Delivery of Drugs in Temperature-Sensitive Liposomes
In the presence of certain serum components, principally the lipoproteins, small unilamellar vesicles (SUV) can be made to release their contents rapidly and completely at the liquid crystalline phase transition temperature. By using a mixture of lipids with phase transition at about 42°C the SUV can be designed to release a drug preferentially in a capillary bed (for example, in a tumor) subjected to moderate local hyperthermia. We have made such “temperature-sensitive” liposomes from 7:1 to 7:3 (molar) mixtures of dipalmitoyl and distearoyl phosphatidylcholines and have characterized their interactions with serum components. All of the standard lipoprotein fractions promote release of contents at the transition, as does at least one non-lipoprotein component.
The SUV released essentially all of their contents of carboxyfluorescein dye during a single pass through a heated capillary bed in rat intestine. When injected i.v. in mice with subcutaneous L1210 tumors, they delivered 14 times as much 3H-methotrexate (MTX) to tumors heated to 42°C by water bath as compared to unheated tumors in the same animals. Inhibition studies with unlabelled MTX and with folinic acid indicated that the 3H-MTX had reached its site of action in the cell cytoplasm and that it had entered the cells by its normal transport mechanisms. Local heating did not increase accumulation of MTX in other parts of the body, suggesting that an increase in therapeutic index can be achieved with temperature-sensitive liposomes. Qualitatively similar results were obtained when subcutaneous Lewis lung tumors in the flanks of mice were heated with microwaves. Using therapeutic levels of liposomal MTX we obtained a 4- to 16-fold greater cell kill for the L1210 tumor than could be explained by the separate effects of heat and liposome-entrapped MTX.
Large multilamellar vesicles do not have characteristics appropriate for use as temperature-sensitive liposomes, but large uni-lamellar liposomes appear more favourable in that they can be made to release their contents (carboxyfluorescein, MTX, cytosine arabinoside) rapidly in the presence of serum. Because of their much larger ratio of internal volume to lipid, large unilamellar temperature-sensitive liposomes may prove especially useful in vivo.
KeywordsHigh Density Lipoprotein Serum Component Small Unilamellar Vesicle Large Unilamellar Vesicle Local Hyperthermia
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- Haest, C.M.W., de Gier, J.A., van Es, G.A., Verkleij, A.J. and van Deenan, L.L.M., 1972, Fragility of the permeability barrier of Escherichia coli, Biochim. Biophys. Acta 288: 43Google Scholar
- Hagins, W.A. and Yoshikami, S., 1977, Intracellular transmission of visual excitation in photoreceptors: Electrical effects of chelating agents introduced into rods by vesicle fusion, in: Vertebrate Photoreception, P. Fatt, H.B. Barlow, eds. Academic Press, New York.Google Scholar
- Hahn, G.M., 1978, Interactions of drugs and hyperthermia in vitro and in vivo., in: Cancer Treatment by Hypertheria and Radiation, C. Streffer, ed., Urban and Schwarzenberg, Baltimore.Google Scholar
- Har-Kedar, I. and Bleehen, N.M., 1976, Expereimental and clinical aspects of hyperthermia applied to the treatment of cancer with special reference to the role of ultrasonic and microwave heating, Adv. Radiat. Biol. 6: 229Google Scholar
- Schabel, F.M., 1977, Quantitative evaluation of anticancer agent activity in experimental animals, Pharmacology and Therapeutics (Part A) 1: 411.Google Scholar
- Scherphof, G., Morselt, H., Regts, J. and Wilschut, J.C., 1979, The involvement of the lipid phase transition in the plasma-induced dissolution of multilamellar phosphatidylcholine vesicles, Biochim. Biophys. Acta 56: 196.Google Scholar
- Streffer, C., 1978, “Cancer Therapy by Hyperthermia and Radiation”, Urban and Schwarzenberg, Baltimore.Google Scholar
- Weinstein, J.N., Klausner, R.D., Innerarity, T.L., Ralston, E., and Blumenthal, R., 1981, “Phase transition release” (PTR), a new approach to the interaction of proteins with lipid vesicles: Application to lipoproteins, Biochim. Biophys. Acta, in press.Google Scholar
- Weissmann, G., Bloomgarden, D., Kaplan, R., Cohen, C., Hoffstein, S., Collins, T., Gotlieb, A. and Nagle, D., 1975, A general method for the introduction of enzymes, by means of immunoglobulincoated liposomes, into lysosomes of deficient cells, Proc. Natl. Acad. Sci. USA. 72: 88.PubMedCrossRefGoogle Scholar
- Zaharko, D.S., Dedrick, R.L., Peale, A.L., Drake, J.C. and Lutz, R.J., 1974, Relative toxicity of methotrexate in several tissues of mice bearing Lewis lung carcinoma, JPET 189: 585.Google Scholar