Long Circulating Liposomal Camptothecins CAP and EAP

描述（由申请人提供）：基于生成的大量数据 在我们研究的第一阶段， 信息，以支持进一步开发的高度亲脂性和 血液稳定的拓扑异构酶抑制剂DB-67在某种程度上，临床前和 DB-67的临床评价目前正由NCI通过以下方式提供支持： RAID计划; RAID计划研究侧重于非靶向脂质体 DB-67的递送，其中DB-67被配制在脂质体的双层中 囊泡这一II期STTR提案的重点是脂质体递送 负载核心的DB-67前药酯。脂质体核心装载是 FDA批准的脂质体产品，如Doxil和DaunoXome和肿瘤靶向 已记录这些制剂。下文提议的II期研究 集中在一种新的方法，允许脂质体递送的核心负载 DB-67前药酯，其将允许肿瘤靶向，因此， 对DB-67药剂的全身毒性较低。的化学性质 将调整脂质体载体以优化以下内容： 保留在循环中的颗粒中;通过 被动机制;活性药物的受控、缓慢和持续释放， 肿瘤部位的S期特异性药物导致最佳抗癌效果 具有最小全身毒性的活性。因此，具体目标如下： 如下：1）化学活化的前药（CAP）的放大合成， DB-67的酶促活化前药（EAP）酯，其主动装载信息 脂质体水核心和2）CAP和EAP的脂质体核心负载 DB-67酯和药物保留的优化;和3）体外和体内 CAP和EAP DB-67酯的脂质体核心负载的评价。最后， 我们将寻求表现出优化的药物保留和体内 和体外性能。 拟定商业应用： 不可用

DESCRIPTION (provided by applicant): Based on the extensive data generated during the phase I portion of our studies, there is sufficient and compelling information to support the further development of the highly lipophilic and blood-stable topoisomerase inhibitor, DB-67. In part, the pre-clinical and clinical evaluation of DB-67 is currently being supported by the NCI through the RAID program; the RAID program studies focus on the non-targeted, liposomal delivery of DB-67, in which DB-67 is formulated in the bilayer of the liposome vesicle. This phase II STTR proposal focuses on the liposomal delivery of core-loaded DB-67 prodrug esters. Liposomal core-loading is a feature of FDA-approved liposomal products such as Doxil and DaunoXome and tumor-targeting has been documented for these formulations. The phase II studies proposed below focus on a novel approach allowing for the liposomal delivery of core-loaded DB-67 prodrug esters, which will permit tumor targeting and, accordingly, effect lower systemic toxicity to the DB-67 agent. The chemistry of the liposomal carriers will be adjusted in order to optimize the following: drug retention in the particle in circulation; particle targeting to the tumor by passive mechanisms; the controlled, slow and continuous release of the active, S-phase specific agent at the tumor site resulting in optimal anticancer activity with minimal systemic toxicity. Thus, the specific aims are as follows: 1) scale-up synthesis of chemically-activated pro-drug (CAP) and enzymatically-activated pro-drug (EAP) esters of DB-67 which actively load info the aqueous core of liposomes and 2) liposomal core-loading of CAP and EAP DB-67 esters and optimization of drug retention; and 3) in vitro and in vivo evaluation of liposomal core-loading of CAP and EAP DB-67 esters. Ultimately, we will seek formulation(s) that display optimized drug retention and in vivo and in vitro performance. PROPOSED COMMERCIAL APPLICATION: Not Available