Within this grant application we present exciting new data that demonstrate long-circulating liposomal formulations of camptothecins markedly improve blood stabilities, enhance drug circulation half-lives, and dramatically potentiate and enhance anti-tumor activities. We also describe our very recent synthetic efforts which have developed highly potent A,B,E-ring modified camptothecins displaying markedly improved human blood stabilities. We now intend to combine the rational drug design with liposomal delivery approaches to generate long-circulating and tumor- targeted liposomal camptothecin formulations for the treatment of cancer.
Our specific aims i nclude: 1) to develop novel and potent 7-alkylamino- homocamptotechin as well as 7-silylalkylaminohomocamptothecin topoisomerase I inhibitors capable of being remote-loaded into stealth-like, long-circulating liposomes; 2) to formulate long-circulating and is highly preferred by the pharmaceutical industry for manufacturing reasons) and to implement our synthetic abilities to create the camptothecin agents that display optimal retention in liposomes thereby optimizing drug delivery to the tumor; 3) to characterize the cellular pharmacology and blood chemistry of the new analogues and their liposomal formulations; 4) to determine in vivo anti-tumor activities, and tumor localization of the various camptothecin liposomal formulations against human xenografts; 5) to utilize fluorescence imaging methods to non-invasively study in situ the accumulation camptothecins delivered in liposomes at tumor sites in athymic nude mice.
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