Liposomes toxicity

H. Schreier, K. J. McNicol, M. Ausborn, D. M. Soucy, H. Derendorf, A. A. Stec-enko, and R. J. Gonzalez-Rothi, Pulmonary delivery of amikacin liposomes and acute liposome toxicity in sheep, Int. J. Pharm. 87 183 (1992). 

The formation of ordered two- and three-dimensional microstructuies in dispersions and in liquid systems has an influence on a broad range of products and processes. For example, microcapsules, vesicles, and liposomes can be used for controlled drug dehvery, for the contaimnent of inks and adhesives, and for the isolation of toxic wastes. In addition, surfactants continue to be important for enhanced oil recovery, ore beneficiation, and lubrication. Ceramic processing and sol-gel techniques for the fabrication of amorphous or ordered materials with special properties involve a rich variety of colloidal phenomena, ranging from the production of monodispersed particles with controlled surface chemistry to the thermodynamics and dynamics of formation of aggregates and microciystallites. 

Encapsulation of cDDP in liposomes did not show such favorable effects. Liposome encapsulation of cDDP decreased the antitumor effect (Fig. 9). It was demonstrated that administration of cDDP liposomes resulted in a lower incidence as well as reduced severity of focal alterations of the epithelium of the proximal tubuli compared to administration of the free drug (Steerenberg et al., 1988). However, despite this reduction in renal toxicity the therapeutic index... 

Because of its clinical importance and the expected benefits of the drug in liposomal form for cancer treatment, all three American "liposome enterprises" (i.e.. Liposome Technology Inc., Erbamont, LyphoMed/Vestar joint ventures, and the Liposome Company, Inc.) are developing a formulation of liposomal doxorubicin. Clinical studies already show promising results as far as the acute toxicity is concerned (less vomiting, nausea, and hair loss) (Gabizon et al., 1989 Treat et al., 1989),... 

Kim et al. (1987) showed that the prolonged retention time of Ara-C in the peritoneal cavity after intraperitoneal administration of the drug in liposomal form as discussed above resulted in better therapeutic effects on intraperitoneally inoculated L1210 cells, as compared to the free drug. The activity of intraperitoneally administered cDDP on Ehrlich ascites carcinoma in mice was increased after encapsulation in neutral liposomes (Sur et al., 1983). The in vivo studies revealed improved antitumor activity and a lower toxicity sifter administration of cDDP liposomes compared to free drug. 

Presently, several clinical trials with liposome-encapsulated agents are under way and more are planned (Zonneveld and Crommelin, 1988 Klausner, 1988). During the last 5 years, key issues related to the pharmaceutical manufacturing of liposomes such as stability, sterilization, upscaling, and reproducibility have been successfully addressed. Although it is generally believed that a proper selection of the bi-layer components can minimize the occurrence of toxic effects due to the use of natural body constituents, the issue of liposome-related toxicity is not a trivial one and should be carefully studied,... 

A number of aspects related to the potential toxicity of liposomes has to be considered. They include effects due to (1) their particulate nature, (2) the individual components, and (3) a changed distribution of the encapsulated drug. 

Changing the distribution of a drug can lead to toxic effects not described before. It is possible that after liposomal delivery high concentrations of drugs (e.g., cytotoxic drugs) inside macrophages affect these cells detrimentally (Poste and Kirsch, 1983). This results in toxic effects in liver, spleen, and bone marrow which were not previously associated with the use of these drugs. 

Peroxidation of lipids is another factor which must be considered in the safety evaluation of liposome administration. Smith and coworkers (1983) demonstrated that lipid peroxides can play an important role in liver toxicity. Allen et al. (1984) showed that liposomes protected by an antioxidant caused less MPS impairment than liposomes subjected to mild oxidizing conditions. From the study of Kunimoto et al. (1981) it can be concluded that the level of peroxidation in freshly prepared liposome preparations and those on storage strongly depends both on the phospholipid fatty acid composition and on the head group of the phospholipid. Addition of appropriate antioxidants to liposomes composed of lipids which are liable to peroxidation and designed for use in human studies is therefore necessary. 

In view of the fact that large volumes have been administered to man without causing serious side effects (Zonneveld and Crommelin, 1988), it may be concluded that although liposomes can damage in vitro-cultured human cell lines (Nuzzo et al., 1985 Mayhew et al., 1987b), adverse effects observed in vivo are expected to be minimal. One should realize that liposomes reduce the toxicity of the encapsulated drug. Thus, the toxicity of liposomes may be of minor importance compared to the advantages of administration of certain chemotherapeutics encapsulated in liposomes. 

For a number of liposome preparations—both injectables and locally administered products—the therapeutic advantages over existing formulations have been proven in animal models clinical trials with liposome preparations are now under way. So far, clinical studies showed no significant toxic effects which could be ascribed to the lipid components of the liposomes used. 

J. (1985). Ocular toxicity of intravitreally injected liposomal amphotericin B in rhesus monkeys. Am. J. Ophthalmol., 100, 259-263. 

Daoud, S. S., and Juliano, R. L. (1986). Reduced toxicity and enhanced antitumor effects in mice of the ionophoric drug valino-mycin when incorporated in liposomes. Cancer Res., 46, 5518-5523. 

Mayhew, E., Ito, M., and Lazo, R. (1987b). Toxicity of non-drug containing liposomes for cultured human cells, Exp. Cell Res.. 

Mehta, R., Lopez-Berestein, G., Hopfer, R., Mills, K., and Juliano, R. L. (1984). Liposomal amphotericin B is toxic to fungal cells but not to mammalian cells. Biochim. Biophys. Acta, 770. 230-234. 

Tremblay, C., Barza, M., Szoka, F., Lahav, M., and Baum, J. (1985). Reduced toxicity of liposome-associated amphotericin B injected intravitreally in rabbits. Invest. Ophthalmol. Visual Sci., 26, 711-16. 

Weereratne, E. A. H., Gregoriadis, G., and Crow, J. (1983). Toxicity of sphingomyelin-containing liposomes after chronic administration in mice, Br. J. Exp. Pathol.. 64, 670-676. 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

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