Reduced Toxicity and Superior Therapeutic Activity of a Mitomycin C Lipid-Based Prodrug Incorporated in Pegylated Liposomes
| Autor: | Aviva T. Horowitz, Samuel Zalipsky, Dinah Tzemach, Hilary Shmeeda, Alberto Gabizon, Jerry Yeh |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Time Factors Cell Survival Antineoplastic Agents Pharmacology Mitomycins Polyethylene Glycols Rats Sprague-Dawley Inhibitory Concentration 50 Mice Therapeutic index Pharmacokinetics In vivo Cell Line Tumor Animals Medicine Prodrugs Doxorubicin Mice Inbred BALB C Liposome Molecular Structure business.industry Mitomycin C Neoplasms Experimental Prodrug Rats Treatment Outcome Oncology Liposomes Female business Drug carrier medicine.drug |
| Zdroj: | Clinical Cancer Research. 12:1913-1920 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-05-1547 |
| Popis: | Purpose: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4′-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol–coated (pegylated) liposomes. Experimental Design: MMC was released from the MMC lipid–based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of ∼90 nm. This formulation was used for in vitro and in vivo tests in rodents. Results: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was ∼3-fold less toxic than free MMC. The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype. Conclusions: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC. |
| Databáze: | OpenAIRE |
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