| Autor: |
Viola-Villegas NT; Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology., Carlin SD; Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology., Ackerstaff E; Medical Physics., Sevak KK; Departments of Radiology., Divilov V; Departments of Radiology., Serganova I; Neurology, and., Kruchevsky N; Medical Physics., Anderson M; Department of Physics, University of Rhode Island, Kingston, RI 02881; and., Blasberg RG; Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology,Neurology, and., Andreev OA; Department of Physics, University of Rhode Island, Kingston, RI 02881; and., Engelman DM; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520 donald.engelman@yale.edu lewisj2@mskcc.org., Koutcher JA; Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology,Medical Physics,Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;, Reshetnyak YK; Department of Physics, University of Rhode Island, Kingston, RI 02881; and., Lewis JS; Program in Molecular Pharmacology and Chemistry, andDepartments of Radiology, donald.engelman@yale.edu lewisj2@mskcc.org. |
| Abstrakt: |
Generally, solid tumors (>400 mm(3)) are inherently acidic, with more aggressive growth producing greater acidity. If the acidity could be targeted as a biomarker, it would provide a means to gauge the pace of tumor growth and degree of invasiveness, as well as providing a basis for predicting responses to pH-dependent chemotherapies. We have developed a (64)Cu pH (low) insertion peptide (pHLIP) for targeting, imaging, and quantifying acidic tumors by PET, and our findings reveal utility in assessing prostate tumors. The new pHLIP version limits indiscriminate healthy tissue binding, and we demonstrate its targeting of extracellular acidification in three different prostate cancer models, each with different vascularization and acid-extruding protein carbonic anhydrase IX (CAIX) expression. We then describe the tumor distribution of this radiotracer ex vivo, in association with blood perfusion and known biomarkers of acidity, such as hypoxia, lactate dehydrogenase A, and CAIX. We find that the probe reveals metabolic variations between and within tumors, and discriminates between necrotic and living tumor areas. |
