Conventional liposomes

The "stealth" concept may offer two other opportunities for liposome application (1) Conventional immunoliposomes (see Sec. VI.C) have been shown to be removed rapidly firom the circulation by the MPS (Peeters et al., 1987). The combination of the stealth approach for longer circulation with the attachment of antibodies or antibody fragments may provide a means of delivery of drugs to their sites of action with a high degree of specificity. This could be useful for treating leukemia, graft-vs.-host diseases, and HIV disease. 

Amphotericin B-induced ARF occurs in as many as 40% to 65% of patients treated with the conventional desoxycholate formulation.30 Nephrotoxicity is due to renal arterial vasoconstriction and distal renal tubule cell damage. Risk factors include high doses, treatment for at least 7 days, preexisting kidney dysfunction, and concomitant use of other nephrotoxic drugs.31 Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease the incidence of ARF amphotericin B lipid complex, amphotericin colloidal dispersion, and liposomal amphotericin B. The range of... 

Liposomes are formed due to the amphiphilic character of lipids which assemble into bilayers by the force of hydrophobic interaction. Similar assemblies of lipids form microspheres when neutral lipids, such as triglycerides, are dispersed with phospholipids. Liposomes are conventionally classified into three groups by their morphology, i.e., multilamellar vesicle (MLV), small unilamellar vesicle (SUV), and large unilamellar vesicle (LUV). This classification of liposomes is useful when liposomes are used as models for biomembranes. However, when liposomes are used as capsules for drugs, size and homogeneity of the liposomes are more important than the number of lamellars in a liposome. Therefore, "sized" liposomes are preferred. These are prepared by extrusion through a polycarbonate... 

All of the above-mentioned examples describe organosiloxane hybrid sheet-like structures. However, cell-mimicry requires spherical structures that can form an inner space as a container. Liposomes and lipid bilayer vesicles are known as models of a spherical cell membrane, which is a direct mimic of a unicellular membrane. However, the limited mechanical stability of conventional lipid vesicles is often disadvantageous for some kinds of practical application. 

Table 23.1 details all of the recent Food and Drug Administration (FDA)-approved agents. In this section we will detail some interesting aspects of the approach to their development. As can be seen in Table 23.1 there are 21 new entities. Of note is that only seven (33%) of the agents including capecitabine, liposomal doxorubicin, temozolomide, and oxaliplatin, ABl-007, liposomal cytarabine, and pemetrexed could be considered conventional cytotoxic... 

Shmeeda H, Even-Chen S, Honen R, Cohen R, Weintraub C, Barenholz Y. Enzymatic assays for quality control and pharmacokinetics of liposome formulations comparison with nonenzymatic conventional methodologies. Methods... 

Over the past 20 years, our laboratory has played a major role in the development of liposomal systems optimized for the delivery of conventional drugs, almost all of which are encapsulated by pH-gradient techniques. Our initial studies led to the development of several liposomal drug delivery systems in which uptake was driven by the citrate method of generating pH gradients (15,21-23,27,54—58). This was followed by the development of new... 

Chang CW, Barber L, Ouyang C, Masin D, Bally MB, Madden TD. Plasma clearance, biodistribution and therapeutic properties of mitoxantrone encapsulated in conventional and sterically stabilized liposomes after intravenous administration in BDFl mice. Br J Cancer 1997 75 169. 

Miller CR, Bondurant B, McLean SD, et al. Liposome-cell interactions in vitro effect of liposome surface charge on the binding and endocytosis of conventional and sterically stabilized liposomes. Biochemistry 1998 37 12875. 

Inselmann G, Volkmann A, Heidemann H. Comparison of the effects of liposomal amphotericin B and conventional amphotericin B on propafenone metabolism and cytochrome P450 in rats. Antimicrob Agents Chemother 2000 44 131. 

Finally, besides conventional liposomes that are made from natural (e.g., egg yolk and soybean) or synthetic phospholipids, novel liposomes called archaeosomes that are prepared from the polar ether lipids extracted from various archaeobacteria proved also interesting for the design of vaccines as peptide antigen carriers (71) and as powerful self-adjuvanting vaccine delivery vesicles that promote both humoral and cell-mediated immunity (72). Related to this, one can mention that pseudopeptides, which are less prone to proteolysis when conjugated to liposomes, were also competent in triggering a humoral immune response (73). 

Mayer LD, Cullis PR, Bally MB. Designing therapeutically optimized liposomal anticancer delivery systems lessons from conventional liposomes. In Papahad-jopoulos L, ed. Medical Applications of Liposomes. New York Elsevier Science, 1998. 

Immunopotentiating reconstituted influenza virosomes (IRTV) are spherical 150-nm sized particles consisting of a phospholipid bilayer in which influenza virus A/Singapore strain-derived hemagglutinin (HA) and neuraminidase (NA) are intercalated. As such, they resemble and mimic the influenza virus envelope. The difference from conventional liposome formulations lies in the inclusion of the viral envelope proteins HA and NA as well as viral phospholipids. Especially, the inclusion of influenza virus HA provides IRIV with delivery and immimogenic capacities. IRTV are licensed for human use as adjuvant in hepatitis A vaccination and as influenza subunit vaccine (1). 

Cell proliferation was addressed by conventional H-thymidine incorporation assays. Briefly, PBMCs were cultured in the presence of IRIV and liposomes, and in absence of any stimuli. On day 5 of culture, cells were pulsed with H-thymidine for 18 hours, then harvested, and cell proliferation was determined by tracer incorporation measurement. 

PEG is a widely used molecule as a component in pharmaceutical formulations. PEG is particularly useful thanks to its low cost and various simple synthetic methods (26). PEG-lipid has been developed as a means of stabilizing conventional liposomes. A lipid moiety has been linked to the large PEGylated head in order to anchor the molecule to the particles. Instead of shielding a direct layer of polymer PEG around the particle, which would be less stable, the idea is to favor hydrophobic interactions between the PEG-lipid and the particle bilayer lipids. This anchor had led to two conformations of the PEG on the particle surface commonly called mushroom and brush regimes (27), representing a more condensed or extended conformations... 

As for conventional liposomes, temperature and time of incubation are important factors for PEG-lipid insertion into cationic bilayers (48). Transition temperature of cationic lipids has not always been determined, although it would be interesting data to have. The incorporation of PEG-lipid into the film before hydration is usually more efficient than its postinsertion into the particles. However, postincorporation allows to work with limited amounts of materials, and to test more easily multiple conditions. 

Insertion of PEG-lipid into conventional liposome phospholipid bilayer had substantially increased their circulation half-life. Pharmacokinetic of PEGylated liposome is clearly modified by the presence of the PEG-lipid extended circulation time was reported as reviewed (4). 

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