Liposomal delivery of anti-neoplastic drugs: preparation, characterization and evaluation of their in vitro and in vivo antitumor activity.

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Liposomal delivery of anti-neoplastic drugs: preparation, characterization and evaluation of their in vitro and in vivo antitumor activity.

Diss Abstr Int [B]; 55(6):2172 1994. Unique Identifier : AIDSLINE ICDB/95615339
Sharma A; State Univ. of New York at Buffalo

Abstract: Liposome-based formulation of certain antineoplastic agents may provide an opportunity to increase the antitumor efficacy and/or therapeutic index of the agents. In this research work we have prepared, characterized and evaluated several liposome formulations of two anticancer drugs, N-(phosphonacetyl)-L-aspartate (PALA) and Taxol. PALA was encapsulated in several liposome formulations to increase its cellular delivery which in turn will improve its antitumor activity. Cytostatic efficacy of liposome formulations were examined against human ovarian cancer cell lines. The optimal liposome composition was found to be DSPG:Chol (2:1), which increased the potency of encapsulated PALA by 22- to 570-fold compared to free PALA, depending on the cell line. Our studies suggested that high liposome negative surface charge density and high phase transition temperature increase both retention of liposome contents and potency of the drug. Briefer exposure of tumor cells to treatment, which simulates conditions existing in vivo more closely, further accentuates the cytostatic potency of these liposome formulations. The considerable increase in potency of PALA in liposomes suggests the possibility of enhanced antitumor activity of liposome-encapsulated PALA for ovarian cancer chemotherapy. Taxol was formulated in liposomes of various compositions to eliminate Cremophor/ethanol from the current formulation. A method of producing taxol-liposomes by lyophilization was developed, by which large batches may be prepared reproducibly in a 'pharmaceutically rational' manner. Taxol-liposomes were well-tolerated by both iv and ip routes when given as single or multiple doses to both normal and tumor-bearing mice, with lower acute and chronic toxicity than the taxol-Cremophor formulation. Antitumor effect of taxol-liposome formulations was evaluated against murine tumor models (Colon-26 and P388 leukemia) and also against a human ovarian tumor (A121a) model. Against Colon-26, free taxol was ineffective at delaying tumor growth at doses that included its MTD. In contrast, taxol-liposomes showed significant tumor growth inhibition at all the doses tested. Against P388, the free- and liposomal-taxol showed similar antitumor activity upon ip administration. Taxol-liposome formulations showed somewhat greater antitumor activity against A121a xenografts in nude mice compared to free taxol. Studies presented here have shown that liposomes are not only useful as formulation aids but may also contribute to an improvement in cytostatic and antitumor activity, and a decrease in toxicity. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-29857)

Keywords: Animal Antineoplastic Agents/*ADMINISTRATION & DOSAGE Aspartic Acid/*ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE Colonic Neoplasms/DRUG THERAPY Drug Carriers Female Human Leukemia, Experimental/DRUG THERAPY Liposomes Mice Ovarian Neoplasms/*DRUG THERAPY Paclitaxel/*ADMINISTRATION & DOSAGE Phosphonoacetic Acid/*ANALOGS & DERIVATIVES/ADMINISTRATION & DOSAGE Polyethylene Glycols THESIS
951230
M95C3243

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