LONG-CIRCULATING LIPOSOMAL CAMPTOTHECINS

在这项拨款申请中，我们提出了令人兴奋的新数据，证明喜树碱的长循环脂质体制剂显着改善血液稳定性，延长药物循环半衰期，并显着增强和增强抗肿瘤活性。我们还描述了我们最近的合成努力，开发了高效的A，B， e环修饰喜树碱，显着改善了人类血液的稳定性。我们现在打算将合理的药物设计与脂质体给药方法结合起来，以产生长循环和肿瘤靶向的喜树碱脂质体制剂，用于治疗癌症。我们的具体目标包括：1)开发新型有效的7-烷基氨基-同型星樟碱以及7-硅基烷基氨基-同型星樟碱拓扑异构酶I抑制剂，这些抑制剂能够远程加载到隐形的、长循环的脂质体中；2)配制长循环的（制药行业出于制造原因高度偏爱的），并实施我们的合成能力来制造喜树碱制剂，该制剂在脂质体中显示最佳保留率，从而优化药物向肿瘤的输送；3)表征新的类似物及其脂质体制剂的细胞药理学和血液化学；4)确定各种喜树碱脂质体制剂对人类异种移植物的体内抗肿瘤活性和肿瘤定位；5)利用荧光成像方法无创原位研究喜树碱脂质体在胸腺裸鼠肿瘤部位的蓄积。

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 include: 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.