Cells Designed to Deliver Anticancer Drugs by Apoptosis

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，以选择性地将药物定位在肿瘤内。 凋亡诱导的药物递送（AIDD）是一种新的基于生物学的药物递送策略，是本申请的焦点。 AIDD使用基因工程内皮细胞（GEEC）通过细胞凋亡来递送抗癌药物。 设计载药GEEC以表达生长因子受体：死亡结构域融合蛋白，如flk-1：fas，其在结合血管内皮生长因子（VEGF）时触发细胞凋亡。 凋亡的GEEC可以通过扩散、缝隙连接和吞噬转运刺激药物递送至肿瘤细胞。 本申请的总体目标是开发、改进和优化用于治疗脑肿瘤的GEEC。 有三个具体目标，以满足这些目标，使用体外和体内技术。 目的1研究将评估两种前药以最小化非特异性细胞凋亡（NSA）或由负载药物诱导的细胞凋亡。两种前药都需要酶促活化细胞毒性物质以诱导细胞凋亡，因此应使GEEC中的NSA最小化。 目的2研究胶质瘤细胞吞噬凋亡GEEC的机制。 吞噬作用可以提供通过AIDD靶向肿瘤细胞的选择性手段，因为GEEC-神经胶质瘤细胞管道可以使药物暴露于邻近正常组织最小化。 药代动力学和疗效研究将在Aim 3中在携带脑内肿瘤的scid小鼠中进行。 药代动力学部分将确定不同GEEC系统的剂量依赖性特征和肿瘤靶向能力。 随后的有效性试验将仅评价那些具有最有利的肿瘤靶向特性的GEEC系统。 功效试验将比较前药负载的GEEC与许多对照治疗，包括前药本身的施用。 AIDD是一种新的策略，提供了许多机制来选择性地将抗癌药物递送到肿瘤。

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.