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: 6692985
• 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 2004-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692985
• 关键词: Cells; Designed; Deliver; Anticancer; Drugs

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（申请人提供）：当前将药物靶向实体瘤的方法依赖于物理和化学化学策略来选择性地将药物定位在肿瘤中。 凋亡诱导的药物输送（AIDD）是一种基于生物学的药物输送策略，是该应用的重点。 AIDD使用遗传工程的内皮细胞（GEEC）通过细胞凋亡提供抗癌药物。 该药物负载的地理位置旨在表达生长因子受体：死亡结构域融合蛋白，例如FLK-L：FAS，可在血管内皮生长因子（VEGF）结合时触发凋亡。 凋亡的地理位置可能会通过扩散，间隙连接和吞噬转运刺激药物递送到肿瘤细胞中。 该应用程序的总体目标是开发，完善和优化用于治疗脑肿瘤的地理位置。 有三个特定的目的旨在实现这些在体外和体内技术都使用的目标。 AIM 1研究将评估两种前药，以最大程度地减少非特异性细胞凋亡（NSA）或已加载药物诱导的凋亡。这两种前药都需要酶促激活对细胞毒性物种，以诱导凋亡，因此应最大程度地减少NSA。 AIM 2研究集中于神经胶质瘤细胞凋亡地质的吞噬摄取机制。 吞噬作用可以通过AIDD靶向肿瘤细胞的选择性手段，因为地质 - 胶质瘤细胞导管可以最大程度地减少药物暴露于相邻的正常组织。 在具有脑内肿瘤的SCID小鼠中，将在AIM 3中进行药代动力学和功效研究。 药代动力学成分将确定不同地质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地理系统。 功效试验将将前药的地理位置与多种控制治疗（包括给药本身）进行比较。 AIDD是一种新型策略，它提供了许多机制，可以选择性地将抗癌药物输送到肿瘤中。