MEDI 228 |
| Controlling the rate of drug release from liposomal carriers is essential for optimum drug delivery. We have developed a novel nanoliposome construct encapsulating a variety of difficult to entrap anticancer drugs, including irinotecan, vincristine, topotecan, vinorelbine, and the histone deacetylase inhibitor LAQ824 with a high degree of drug loading efficiency and in vivo retention. Using a modified gradient loading method featuring a sterically hindered amine with highly charged, multivalent anionic trapping agents, including both polymeric (polyphosphate) or non-polymeric (sucrose octasulfate or inositol hexaphosphate) agents, liposomes were capable of entrapping drugs at exceptionally high drug-to-lipid ratios (> 1000 g CPT-11/mol phospholipid) and retaining encapsulated drug in vivo with a half-life of drug release significantly improved compared to formulations prepared using more standard loading technologies (t1/2 for nanoliposomal CPT11, vinorelbine, and LAQ824 was 56.8, 27.2, and 26.1 h, respectively). The acute toxicity of various liposomal formulations was affected differently, with the MTD of the liposomal formulation increasing considerably for CPT11 compared to the free drug (>320 vs 60 mg/kg), remaining similar for others (VNB), and decreasing for others (TPT and LAQ824). However, the observed therapeutic index was improved for all the drugs studied following stable liposome encapsulation. Nanoliposomal CPT-11 demonstrated markedly superior efficacy when compared to free CPT-11 in human breast (BT474) and colon (HT29) cancer xenograft models, while nanoliposomal vinorelbine displayed improved activity in a wide range of lung, colon, and breast cancer xenograft models. LAQ824 displayed improved efficacy and also demonstrated improved histone acetylation levels and ErbB2 receptor downregulation over extended periods when encapsulated. These studies shows that intraliposomal stabilization of many anticancer drugs using a polymeric or highly charged, non-polymeric polyanionic trapping agent results in stable and long circulating nanocarrier formulations of important drugs and strikingly active antitumor agents. |
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Drug Delivery
1:30 PM-4:50 PM, Tuesday, August 21, 2007 BCEC -- 210B, Oral
Division of Medicinal Chemistry |