Targeting Applications of Biotinylated Liposomes

Abstract

Introduction

A number of studies suggest that topically applied lipid vesicles are one type of the so-called “percutaneous penetration enhancer” which suppress the dominating role of the stratum corneum penetration barrier (1,2). It has been shown by these authors that phospholipid vesicles enhance the penetration of compounds incorporated and/or encapsulated in them. One-dimensional electron paramagnetic resonance imaging and EPR reduction kinetics of the hydrophilic spin probe ASL also showed that egg lecithin/cholesterol liposomes facilitated the transport of this probe into porcine skin (3). However, most of the vesicles disintegrated and only 5% of the encapsulated spin probe were protected from reduction in the horny layer. The authors presume that small amounts of the probe are either transported encapsulated into the skin or that their transport is facilitated by liposomal lipids.     

Subcutaneous Administration of Liposomes for Lymphatic Targeting

Abstract

Liposomes have received considerable interest for targeting to regional lymph nodes after s.c. administration. Detailed information on factors influencing lymphatic uptake and lymph node localization of s.c. administered liposomes is, however, not readily available. The present paper provides a short overview of the outcome of recently performed studies on factors potentially affecting lymphatic disposition of liposomes after s.c. injection into rats. An important factor influencing lymphatic disposition was found to be the anatomical site of injection. S.c. injection into the dorsal side of the foot or in the footpad resulted in relatively high uptake (about 40% of the injected dose (%ID)) of small liposomes (mean size about 0.10 μm) from the site of injection compared to uptake from the s.c. injection site at the flank from which uptake was low (< 5 %ID). Liposome size was found to be the most important liposome characteristic influencing lymphatic disposition of s.c. administered liposomes. Small, liposomes (mean size about 0.04 μm) were taken up by the lymphatic system to a relatively high extent (about 74 %ID) compared to large, non-sized liposomes which remained present almost completely at the site of injection. Small liposomes were less efficiently retained by regional lymph nodes than larger liposomes. Liposomal lipid composition did not influence lymphatic disposition significantly with one exception: lymph node localization of liposomes was substantially enhanced by inclusion of phosphatidylserine into the liposomal bilayers. Remarkably, lymphatic uptake and lymph node localization was only slightly affected by distearoylphosphatidylethanolamine-poly(ethyleneglycol) (DSPE-PEG¹) mediated steric stabilization of the liposome surface. Studies designed to elucidate the intranodal fate of liposomes confirmed that liposomes are mainly taken up by lymph node macrophages. Small liposomes may also be taken up by other cells such as endothelial cells. In addition, it was found that PEG-liposomes retained by lymph nodes are also taken up by lymph node macrophages.     

Targeting of Antibiotics in Bacterial Infections Using Pegylated Long-Circulating Liposomes

Abstract

PEGylated long-circulating liposomes were used as a delivery system of antibiotics providing enhancements in antibiotic pharmacokinetics and penetration to infected sites. Pharmacokinetic and therapeutic efficacy studies were performed in the model of unilateral pneumonia/septicemia caused by Klebsiella pneumoniae in rats with intact host defense or leukopenic rats. Gentamicin was encapsulated in PEGylated liposomes designed to achieve delivery of antibiotic to the infected left lung tissue. Our data show that the efficacy of liposomal gentamicin was superior to free gentamicin particularly in difficult to treat infection due to impaired host defense (leukopenia) or low antibiotic susceptibility of the infectious organism. In leukopenic rats infected with a high gentamicin-susceptible bacterial strain, free gentamicin must be administered at the maximum tolerated dose to be therapeutically effective. The addition of a single dose of liposome-encapsulated gentamicin on the first day of treatment with free gentamicin leads to full therapeutic efficacy while keeping the antibiotic doses low. In even more difficult to treat infection due to both an impaired host defense (leukopenia) and low gentamicin-susceptibility of the bacterial strain, free gentamicin is not effective, and the addition of the liposome-encapsulated form of gentamicin is needed to achieve full therapeutic efficacy. In this respect, the lipid composition of the liposomes is an important determinant in establishing both sufficient antibiotic levels in blood and sufficient release of antibiotic from the liposomes at the infectious focus.

