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alpha(v)beta(3) integrin is a marker of tumor neoangiogenesis that specifically binds to RGD containing peptides. Hence, the present study is focused on the development of Tc-99m-labeled bivalent DTPA-bis-c(RGDfK) conjugate and its preclinical evaluation on human tumor cell lines expressing alpha(v)beta(3) targets. Homobivalent DTPA-bis-c(RGDfK) was prepared and assessed for its affinity and specificity in alpha(v)beta(3) positive (and negative) receptor cell lines. DTPA-bis-c(RGDfK) conjugate was labeled with Tc-99m and subjected to cells/tissue sections. Localization of alpha(v)beta(3) expression was corroborated using immunostaining and ex vivo imaging of the distribution pattern of Tc-99m-DTPA-bis-c(RGDfK). The radiolabeling of the DTPA-bis-c(RGDfK) with Tc-99m is obtained after 45 min at 95 degrees C with a radiochemical yield of about 45%. Radiochemical purity was >95% after C18 Oasis HLB cartridge purification with specific activity of 1475 GBq mmoL(-1). In vitro experiments showed high affinity and specificity for alpha(v)beta(3) with IC50 of 32.86 +/- 7.83 nmol L-1. Ex vivo imaging on tissue sections confirmed preliminary specificity results. In vivo analysis in a mouse model showed that this tracer was able to detect and readily identify U87MG and B16F10 alpha(v)beta(3) positive tumors 60 minutes post-injection. c(RGDfK) blocking experiments confirmed its excellent affinity and specificity to alpha(v)beta(3) receptors in U87MG tumors. The radiotracer was mainly excreted through the renal route with minimal radioactivity being excreted through the hepatobiliary route. Tc-99m-DTPA-bis-c(RGDfK) can be an excellent scintigraphic agent for imaging of alpha(v)beta(3) receptors being expressed in abundance in malignant glioma and melanoma cancer.