IN VIVO IMAGING OF MATRIX METALLOPROTEASE

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION: (Applicant's Description) The ability to detect specific enzyme activities in vivo would have far reaching applications in diagnosing, characterizing and assessing novel treatments of cancer. We have recently developed and validated imaging probes for the in vivo sensing of specific proteases and have targeted enzymes that play key roles in different aspects of cancer growth, metastases formation and angiogenesis. The probes are based on 1) biocompatible long circulating graft copolymers which are efficiently internalized into tumor cells and 2) contain autoquenched near infrared fluorochromes (NIRF) positioned on cleavable peptide stalks attached to a delivery graft copolymer. When the peptide substrate is cleaved, released fluorochromes become highly fluorescent (up to 350-fold signal amplification documented so far). The overall goal of this proposal is to develop and test matrix metalloproteinase-2 (MMP-2) specific probes since the enzyme is prominently involved in angiogenesis and metastagenesis. During the R21 phase of the grant proposal (year 01), we will scale up the synthesis of a prototype MMP-2 probe, characterize it and perform key in vivo imaging experiments in a murine tumor model. In the subsequent R33 phase of the proposal (years 02-04 ) we will pursue the following aims: 1) optimize the substrate using combinatorial peptide libraries to further increase signal amplification; 2) test the in vivo imaging approach using different NIRF imaging systems; and 3) test the probes and imaging techniques during therapy in models of ovarian cancer disseminated to the peritoneal cavity. Regarding the latter we will ask the following clinically highly relevant questions: 1) can the methodology be applied to detect micrometastatic serosal tumor implants and 2) can the efficacy of MMP inhibitors be imaged at the molecular level before phenotypic changes become apparent? This proposal represents a multidisciplinary effort in developing a novel approach to detect minimal residual tumor and assess anti-MMP-2 treatment of cancer at the molecular level. The approach, if successful, is expected to have broad applications to a wide variety of biologic, immunologic, and molecular therapies designed to promote the control and eradication of cancer.