Ciprofloxacin was encapsulated in PEGylated liposomes designed to serve as a microreservoir of antibiotic during circulation in blood. Our data show that the administration of ciprofloxacin in the liposomal form resulted in slow release of ciprofloxacin from the liposomes over time in blood. Delayed ciprofloxacin clearance, as well as increased and prolonged ciprofloxacin concentrations in blood and tissues was observed. The therapeutic efficacy of liposomal ciprofloxacin was superior to that of free ciprofloxacin. PEGylated liposomal ciprofloxacin was well tolerated in relatively high doses (increasing the maximum tolerated dose for free ciprofloxacin), permitting the administration on a once-a-day schedule without loss in therapeutic efficacy.     

Fibrin Targeting of Echogenic Liposomes with Inactivated Tissue Plasminogen Activator

Fibrin-specific molecular targeting strategies are desirable for site-specific imaging and treatment of late stage atheroma, but fibrin-specific antibodies are difficult to produce and present immunogenicity problems. Tissue plasminogen activator (tPA) is an endogenous protein that has been shown to bind fibrin with high affinity and may circumvent antibody difficulties. Use of tPA-derived proteins or peptides, however, requires that the plasminogen-activating proteolytic activity be neutralized or removed. As an initial step in determining the feasibility of this targeting strategy, human recombinant tPA (Activase®) was irreversibly inhibited with D-phe-L-pro-L-arg-chloromethyl ketone (PPACK) and conjugated to intrinsically echogenic liposomes (ELIP) by a thioether coupling protocol. Fibrin-binding affinities were assessed with a novel two‐stage fibrin pad ELISA. We achieved 95–99% inactivation, while retaining both tPA fibrin-binding activities of K_D ～ 2 nM and 33 nM. Thermodynamic analysis of the PPACK-inactivated tPA (tPA(P)) revealed highly exothermic interactions, indicative of ionic associations, especially for the higher affinity. The conjugation efficiency of tPA(P) to ELIP was within the range of that previously achieved for IgG and exhibited satisfactory fibrin targeting, characterized by striking increases of enthalpy and entropy increments. Evidence for coupling of noncovalent association energetics with the phosphatidylethanolamine major phase transition, observed in previous IgG antibody conjugations, was also evident in this case, but the nature of the transduction mechanism was different. These results demonstrate that tPA-derived components lacking proteolytic activity can be employed as fibrin-targeting agents for delivery of therapeutic and diagnostic formulations.     

Agent Targeting by Means of the Chemically or Physically Directed,Fusogenic Liposomes

Abstract

Based on the concept of rational membrane design it is proposed how to develop liposomes suitable for the targeting in vitro and in vivo. Such targeting can rely on the chemical or physical 'pointers'. Hyperthermia is a particularly convenient example of the latter, suggesting that thermolabile fusogenic liposomes should be devised and used for the agent delivery into cells. The resulting efficacy depends on the extent to which the phase characteristics of the fusogenic lipid membrane are made to fit the delivery-triggering signal: increasing the temperature and/or lowering the pH-value in the investigated system are most useful for this purpose, the role of membrane defects, such as may arise during the liposome manufacturing process or in the vicinity of lipid phase transitions also being of extreme importance. Thermolabile fusogenic liposomes prepared from the stoichiometric 1/2 mixture of diacylphos-?hatidylcholines with appropriate fatty acids implement these requirements. 'heir temperature dependence permitting physical targeting and their pH-dependence being suitable for the 'chemical targeting' to the acidic surrounding. Dipalmitoylphosphatidylcholine/elaidic acid mixture is, perhaps, the best such combination for the use in vivo. The efficacy of fusion between the corresponding lipid vesicles and cells in vitro as well as the delivery of radioactive labels into the heated tumours (but not in the normal muscle tissue with the inpenetrable micro-vasculature) provide compelling evidence for this.     

