Stabilized liposomes

Besides the possible use of such stabilized liposomes as drug carriers (10) another application could be their use as models for the ceTT-cell interaction and as polymeric antitumor agents on a cellular level (11) i.e. trying to mimic the body defense against tumor cells (17J. We hope that this article which in many terms is more a pre- than a review will help to stimulate the discussions on polymeric antitumor agents not only on the al-... 

Polymeric vesicles could be of better use for such an antitumor therapy on a cellular level, since they have at least one of the properties required, namely an extraordinary membrane stability. For a successful application, however, the simple systems prepared so far must be varied to a great extent, because the stability of a model cell membrane is not the only condition to be fulfilled. Besides stability and possibilities for cell recognition as discussed above the presence of cell membrane destructing substances such as lysophospholipids is necessary. These could e.g. be incorporated into the membrane of stabilized liposomes without destruction of the polymeric vesicles. There have already been reports about thekilling of tumor cells by synthetic alkyl lysophospholipids (72). 

Development of sterically stabilized liposomes (SSL) composed of high Tm lipids, cholesterol, and a lipopolymer, such as poly-(ethylene glycol methyl ether)-l,2-distearoyl-i n-glycero-3-phospho-ethanolamine triethyl ammonium salt (1,3-5,8,9,14,15)... 

Figure 1 Facing page) (A) Mechanism of remote loading of doxorubicin by transmembrane ammonium sulfate gradient. (B) Collapse of transmembrane ammonium ion gradient in SSL by nonactine induces doxorubicin release. (C) Collapse of transmembrane proton gradient in SSL by nigericin induces collapse of transmembrane ammonium ion gradient followed by release of DOX. Abbreviations. DOX, doxorubicin SSL, sterically stabilized liposome.

Abbreviations DOX doxorubicin AO, acridine orange MA, methylamine SSL, sterically stabilized liposome. 

Abbreviations DOX, doxorubicin, SSL, sterically stabilized liposome AS, ammonium sulfate AG, ammonium glucuronate. 

Lasic DD, Vainer JJ, Working PK. Sterically stabilized liposomes in cancer therapy and gene delivery. Curr Opin Mol Ther 1999 1 177-185. 

Woodle MC, Newman MS, Cohen JA. Sterically stabilized liposomes physical and biological properties. J Drug Target 1994 2 397. 

Allen TM. Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends Pharmacol Sci 1994 15 215. 

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. 

Woodle MC, Newman MS, Working PK. Biological properties of sterically stabilized liposomes. In Lasic DD, Martin F, eds. Stealth Liposomes. Boca Raton CRC Press, 1995 103. 

The mode of association of peptides to liposome carriers might also be critical to induce a preferential immune response either humoral or cell mediated. For example, using a human mucin MUCl 20-mer peptide, it was found that only the physical association of the peptide to liposomes (either encapsulated or surface exposed after anchoring) was necessary to observe a cell-mediated response (34). In line with this observation, it was recently shown that a soluble peptide, representing a Melan-A/MART-1 tumor-associated antigen, when encapsulated into sterically stabilized liposomes, was able to stimulate a CTL response and this construct represented a suitable formulation for a specific tumor immunotherapy (69). In contrast, and in agreement with other studies (16), only the liposome surface exposed... 

Dagar S, et al. VIP grafted sterically stabilized liposomes for targeted imaging of breast cancer in vivo studies. J Control Release 2003 91 123. 

Sauer I, et al. An apolipoprotein E-derived peptide mediates uptake of sterically stabilized liposomes into brain capillary endothelial cells. Biochemistry 2005 44 2021. 

Figure 6 Encapsulation of plasmid DNA (pDNA) in small sterically stabilized liposomes [stabilized plasmid-lipid particles (SPLP)] using a detergent dialysis procedure. (A) Entrapped pDNA-to-lipid ratio as a function of the initial pDNA-to-lipid ratio (mg/mg). The initial lipid concentration was lOmg/mL. (B) Cryo-electron micrograph showing the structure of SPLP. The location of the plasmid is indicated by the striated pattern superimposed on the liposomes. The bar represents 100 nm.

Allen TM, Newman MS, Woodle MC, et al. Pharmacokinetics and anti-tumor activity of vincristine encapsulated in sterically stabilized liposomes. Int J... 

