Research Project
6479039
DESCRIPTION (provided by applicant): The objective of this proposal is to advance the development of a novel tumor- targeted antineoplastic drug conjugate. Our concept is based on the use of the vitamin folate to deliver a potent, covalently-attached chemotherapeutic drug to folate receptor (FR)-positive tumors in vivo and to potentiate a greater anti-tumor response in syngeneic animal models relative to that obtained with the un-conjugated drug. It is well-known that many types of human cancers vastly over-express FR and that folate-macromolecule conjugates specifically bind to and enter FR-expressing tumor cells via an endocytosis mechanism. Importantly, internalized folate-drug conjugates are exposed to both acidic and reducing environments within these intracellular endocytic compartments. Thus, high therapeutic efficacy may result from the use of potent folate-drug conjugates constructed with endosome-labile linkers. As such, the following specific aims are proposed: i) synthesize a novel acid- cleavable folate-drug conjugate, ii) synthesize a related thiol-labile folate- drug conjugate, iii) conduct in vitro dose-response cytotoxicity studies, and iv) conduct an initial therapeutic animal study with the more potent folate- drug conjugate. Following the completion of these specific aims, a Phase II project will be initiated which will include the submission of a corporate IND application for a folate-drug conjugate to the FDA and the initiation of an IND Phase I clinical study.
