Re/99mTc Tricarbonyl Phenformin Complexes Targeting Mitochondria as Pancreatic Cancer Theranostics

Phenformin has antitumor effects against pancreatic cancer. We report a phenformin complex with the technetium-99m tricarbonyl [99mTc(CO)3], termed 99mTc-Phen, that permitted noninvasive visualization of tumor uptake in models of pancreatic cancer by single-photon emission computed tomography. 99mTc-Phen’s nonradioactive, structurally matched counterpart [Re(CO)3]-phenformin, termed Re-Phen, showed antitumor activity against an orthotopic murine pancreatic ductal adenocarcinoma tumor with KrasG12D mutation in immunocompetent mice but not against orthotopically inoculated human MiaPaca-2 PDAC xenografts in nude mice. In vitro, Re-Phen was less potent than phenformin in inhibiting cell proliferation and colony formation and inducing cell death. However, Re-Phen but not phenformin potently reduced mitochondrial membrane potential. Unlike phenformin, Re-Phen caused no significant changes in mitochondrial ATP production or ATP generation by glycolysis at 10–100 μM, suggesting that Re-Phen and phenformin may act through distinct mechanisms. These findings underscore the potential utility of structurally matched Re/99mTc(CO)3-biguanide complexes as a new class of theranostic pairs.