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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA085577-01A1
Application #
6579486
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Fu, Yali
Project Start
2003-01-01
Project End
2006-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$302,600
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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