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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Photodynamic Molecular Beacons Triggered by MMP-2 and MMP-9: Influence of the Distance Between Photosensitizer and Quencher onto Photophysical Properties and Enzymatic Activation

Author(s): M. Verhille, H. Benachour, A. Ibrahim, M. Achard, P. Arnoux, M. Barberi-Heyob, J.-C. Andre, X. Allonas, F. Baros, R. Vanderesse and C. Frochot

Volume 19 , Issue 32 , 2012

Page: [5580 - 5594] Pages: 15

DOI: 10.2174/092986712803833128

Price: $65

Abstract

Angiogenesis is a key step in the tumoral progression process. It is characterized by an over-expression of a number of matrix metalloproteinases (MMP). Among these MMPs, gelatinases (MMP-2 and MMP-9) are known to play a critical role in tumor angiogenesis and the growth of many cancers. Photodynamic Molecular Beacons (PMB) can be designed for cancer treatment by associating a chlorin-like photosensitizer and a black hole quencher linked by a gelatinase substrate peptide with the aim of silencing photosensitizer toxicity in non-targeted cells and restore its toxicity only in surrounding gelatinases. This article provides a report on the synthesis and photophysical and biochemical studies of new families of PMB, using tetraphenylchlorin and a black hole quencher as a donor-acceptor pair, and MMP specific sequence (H-Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln-Lys-OH or H-Pro-Leu-Gly-Leu-OH) to keep them in close proximity. Different spacers were used to evaluate the influence of the distance between the photosensitizer and the quencher on the photophysical properties and enzymatic activation of the PMB. Time-resolved quenching experiments were performed and FRET energy transfer could be observed. Photosensitizers’ triplet state band in transient absorption disappears in PMB. However, even if both MMP-2 and MMP-9 were found to efficiently cleave the peptide alone, no cleavage was observed for all PMB. Further studies would be required to assess the ability of the PMB constructs to retain the sensitivity of the peptide linker to be cleaved by matrix metalloproteinases.

Keywords: Energy transfer, molecular beacon, matrix metalloproteinases activities, photodynamic therapy, photosensitizer, targeting, quenching, "Angiogenesis", "MMPs, gelatinases", "olecular Beacons"


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