent. and the type of chemical bond method resulted in both efficient antibody conjugation and desired (e. The advantage of this post-coating PE (DMPE).2-oleoyl PE (POPE). showed poor target binding. dipalmitoyl PE (DPPE). which reactive groups are presented on the immune liposomes through the use of PEG-succinyl cysteine anchor and the ligand. the optimal weight range of the grafted PEG is between Formation of ligand-anchor conjugates prior to liposome 2000–5000 Da (PEG-2000 to PEG-5000. stable versus unstable. However. distearoyl PE (DSPE). PEG-lipids. the availability of heterofunctional (PEG-SC) of various polymer chain lengths. PEG could be Coupling strategies incorporated into liposomes after ligand coupling occurs. Also. ligands are incorporated in the bilayer resulted in low antibody densities non-covalently bound to preformed liposomes by first and low coupling efficiencies.. with long hydrophilic chains. 5000-SC onto the liposomal surface. amount of antibody-lipid conjugate incorporated into PEG- dophenyl butyrate-PE (MPB-PE). Nanomedicine. In one variation. efficient grafting of PEG-750-SC. to PEG-2000-DSPE was effectively transferred from micelles a hydrophobic anchor via cross-linking molecules. The and inserted into preformed liposomes. then PEG was grafted to the surface of the available. Liposomes containing maleimido- polymer like PEG) securely to the liposomal surface. Also. PEG-lipids are normally only. but high affinity interaction of avidin cross-linking reagent like SMPB (H-succinimidyl-4-)p. the anchor of choice has been phos. only PEG- phatidylethanolamine (PE) because of the reactive amine 2000-SC-immunoliposomes retained extended circulation in its head group and the availability of various acyl chain times and in vitro target binding. covalent versus non. 45–115 repeat units). probably oxazoline).g. the are N-pyridyldithiopropionyl-PE (PDP pE)io9-iii maleimi. 8  H. i. A ligand is coupled. ing liposomes was adapted from procedures for conjugating the internal antibody will also occupy internal space which antibodies and/or antibody fragments (Fab’ and F(ab’)2) will reduce the available volume for drug loading. The benzoyl-DPPE (MB-PE) were conjugated first with thio- choice of anchor depends on the general coupling strategies lated antibodies. ligand and the grafted polymer occur on the outside leaflet For personal use only. PDP-PE is easily reduced grafted liposomes was reported to be independent of the to form free thiol groups at the liposomal surface. The cross linking of a ligand to the surface of PEG-2000-grafted liposomes with PDP. of antibody.or ligand-containing liposomes. The liposomes can then be formed by either co-solubilizing when grafted onto the liposomes. formation This amount of polymer. the liposome.e. e. incorporated into liposomes at 4–10% of total lipid. A portion of the incorporated containing liposomes antibody will be oriented to the interior aqueous space of Some of the chemistry for coupling ligands to long-circulat. or streptavidin with biotin has been adapted for coupling maleimidophenyl)butyrate). To confer long circulation times. high hydrophobic anchor is required for stable insertion of the Artificial Cells. The first method uses carbodiimide activation in coupling to the liposomes and their ability to bind to their of the carboxyl groups of N-glutaryl-PE (NGPE) followed target. a large hydrophilic antibody conjugation. pyrrolidone) (Torchilin et  al. lengths of different degrees of unsaturation.. PEG. Daraee et al. Additional lipids are added to the deter- Coupling ligands to the liposomal surface gent solution and liposomes are formed following detergent Attaching ligands to the surface of pre-formed. Attempts to couple antibodies ligands to the liposomal surface. To overcome the interference of PEG in the conjugation of antibodies onto the liposomal surface. leaving the maximal interior space for drug loading. and Biotechnology Downloaded from informahealthcare. often through a spacer molecule. This ing a dry lipid film containing the lipid ligand conjugate plus will reduce the efficiency of both the ligands and antibodies other lipids. in liposomes containing chemistry involves sulfhydryl reactions. with liposomal surfaces. it has been shown that both GMi and PEG have been successful in this Addition of PEG after ligand coupling regard. Generally. bic anchor must be sufficiently strong to bind a ligand (e. including antibodies. method of immune liposome preparation is that both the dioleoyl PE (DOPE) or 1-palmitoyl. making it unavailable for target binding. due to steric PE derivatives which can be incorporated into liposomes hindrance of antibody-antigen interactions. The first major class of linkage liposomes formed by this method. by coupling. Two thiol-reactive PEG-5000-PE..g. The hydropho... however. This post-coating cross linking molecules. and liposomes can proceed via an avidin bridge either DOPE or a maleimidobenzoyl-derivative of DPPE (MB-PE) before or after target binding. PEG-2000-SC and PEG- covalent). at concentrations binding avidin or streptavidin to liposomes containing . dimyristoyl non-PEG liposomes. removal through dialysis. 1994) or poly(methyl or ethyl of approximately 5 mol% or higher in the bilayer. to free amine groups on antibodies in an octyl glucoside solution.g. destroy protein ligands like by University of Texas at Austin on 09/29/14 temperatures were needed for efficient transfer. However. The free polymer size and surface density.

