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Abstract
Grant Number: 5R42CA075761-03 PI Name: PEREZ-SOLER, ROMAN PI Email: rperezso@montefiore.org PI Title: CHAIRMAN Project Title: Long-Circulating Liposomal Camptothecins CAP and EAP Abstract: DESCRIPTION (provided by applicant): Based on the extensive data generated during the phase I portion of our studies, there is sufficient and compelling information to support the further development of the highly lipophilic and blood-stable topoisomerase inhibitor, DB-67. In part, the pre-clinical and clinical evaluation of DB-67 is currently being supported by the NCI through the RAID program; the RAID program studies focus on the non-targeted, liposomal delivery of DB-67, in which DB-67 is formulated in the bilayer of the liposome vesicle. This phase II STTR proposal focuses on the liposomal delivery of core-loaded DB-67 prodrug esters. Liposomal core-loading is a feature of FDA-approved liposomal products such as Doxil and DaunoXome and tumor-targeting has been documented for these formulations. The phase II studies proposed below focus on a novel approach allowing for the liposomal delivery of core-loaded DB-67 prodrug esters, which will permit tumor targeting and, accordingly, effect lower systemic toxicity to the DB-67 agent. The chemistry of the liposomal carriers will be adjusted in order to optimize the following: drug retention in the particle in circulation; particle targeting to the tumor by passive mechanisms; the controlled, slow and continuous release of the active, S-phase specific agent at the tumor site resulting in optimal anticancer activity with minimal systemic toxicity. Thus, the specific aims are as follows: 1) scale-up synthesis of chemically-activated pro-drug (CAP) and enzymatically-activated pro-drug (EAP) esters of DB-67 which actively load info the aqueous core of liposomes and 2) liposomal core-loading of CAP and EAP DB-67 esters and optimization of drug retention; and 3) in vitro and in vivo evaluation of liposomal core-loading of CAP and EAP DB-67 esters. Ultimately, we will seek formulation(s) that display optimized drug retention and in vivo and in vitro performance. PROPOSED COMMERCIAL APPLICATION: Not Available
Thesaurus Terms:
analog, camptothecin, drug design /synthesis /production, liposome, prodrug
DNA topoisomerase, enzyme inhibitor
laboratory mouse
Institution: TIGEN PHARMACEUTICALS UNIVERSITY OF KENTUCKY LEXINGTON, KY 40506 Fiscal Year: 2003 Department: Project Start: 06-MAY-1998 Project End: 31-DEC-2003 ICD: NATIONAL CANCER INSTITUTE IRG: ZRG1
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