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===========================================
