IGF::OT::IGF R&D- NANOEMULSION FORMULATION AND IND-ENABLING STUDIES OF A NOVEL CENTER STEM CELL CYTOTOXIC AGENT

拟议的研究将创建、评价和验证新型癌症干细胞（CSC）细胞毒性药物DHA-SBT-1214的纳米乳剂的配方、给药、药效学、细胞毒性、疗效和毒理学。使用FACS纯化的CSC的体外和体内测定将用于评估杀死分化的肿瘤细胞和CSC的功效。NE-DHA-SBT-1214将静脉内（i. v.）使用经验证的分析方法检查药物随时间的蓄积和生物分布。该提案的目标是充分表征DHA-SBT-1214的一种新型纳米药物剂型，该剂型解决了多药耐药胃肠道癌（GIC）和其他癌症，并准备将这种疗法推向临床所需的IND前数据。改善CSC细胞毒性药物的递送、积累和药代动力学，同时限制全身暴露将使累积剂量依赖性副作用最小化并大大提高功效。对于新诊断的GIC患者，其中大多数人由于CSC而迅速进展到化疗耐药状态，这项研究的结果将提供一种治疗解决方案，在用尽高度侵袭性癌症形式的临床选择之前迫切需要。概述的Pre-IND研究将在临床知识和经验的指导下进行首次人体临床试验。

The proposed studies will create, evaluate and validate the formulation, dosing, pharmacodynamics, cytotoxicity, efficacy and toxicology of a nanoemulsion of a novel cancer stem cell (CSC) cytotoxic drug DHA-SBT-1214. In vitro and in vivo assays using FACS purified CSCs will be used to assess efficacy to kill differentiated tumor cells and CSCs. NE-DHA-SBT-1214 will be administered intravenously (i.v.) to examine drug accumulation and biodistribution over time using validated analytical methods. The goals of this proposal are to fully characterize a novel nanomedicine-based dosage form of DHA-SBT-1214, that addresses multi-drug resistant gastrointesintal cancer (GIC) and other cancers and to prepare pre-IND data required to move this therapy to the clinic. Improving the delivery, accumulation, and pharmacokinetics of the CSC cytotoxic drug while limiting the systemic exposure will minimize cumulative dose-dependent side effects and greatly increase efficacy. For newly diagnosed GIC patients, a majority of whom rapidly progress to a chemoresistant state due to CSCs, the results of this investigation will offer a therapeutic solution that is urgently needed prior to exhausting the clinical options for highly aggressive forms of cancer. The Pre-IND studies outlined will be guided by clinical knowledge and experience as they advance to first-in-human clinical trials.