A clinically promising prodrug for cancer chemotherapy is irinotecan or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)which is converted to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) in the presence of carboxylesterases (CE). SN-38 inhibits topoisomerase I, causes DNA damage and induces apoptosis. A limiting factor for the effective use of CPT-11 in patients is the dose limiting side effects such as diarrhea. Comparison of activation of CPT-11 by rabbit and human carboxylesterases has shown superior antitumor activity for rabbit CE. The goal of this research is to develop a delivery system for the SN-38 prodrug/ rabbit CE combination using a novel polymer directed enzyme prodrug therapy (PDEPT) approach. The potential for technological innovation lies in the development and commercialization of the PDEPT approach for targeted cancer chemotherapy. If successful, this strategy can be utilized for the selective delivery of other clinically useful prodrug/enzyme combinations.
The Specific Aims of this Phase I STTR application are formulated to establish the feasibility of the following: 1) To synthesize and characterize a series of N-(2-hydroxypropyl)methacrylamide -irinotecan/ SN-38 (HPMA - CPT11 ISN-38) conjugates. 2) To synthesize and characterize a series of polyethylene glycol - rabbit carboxylesterase (PEG -CE) conjugates. 3) To characterize the conjugates by biological methods in vitro to determine the release profile and cytotoxicity of the active metabolite SN-38 from HPMA - drug conjugates in the presence of CE and PEG -CE.
The goal of this research is to develop a delivery system for clinically promising prodrug/enzyme combinations for cancer chemotherapy using a polymer directed enzyme prodrug therapy (PDEPT) approach. Anti-cancer therapy represents a multibillion dollar market. The PDEPT approach allows for the selective delivery of both enzyme and the prodrugs to the tumor, therefore minimizing toxicity and maximizing efficacy.
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