Enhanced Active Targeting via Cooperative Binding of Ligands on Liposomes to Target Receptors

To achieve effective active targeting in a drug delivery system, we previously developed dual-targeting (DT) liposomes decorated with both vascular endothelial growth factor receptor-1 (VEGFR-1)-targeted APRPG and CD13-targeted GNGRG peptide ligands for tumor neovessels, and observed the enhanced suppression of tumor growth in Colon26 NL-17 tumor-bearing mice by the treatment with the DT liposomes encapsulating doxorubicin. In this present study, we examined the binding characteristics of DT liposomes having a different couple of ligands, namely, APRPG and integrin α_vβ₃-targeted GRGDS peptides. These DT liposomes synergistically associated to stimulated human umbilical vein endothelial cells compared with single-targeting (ST) liposomes decorated with APRPG or GRGDS. The results of a surface plasmon resonance assay showed that ST liposomes modified with APRPG or GRGDS peptide selectively bound to immobilized VEGFR-1 or integrin α_vβ₃, respectively. DT liposomes showed a higher affinity for a mixture of VEGFR-1 and integrin α_vβ₃ compared with ST liposomes, suggesting the cooperative binding of these 2 kinds of ligand on the liposomal surface. In a biodistribution assay, the DT liposomes accumulated to a significantly greater extent in the tumors of Colon26 NL-17 tumor-bearing mice compared with other liposomes. Moreover, the intratumoral distribution of the liposomes examined by confocal microscopy suggested that the DT liposomes targeted not only angiogenic endothelial cells but also tumor cells due to GRGDS-decoration. These findings suggest that "dual-targeting" augmented the affinity of the liposomes for the target cells and would thus be useful for active-targeting drug delivery for cancer treatment.     

Antiangiogenic Targeting Liposomes Increase Therapeutic Efficacy for Solid Tumors

