Cells Designed to Deliver Anticancer Drugs by Apoptosis

旨在通过细胞凋亡传递抗癌药物的细胞

• 批准号: 6579486
• 负责人: James M. Gallo
• 金额: $ 30.26万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6579486
• 关键词: SCID mouse; antineoplastics; apoptosis; brain neoplasms; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; esterase; gemcitabine; genetic manipulation; glioma; high performance liquid chromatography; method development; microdialysis; neoplasm /cancer chemotherapy; neoplastic cell; nonhuman therapy evaluation; nucleoside phosphate kinase; omega 3 fatty acid; paclitaxel; phagocytosis; pharmacokinetics; prodrugs; tissue /cell culture; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Current methods to target drugs to solid tumors rely on physical and chemical based strategies to selectively localize the drug within the tumor. Apoptotic-induced drug delivery (AIDD) is a new biologically based drug delivery strategy that is the focus of this application. AIDD uses genetically-engineered endothelial cells (GEECs) to deliver anticancer drugs by apoptosis. The drug loaded GEECs are designed to express a growth factor receptor:death domain fusion protein, such as flk-l:fas, that triggers apoptosis upon binding of vascular endothelial growth factor (VEGF). The apoptotic GEECs may stimulate drug delivery to tumor cells by diffusional, gap junctional, and phagocytic transport. The overall objectives of this application are to develop, refine and optimize GEECs for the treatment of brain-tumors. There are three Specific Aims to meet these objectives that use both in vitro and in vivo techniques. Aim 1 investigations will evaluate two prodrugs to minimize nonspecific apoptosis (NSA) or apoptosis induced by the loaded drug. Both prodrugs require enzymatic activation to cytotoxic species to induce apoptosis, and thus, should minimize NSA in the GEECs. Aim 2 studies focus on the phagocytic uptake mechanism of apoptotic GEECs by glioma cells. Phagocytosis may offer a selective means to target tumor cells by AIDD because the GEEC-glioma cell conduit may minimize drug exposure to adjacent normal tissues. Pharmacokinetic and efficacy studies will be conducted in Aim 3 in scid mice bearing intracerebral tumors. The pharmacokinetic component will determine dose-dependent characteristics and tumor targeting ability of different GEEC systems. The subsequent efficacy trials will evaluate only those GEEC systems that possessed the most favorable tumor targeting properties. The efficacy trials will compare prodrug-loaded GEECs with a number of control treatments including administration of the prodrugs themselves. AIDD is a novel strategy that offers many mechanisms to selectively deliver anticancer drugs to tumors.

描述（由申请人提供）：目前将药物靶向实体瘤的方法依赖于基于物理和化学的策略来选择性地将药物定位在肿瘤内。 细胞凋亡诱导药物递送（AIDD）是一种新的基于生物学的药物递送策略，是本申请的重点。 AIDD 使用基因工程内皮细胞 (GEEC) 通过细胞凋亡来输送抗癌药物。 负载药物的 GEEC 旨在表达生长因子受体：死亡域融合蛋白，例如 flk-l:fas，该蛋白在与血管内皮生长因子 (VEGF) 结合后触发细胞凋亡。 凋亡的 GEEC 可能通过扩散、间隙连接和吞噬转运刺激药物递送至肿瘤细胞。 该应用的总体目标是开发、完善和优化用于治疗脑肿瘤的 GEEC。 使用体外和体内技术来实现这些目标有三个具体目标。 目标 1 研究将评估两种前药，以尽量减少非特异性细胞凋亡 (NSA) 或由负载药物诱导的细胞凋亡。两种前药都需要酶激活细胞毒性物质以诱导细胞凋亡，因此应最大限度地减少 GEEC 中的 NSA。 目标 2 研究重点是胶质瘤细胞对凋亡 GEEC 的吞噬机制。 吞噬作用可能提供一种通过 AIDD 靶向肿瘤细胞的选择性方法，因为 GEEC-神经胶质瘤细胞导管可以最大限度地减少药物对邻近正常组织的暴露。 Aim 3 将在患有脑内肿瘤的 scid 小鼠中进行药代动力学和功效研究。 药代动力学成分将决定不同GEEC系统的剂量依赖性特征和肿瘤靶向能力。 随后的功效试验将仅评估那些具有最有利的肿瘤靶向特性的 GEEC 系统。 功效试验将负载前药的 GEEC 与许多对照治疗（包括前药本身的给药）进行比较。 AIDD 是一种新颖的策略，提供了多种机制来选择性地将抗癌药物递送至肿瘤。