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、评估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、剂量、药效学、细胞毒性、疗效和毒理学。使用FACS纯化的CSCs的体外和体内实验将用于评估杀伤分化的肿瘤细胞和CSCs的效果。NE-DHA-SBT-1214将静脉注射(i.v.)使用经过验证的分析方法检查药物随时间的累积和生物分布。这项提案的目标是全面描述一种新型的基于纳米药物的DHA-SBT-1214剂型，该剂型用于治疗耐多药的胃肠道癌(GIC)和其他癌症，并准备将这种疗法推向临床所需的Pre-IND数据。改善CSC细胞毒性药物的传递、蓄积和药代动力学，同时限制全身暴露，将最大限度地减少累积的剂量依赖副作用，并大大提高疗效。对于新诊断的GIC患者，他们中的大多数由于CSCs而迅速进展到化疗耐药状态，这项研究的结果将提供一种在用尽高度侵袭性癌症的临床选择之前迫切需要的治疗方案。概述的IND前研究将以临床知识和经验为指导，因为它们将进入第一次人类临床试验。

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.