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A Novel Technology for the Imaging of Acidic Prostate Tumors by Positron Emission Tomography

Amy L. Vvere¹, Gráinne B. Biddlecombe¹, William M. Spees², Joel R. Garbow², Dayanjali Wijesinghe³, Oleg A. Andreev³, Donald M. Engelman⁴, Yana K. Reshetnyak³ and Jason S. Lewis^1,5

¹ Division of Radiological Sciences and ² Biomedical MR Laboratory, Department of Radiology, Washington University School of Medicine, St. Louis, Missouri; ³ Physics Department, University of Rhode Island, Kingston, Rhode Island; ⁴ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut; and ⁵ Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Jason S. Lewis, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Phone: 646-888-3038; Fax: 646-422-0408; E-mail: lewisj2{at}mskcc.org.

Key Words: extracellular pH • PET • pHLIP • ⁶⁴Cu

Solid tumors often develop an acidic environment due to the Warburg effect. The effectiveness of diagnosis and therapy may therefore be enhanced by the design and use of pH-sensitive agents that target acidic tumors. Recently, a novel technology was introduced to target acidic tumors using pH low insertion peptide (pHLIP), a peptide that inserts across cell membranes as an -helix when the extracellular pH (pH_e) is acidic. In this study, we expanded the application of the pHLIP technology to include positron emission tomography imaging of the acidic environment in prostate tumors using ⁶⁴Cu conjugated to the pHLIP (⁶⁴Cu-DOTA-pHLIP). Studies showed that this construct avidly accumulated in LNCaP and PC-3 tumors, with higher uptake and retention in the LNCaP tumors. Uptake correlated with differences in the bulk pH_e of PC-3 and LNCaP tumors measured in magnetic resonance spectroscopy experiments by the ³¹P chemical shift of the pH_e marker 3-aminopropylphosphonate. This article introduces a novel class of noninvasive pH-selective positron emission tomography imaging agents and opens new research directions in the diagnosis of acidic solid tumors. [Cancer Res 2009;69(10):4510–6]