Cells Designed to Deliver Anticancer Drugs by Apoptosis

描述(由申请人提供)：目前针对实体肿瘤的药物靶向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于肿瘤内。细胞凋亡诱导药物传递(AIDD)是一种新的基于生物的药物传递策略，也是这一应用的重点。AIDD使用基因工程内皮细胞(GEECs)通过细胞凋亡来输送抗癌药物。载药的GEEC可以表达一种生长因子受体：死亡结构域融合蛋白，如Flk-L：Fas，当与血管内皮生长因子结合时，它会触发细胞凋亡。凋亡的GEECs可能通过扩散、缝隙连接和吞噬运输刺激药物输送到肿瘤细胞。这项应用的总体目标是开发、提炼和优化用于治疗脑肿瘤的GEEC。为了达到这些目标，使用体外和体内技术有三个具体目标。目的1研究将评价两种前药以减少非特异性细胞凋亡(NSA)或由载药引起的细胞凋亡。这两种前药都需要对细胞毒物质进行酶激活以诱导细胞凋亡，因此，应将GEECs中的NSA降至最低。目的2研究胶质瘤细胞吞噬凋亡的GEECs的机制。吞噬作用可能提供了一种选择性的AIDD靶向肿瘤细胞的方法，因为GEEC-胶质瘤细胞管道可以最大限度地减少药物对邻近正常组织的暴露。AIM 3将在携带脑内肿瘤的SCID小鼠身上进行药代动力学和疗效研究。药物动力学成分将决定不同GEEC系统的剂量依赖特性和肿瘤靶向能力。随后的疗效试验将只评估那些拥有最有利的肿瘤靶向特性的GEEC系统。疗效试验将对装载前药物的GEEC与一些对照治疗进行比较，包括给药前药物本身。AIDD是一种新的策略，它提供了许多机制来选择性地将抗癌药物输送到肿瘤。

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.