It is known that solid tumors recruit new blood vessels to support tumor growth, but the molecular diversity of receptors in tumor angiogenic vessels might also be used clinically to develop better targeted therapy. In vivo phage display was used to identify peptides that specifically target tumor blood vessels. Several novel peptides were identified as being able to recognize tumor vasculature but not normal blood vessels in severe combined immunodeficiency (SCID) mice bearing human tumors. These tumor-homing peptides also bound to blood vessels in surgical specimens of various human cancers. The peptide-linked liposomes containing fluorescent substance were capable of translocating across the plasma membrane through endocytosis. With the conjugation of peptides and liposomal doxorubicin, the targeted drug delivery systems enhanced the therapeutic efficacy of the chemotherapeutic agent against human cancer xenografts by decreasing tumor angiogenesis and increasing cancer cell apoptosis. Furthermore, the peptide-mediated targeting liposomes improved the pharmacokinetics and pharmacodynamics of the drug they delivered compared with nontargeting liposomes or free drugs. Our results indicate that the tumor-homing peptides can be used specifically target tumor vasculature and have the potential to improve the systemic treatment of patients with solid tumors.One of the primary goals of a cancer treatment regimen is to deliver sufficient amounts of a drug to targeted tumors while minimizing damage to normal tissues. Most chemotherapeutic but cytotoxic agents enter the normal tissues in the body indiscriminately without much preference for tumor sites. The dose reaching the tumor may be as little as 5–10% of the dose accumulating in normal organs (1). One reason is that interstitial fluid pressure in solid tumors is higher than in normal tissues, which leads to decreased transcapillary transport of chemotherapy or anticancer antibodies into tumor tissues (2–4). Cancer cells are therefore exposed to a less than effective concentration of the drug than normal cells, whereas the rest of the body must be subjected to increased toxicity and decreased effectiveness. This phenomenon often limits the dose of anti-cancer drugs that can be given to a patient without severe harm, resulting in incomplete tumor response, early disease relapse, and drug resistance.The development of drug delivery systems represents the ongoing effort to improve the selectivity and efficacy of antineoplastic drugs. Compared with conventional administration methods for chemotherapeutic agents, lipid- or polymer-based nanomedicines have the advantage of improving the pharmacological and therapeutic properties of cytotoxic drugs (5, 6). Most small molecule chemotherapeutic agents have a large volume of distribution upon intravenous administration (7) and a narrow therapeutic window because of severe toxicity to normal tissues. By encapsulating drugs in drug delivery particles, such as liposomes, the volume of distribution is significantly reduced, and the concentration of drug within the tumor is increased (8).The coupling of polyethylene glycol (PEG)² to liposomes (PEGylated liposomes), which have a longer half-life in the blood (9–11), is regarded as having great potential in a drug delivery system. For example, PEGylated liposome-encapsulated doxorubicin has been reported to significantly improve the therapeutic index of doxorubicin in preclinical (10, 12, 13) and clinical studies (14–16). Many of these drug delivery systems have entered the clinic and have been shown to improve the pharmacokinetics and pharmacodynamics of the drugs they deliver (6).The growth of solid tumors is dependent on their capacity to induce the growth of blood vessels to supply them with oxygen and nutrients. However, the blood vessels of tumors present specific characteristics not observed in normal tissues, including extensive angiogenesis, leaky vascular architecture, impaired lymphatic drainage, and increased expression of permeability mediators on the cell surface (17, 18). These characteristics might be used to develop antiangiogenic target therapy for cancer. The hyperpermeability of tumor vasculature, for example, is a key factor for the success of liposome-delivered chemotherapy agents. The angiogenic tumor vasculature is estimated to have an average pore size of 100–600 nm (19). These pores are significantly larger than the gaps found in normal endothelium, which are typically <6 nm wide (8). After intravenous administration, liposomes with diameters of ∼65–75 nm (20–22) are small enough to passively infiltrate tumor endothelium but large enough to be excluded from normal endothelium. In solid tumors, the permeability of the tissue vasculature increases to the point that particulate liposomes can extravasate and localize in the tissue interstitial space (19). In addition, tumor tissues frequently lack effective lymphatic drainage (3), which promotes liposome retention. The combination of these factors leads to an accumulation of the drug delivering liposome within the tumor. This passive targeting phenomenon has been called the “enhanced permeability and retention effect” (23, 24).The use of liposomes for passive targeting has some disadvantages. Normal organ uptake of liposomes leads to accumulation of the encapsulated drug in mononuclear phagocytic system cells in the liver, spleen, and bone marrow, which may be toxic to these tissues. With the increased circulation time and confinement of the particulate liposomes, hematological toxicities, such as neutropenia, thrombocytopenia, and leucopenia, have also appeared (25, 26). Ongoing research aims to enhance the tumor site-specific action of the liposomes by attaching them to ligands that target tumor cell (21, 27) and tumor vasculature (20, 28) surface molecules. These liposomes are called active or ligand-mediated targeting liposomes.Combinatorial libraries displayed on phage have been used successfully to discover cell surface-binding peptides and have thus become an excellent means of identifying tumor specific targeting ligands. Phage-displayed peptide libraries have been used to identify B-cell epitopes (29–31). They can also be used to search for disease-specific antigen mimics (32, 33) and identify tumor cells (21, 34) and tumor vasculature-specific peptides (35). Screening phage display libraries against specific target tissues is therefore a fast, direct method for identifying peptide sequences that might be used for drug targeting or gene delivery. By combining a drug delivery system with tumor-specific peptides, it is possible that targeting liposome can deliver as many as several thousand anticancer drug molecules to tumor cells via only a few targeting ligand molecules.In this in vivo study, we developed a method capable of selecting peptides that home to tumor tissues. We identified several targeting peptides able to bind specifically to tumor vasculature in surgical specimens of human cancer and xenografts. Coupling these peptides with a liposome containing the anti-cancer drug doxorubicin (Lipo-Dox; LD) enhanced the efficacy of the drug against several types of human cancer xenografts in SCID mice. Our results indicate that these targeting peptides can potentially play an important role in the development of more effective drug delivery systems.     

Glycosylated Sertraline-Loaded Liposomes for Brain Targeting: QbD Study of Formulation Variabilities and Brain Transport

