Long Circulating Liposomal Camptothecins CAP and EAP

描述(申请人提供)：基于生成的大量数据 在我们研究的第一阶段，有足够的和令人信服的 信息，以支持进一步发展的高度亲油和 血液稳定的拓扑异构酶抑制剂DB-67。在一定程度上，临床前和 DB-67的临床评估目前由NCI通过以下方式提供支持 Raid计划；Raid计划研究的重点是非靶向脂质体 DB-67的输送，其中DB-67在脂质体的双层中配制 水泡。这项第二阶段的STTR提案侧重于脂质体的给药 核心负载的DB-67前药酯。脂质体载核是阿司匹林的一个特点 FDA批准的脂质体产品，如Doxil和DaunoXome与肿瘤靶向 已经记录了这些配方。第二阶段研究建议如下 聚焦于一种允许脂质体给药的新方法 DB-67前药酯，它将允许肿瘤靶向，相应地， 对DB-67药剂具有较低的全身毒性。美国的化学反应 脂质体载体将进行调整，以优化以下内容：药物 滞留在循环中的颗粒；通过以下方式将颗粒靶向肿瘤 被动机制；受控的、缓慢的和持续的释放主动的、 S-肿瘤部位特异剂抗癌效果最佳 全身毒性最小的活性。因此，具体目标如下 1)化学活化前体药物(CAP)的放大合成 主动负载信息的DB-67酶激活前药物(EAP)酯 脂质体的水核及脂质体CAP和EAP的载药 DB-67酯与药物保留优化；3)体内外研究 CAP和EAP DB-67酯的脂质体载核性评价最终， 我们将寻求显示优化药物保留和体内作用的处方(S) 和体外表现。 建议的商业应用： 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