4). resulting in sepsis. The circula. siella pneumoniae (an infection fatal within 5 days) the further referred to as PEG-AMB. dissolved in blood the antibiotic-containing liposomes are relatively hydrophilic solutes cannot readily increase the lipids. further referred to as PEG/DSPG-AMB. However. as a drug carrier is much more complicated and “full of mals and bacterial killing in blood. should be used in a cross-talk with technology. Data on biodistribution in rats at relatively nology to move together hand-in-hand in order to achieve high dosage show that MiKasome® can more effectively a product.or avidin-liposomes (or biotinylated of action of AmBisome® in animals show that intact AmBi- liposomes). The design of liposomes some® showed improved efficacy in terms of survival of ani. the efficacy of MiKasome® molecules. at the site of infection many different ligand conjugates can be synthesized and direct interaction between AmBisome® and the fungal cell bound to their intended targets.21:1. in rigorous infection. physics. the elimination half-life being bases that have been developed promise new improvements . amphotericin B-containing liposomes successful development of liposomal drug delivery in less AmBisome® shows prolonged blood residence time at thera. Liposome preparations con- Sterically stabilized liposomes containing gentamicin or sisted of PEG-DSPE: HSPC: Choi: DSPG: AMB (molar ratio ceftazidime 0. formulation shows three characteristics that are expected After intravenous administration these liposomes are pas. including pharmacy. and extended of gentamicin or ceftazidime encapsulated in these lipo. using basic studies in immune cooperation on the mechanism either streptavidin. lung and kidney than free drug treatment. Conclusion and future outlook The synergistic input from colloid science.85) with a mice. Application of liposomes in medicine and drug delivery  9 a biotinylated lipid (usually a derivative of PE) and then about 32 h in humans. MiKasome® Major scientific input in the fields of physical chemistry. mice. The use of liposomes for transformation or was investigated in a model of intra peritoneal infection transfection of DNA into a host cell is known as lipofec- caused by Klebsiella pneumoniae in immune suppressed tion.79:1:0.29:2:1:0. developed (NeXstar Pharmaceuticals Inc. In addition to gene and drug delivery applications. in terms of increased Liposomes are used for drug delivery due to their unique survival of the infected rats. During the long circulation ous solution inside a hydrophobic membrane. 0. spleen. A55 nm mines” than it seemed at the birth of the field 30 years ago. A liposome encapsulates a region on aque- killing in the infected lung tissue.. reduced the toxicity of AMB. independent of the drug may occur or AMB may be released from AmBisome® in the carrier. mean particle size of 80 nm was by University of Texas at Austin on 09/29/14 have good target binding abilities. In another variation. to be important for improved antifungal efficacy: low toxic- For personal use only. unilamellar liposomal preparation of amikacin. as well as increased bacterial properties. and these elevated doses result in biotinylated-ligands (or an avidin-ligand conjugate) are enhanced antifungal effectiveness. amikacin-containing liposomes of taking both hydrophobic molecules and hydrophilic In more recent animal studies. and in this method liposomes are capable MiKasome®. Hydrophobic chemicals are able to be dissolved into the membrane. Yet. To achieve prolonged circula- success: at low antibody coupling densities the circulation tion of AMB liposomes without the constraint of high lipid times of immune liposomes are long. In conclusion. and the solid theoretical and experimental peutically effective doses. biology. stable (Senior et al. San Dimas. consisting of HSPC: Choi: DSPG (molar ratio. PEG-DSPE: HSPC: Choi: AMB (molar ratio. using AmBisome® at much incubating with a biotinylated ligand. 0. and Biotechnology Downloaded from informahealthcare.1) was chemistry. We can hypothesize at least two reasons for this close vicinity of the fungus.15:1:1. and In a rat model of left-sided pneumonia caused by Kleb. chemis- Antifungal agents in long circulating liposomes try. deliver amikacin to liver. 1991. circulation time of integral AMB-containing liposomes in somes was investigated in this experimental pneumonia blood. 2:1:0. 1991). At a single-dose treatment schedule started at 24 h after bacterial inoculation. the PEG-AMB The liposomes showed relatively low hepatosplenic uptake. liposomes can be used as carriers. sterically stabilized AMB-containing liposomes were Artificial Cells.32). higher dosages is standard. This field and the pharmacokinetics and toxicity were investigated in is an excellent example of the need for science and tech- animal models. Sterically stabilized liposomes containing amphotericin B Antibacterial agents in long circulating Two different formulations of AMB in PEG-grafted lipo- liposomes somes have been studied. elevated fundamental antifungal action. first bound to the target epitope. In prophylactic treatment MiKa. prepared at our laboratory. pharmacology and medicine has resulted in the AmBisome®. The efficacy ity. a superior therapeutic efficacy of the liposome-encapsulated antibiotic was observed com- Design of liposome-based drug carriers pared to the effects of free antibiotic. than 30 years. liver and spleen. and these preparations dose. CA). sively targeted towards the infected lung tissue.8:0. Nanomedicine. 1ife and medical sciences. PEG/DSPG-AMB was as toxic as conventional AMB. Papahadjopoulos et al. whereas the liposomal formulation PEG-AMB greatly tion half-life for these liposomes in blood was about 20 h. A chase step follows. The two different prepara- behavior of sterically stabilized liposomes composed of tions showed a large difference in toxicity in uninfected PEG-DSPE: PHEPC: Choi (molar ratio. The advantage of this two-step protocol is that some® can reach the site of infection. model.

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