Cells Designed to Deliver Anticancer Drugs by Apoptosis

超出所提供的空间。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在肿瘤内。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，是该应用的重点。AIDD使用!基因工程内皮细胞（GEECs）通过凋亡传递抗癌药物。负载药物的geec被设计用于表达一种生长因子受体：死亡结构域融合蛋白，如flk- 1:fas，在与血管内皮生长因子（VEGF）结合后触发细胞凋亡。凋亡的geec可能通过弥漫性、间隙连接性和吞噬性转运刺激药物传递到肿瘤细胞。这项应用的总体目标是开发、完善和优化用于脑肿瘤治疗的geec。有三个特定的目的，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，以减少非特异性细胞凋亡（NSA）或由负载药物诱导的细胞凋亡。这两种前药都需要酶激活细胞毒性物质来诱导细胞凋亡，因此应尽量减少geec中的NSA。目的2研究胶质瘤细胞吞噬摄取凋亡geec的机制。吞噬作用可能是通过AIDD靶向肿瘤细胞的一种选择性手段，因为geec -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。将在Aim 3中对患有脑瘤的scid小鼠进行药代动力学和疗效研究。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。后续的疗效试验将只评估那些具有最有利的肿瘤靶向特性的GEEC系统。疗效试验将比较3种载药geec与许多对照治疗，包括前药本身的施用。艾滋病是一种新的策略，它提供了许多机制来选择性地向肿瘤输送抗癌药物。性能关键人员 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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 thal 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 _nd efficacy studies will be conducted in Aim 3 in scid mice bearing intracerebral tumors. The )harmacokinetic component will determine dose-dependent characteristics and tumor targeting ability of Jifferent GEEC systems. The subsequent efficacy trials will evaluate only those GEEC systems that )ossessed the most favorable tumor targeting properties. The efficacy trials will compare 3rodrug-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. PERFORMANCE KEY PERSONNEL ========================================Section End===========================================