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Summary: In vitro and in vivo investigation of matrix metalloproteinase
expression in metastatic tumor models
Jennifer E. Sprague1
, Wen Ping Li1
, Kexian Liang, Samuel Achilefu, Carolyn J. Anderson4
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Received 31 March 2005; received in revised form 17 October 2005; accepted 20 October 2005
Abstract
Introduction: Overexpression of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, has been correlated with poor
prognosis in several cancer types including lung, colon and breast. Noninvasive detection of MMP expression might allow physicians to
better determine when more aggressive cancer therapy is appropriate. The peptide CTT (CTTHWGFTLC) was identified as a selective
inhibitor of MMP-2/9 that inhibits the growth of MDA-MB-435 human breast cancer xenografts.
Methods: CTT was conjugated with the bifunctional chelator DOTA (1,4,7,10-tetraazacyclotetradecane-N,NV,NW,Nj-tetraacetic acid) for
radiolabeling with 64
Cu (t1/2 =12.7 h, 17.4% h+
, 39% hÀ
), a radionuclide suitable for positron emission tomography (PET). In vitro affinity
was determined in a fluorogenic substrate assay. Tumor gelatinase targeting was evaluated in both biodistribution and microPET imaging
studies.
Results: Cu(II)-DOTA-CTT inhibited hMMP-2 (EC50 =8.7 AM) and mMMP-9 (EC50 =18.2 AM) with similar affinity to CTT (hMMP-2
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