Woodle M, et al. Sterically stabilized liposomes. Reduction in electrophoretic mobility but not electrostatic surface potential. Biophys J 1992 61 902. 

Figure 1.1. Schematic representation of four major liposome types. Conventional liposomes are either neutral or negatively charged. Stealth liposomes are sterically stabilized and carry a polymer coating to obtain a prolonged circulation time in the body. Immunoliposomes are antibody targeted liposomes and can consist of either conventional or sterically stabilized liposomes. Positive charge on cationic liposomes can be created in various ways. Reproduced from reference [112] with permission.

Brain delivery of the anticancer drug daunomycin provides an example of the in vivo application of OX26-inununoliposomes [111]. Different formulations of [ H]-daunomycin were i.v. administered to rats either as the free drug or encapsulated in conventional liposomes, sterically-stabilized liposomes, or PEG-conjugated immunohposomes (Table 2.3). Plasma samples were taken at defined time points and after 1 h the animal was killed and drug concentrations in brain tissue were determined. 

Plasma clearance (Cl), blood-brain barrier permeability surface area product (PS) and accumulation as % injected dose detected in brain tissue (%ID tissue) at 1 h after administration. Results show free [ H]-daunomycin (Daunomycin), [ H]-daunomycin encapsulated in conventional liposomes (Liposomes), sterically stabilized liposomes (PEG-liposomes), immunoliposomes (29 0X26, where 29 designates the number of 0X26 mAb conjugated per liposome) and control immunoliposomes where the 0X26 mAb was replaced by a non-specific isotype control antibody (IgG2a). Values are means SEM of n = 3 experiments. 

Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, Lee KD, Woodle MC, Lasic DD, Redemann C, Martin FJ. Sterically stabilized liposomes—improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 1991 88 11460-11464. 

In particular, the transition temperature also influences the physical parameters, such as permeability and stability (liposomes can only be prepared at temperatures above Tm), and the encapsulation of solutes is rather low below this temperature (Janiak et al, 1976 Machy and Leserman, 1987 Gennis, 1989). 

Graf, A., Winterhalter, M., and Meier, W. (2001). Nanoreactors from polymer-stabilized liposomes. Langmuir, 17, 919-23. 

Polyelectrolytes have recently found application in the development of pH sensitive liposomal controlled release systems. This application arises from the fact that polyelectrolytes may be used both to stabilize liposomes, and to disrupt liposomes in a pH dependent manner. Although the use of liposomes in oral pharmaceutical compositions has been discussed [424], liposomes generally suffer from poor stability and are therefore prone to leakage of the entrapped active agents. To overcome this problem, several authors have stabilized the liposomes using polyelectrolytes. For example, Tirrell and coworkers have employed ionene [425], and polyethylene imine) [426] to stabilize liposomes. Similarly, Sato and coworkers have studied maleic acid copolymers [427], and Sumamoto and coworkers have studied liposomes [428] coated with polysaccharides. In related work, Kondo and coworkers have emphasized the use of carboxymethyl chitin to produce artificial red blood cells [429-435]. 

Petrikovics I, Hong K et al (1999) Antagonism of paraoxon intoxication by recombinant phos-photriesterase encapsulated within stericaUy stabilized liposomes. Toxicol Appl Pharmacol 156(l) 56-63... 

Hansen, C.B., G.Y. Kao, E.H. Moase, S. ZaUpsky, and T.M. AUen, Attachment of antibodies to sterically stabilized liposomes evaluation, comparison and optimization of coupling procedures. Biochim Biophys Acta, 1995.1239(2) 133-44. 

In principle, a stabilized liposome might be valuable as a passive drug targeting system since the site of disposition in the body is significantly influenced by the diameter of the vesicle. For example, small liposomes below -50 nm diameter can pass through the capillary wall surrounding a tumor, allowing suitably surface-modified... 

Vaccine adjuvant Protein stabilizer Protein stabilizer Liposomes... 

These are known by their registered tradename, Stealth liposomes (see Lasic 1993, p. 284). As discussed by Lasic, the stealth effect is the result of a steric layer surrounding the liposome, and these liposomes are also known as sterically stabilized liposomes. We discuss steric stabilization in Chapter 13. 

Fig. 53. Schematic representation of possible routes to stabilize liposomes via surface coating with polymers...

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