Effectiveness of CNS-acting drugs depends on the localization, targeting, and capacity to be transported through the blood–brain barrier (BBB) which can be achieved by designing brain-targeting delivery vectors. Hence, the objective of this study was to screen the formulation and process variables affecting the performance of sertraline (Ser-HCl)-loaded pegylated and glycosylated liposomes. The prepared vectors were characterized for Ser-HCl entrapment, size, surface charge, release behavior, and in vitro transport through the BBB. Furthermore, the compatibility among liposomal components was assessed using SEM, FTIR, and DSC analysis. Through a thorough screening study, enhancement of Ser-HCl entrapment, nanosized liposomes with low skewness, maximized stability, and controlled drug leakage were attained. The solid-state characterization revealed remarkable interaction between Ser-HCl and the charging agent to determine drug entrapment and leakage. Moreover, results of liposomal transport through mouse brain endothelialpolyoma cells demonstrated greater capacity of the proposed glycosylated liposomes to target the cerebellar due to its higher density of GLUT1 and higher glucose utilization. This transport capacity was confirmed by the inhibiting action of both cytochalasin B and phenobarbital. Using C6 glioma cells model, flow cytometry, time-lapse live cell imaging, and in vivo NIR fluorescence imaging demonstrated that optimized glycosylated liposomes can be transported through the BBB by classical endocytosis, as well as by specific transcytosis. In conclusion, the current study proposed a thorough screening of important formulation and process variabilities affecting brain-targeting liposomes for further scale-up processes.     

Targeting of Liposomes to Cells Bearing Nerve Growth Factor Receptors Mediated by Biotinylated Nerve Growth Factor

We have used biologically active derivatives of beta-nerve growth factor (NGF), modified by biotinylation via carboxyl groups, to target the specific binding of liposomes to cultured rat and human tumor cells bearing NGF receptors. Liposomes, to be used for targeting, were prepared by conjugating streptavidin to phospholipid amino groups on liposomes prepared by reverse-phase evaporation. Approximately 2,000 streptavidin molecules were incorporated per liposome. Addition of biotinylated NGF, but not of unmodified NGF, could mediate the subsequent binding of radiolabeled streptavidin-liposomes to rat pheochromocytoma PC12 cells in suspension at 4 degrees C. In contrast, incubation with biotinylated NGF did not mediate the binding of hemoglobin-conjugated liposomes. Under optimal incubation conditions, approximately 570 streptavidin-liposomes were specifically bound per cell. Biotinylated NGF was also used to obtain specific binding of streptavidin-liposomes containing encapsulated fluorescein isothiocyanate-labeled dextran to PC12 cells or human melanoma HS294 cells. When HS294 cells were incubated at 37 degrees C following targeted liposome binding at 4 degrees C, the cell-associated fluorescence appeared to become internalized, displaying a perinuclear pattern of fluorescence similar to that observed when lysosomes were stained with acridine orange. Trypsin treatment abolished cell-associated fluorescence when cells were held at 4 degrees C but did not alter the fluorescence pattern in cells following incubation at 37 degrees C. When liposomes containing carboxyfluorescein, a dye capable of diffusing out of acidic compartments, were targeted to HS294 cells, subsequent incubation at 37 degrees C resulted in diffuse cytoplasmic fluorescence, suggesting that internalized liposomes encounter lysosomal or prelysosomal organelles.     

Sustained Liver Targeting and Improved Antiproliferative Effect of Doxorubicin Liposomes Modified with Galactosylated Lipid and PEG-Lipid

In this study, a cleavable PEG-lipid (methoxypolyethyleneglycol 2000-cholesteryl hemisuccinate, PEG₂₀₀₀-CHEMS) linked via ester bond and galactosylated lipid ((5-cholesten-3β-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] butanoate, CHS-ED-LA) were used to modify doxorubicin (DOX) liposome. DOX was encapsulated into conventional liposomes (CL), galactosylated liposomes (modified with CHS-ED-LA, GalL), pegylated liposomes (modified with PEG₂₀₀₀-CHEMS, PEG-CL), and pegylated galactosylated liposomes (modified with CHS-ED-LA and PEG₂₀₀₀-CHEMS, PEG-GalL) using an ammonium sulfate gradient loading method and then intravenously injected to normal mice. Both PEG-GalL DOX and GalL DOX gave relatively high overall drug targeting efficiencies to liver ((T _e)_liver) and were mainly taken up by hepatocyte. However, PEG-GalL DOX showed unique “sustained targeting” characterized by slowed transfer of DOX to liver and reduced peak concentrations in the liver. The biodistribution and antitumor efficacy of various DOX preparations were studied in hepatocarcinoma 22 (H22) tumor-bearing mice. The inhibitory rate of PEG-GalL DOX to H22 tumors was up to 94%, significantly higher than that of PEG-CL DOX, GalL DOX, CL DOX, and free DOX, although the tumor distribution of DOX revealed no difference between PEG-GalL DOX and PEG-CL DOX. Meanwhile, the gradual increase in the liver DOX concentration due to the sustained uptake of PEG-GalL DOX formulations resulted in lower damage to liver. In conclusion, the present investigation indicated that double modification of liposomes with PEG₂₀₀₀-CHEMS, and CHS-ED-LA represents a potentially advantageous strategy in the therapy of liver cancers or other liver diseases.     

Propylene Glycol Liposomes as a Topical Delivery System for Miconazole Nitrate: Comparison with Conventional Liposomes

Propylene glycol (PG)-phospholipid vesicles have been advocated as flexible lipid vesicles for enhanced skin delivery of drugs. To further characterize the performance of these vesicles and to address some relevant pharmaceutical issues, miconazole nitrate(MN)-loaded PG nanoliposomes were prepared and characterized for vesicle size, entrapment efficiency, in vitro release, and vesicle stability. An issue of pharmaceutical importance is the time-dependent, dilution-driven diffusion of propylene glycol out of the vesicles. This was addressed by assessing propylene glycol using gas chromatography in the separated vesicles and monitoring its buildup in the medium after repeated dispersion of separated vesicles in fresh medium. Further, the antifungal activity of liposomal formulations under study was assessed using Candida albicans, and their in vitro skin permeation and retention were studied using human skin. At all instances, blank and drug-loaded conventional liposomes were included for comparison. The results provided evidence of controlled MN delivery, constant percent PG uptake in the vesicles (≈45.5%) in the PG concentration range 2.5 to 10%, improved vesicle stability, and enhanced skin deposition of MN with minimum skin permeation. These are key issues for different formulation and performance aspects of propylene glycol-phospholipid vesicles.     

Hormones of the Cardiovascular System

For the past few decades, several hormones secreted by myocardium and blood vessel walls and regulate various physiological functions have been identified. They include natriuretic hormones, endothelins, proteins related to the parathyroid hormone, adrenomedullin and others. Therefore, the heart and blood vessels, apart from their main function, blood circulation, also perform important endocrine function, i.e., they are an organ controlling various physiological processes including hemodynamics, skeletal growth, reproductive function, immunity, etc.     

Tumor Endothelial Cell-Specific Drug Delivery System Using Apelin-Conjugated Liposomes

Background

A drug delivery system specifically targeting endothelial cells (ECs) in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors.

Methods and Results

Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs.

Conclusions

ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors.     

Mitochondriotropic Liposomes

Mitochondrial dysfunction contributes to a large variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Increasing pharmacological efforts toward therapeutic interventions have been made leading to the emergence of “Mitochondrial Medicine” as a new field of biomedical research. The identification of molecular mitochondrial drug targets in combination with the development of methods for selectively delivering biologically active molecules to the site of mitochondria will eventually launch a multitude of new therapies for the treatment of mitochondria-related diseases, which are based either on the selective protection, repair, or eradication of cells. Yet, while tremendous efforts are being undertaken to identify new mitochondrial drugs and drug targets, the development of mitochondria-specific drug carrier systems is lagging behind. To ensure a high efficiency of current and future mitochondrial therapeutics, delivery systems need to be developed, which are able to selectively transport biologically active molecules to and into mitochondria within living human cells. In this study we present the first data demonstrating that conventional liposomes can be rendered mitochondria-specific via the attachment of known mitochondriotropic residues to the liposomal surface.     

Target-Sensitive Liposomes

Abstract

Target-sensitive liposomes are liposomes which spontaneously destablize when they come into contact with target membrane/surface. The principle lipid in the liposomes ingredient is dioleoyl phosphatidylethanolamine (DOPE) which readily forms inverted micelle at physiological conditions. Earlier design of the liposomes uses acylated antibody as both a bilayer stabilizer and a targeting ligand. Although the immunoliposomes specifically release then-contents upon binding with the target membrane, they are not stable enough for long-term storage. Recent improvement in the design uses a charged phospholipid as a bilayer stabilizer and uses acylated antibody or other ligands at a much lower concentration. The new liposomes are stable for long-term storage, yet still destablize when bound with a target membrane. The rate of destabilization is significantly enhanced at elevated temperatures. The physical and biological properties of these liposomes are reviewed in this paper.