Re/ ^99m Tc 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 <i>Kras</i>^G12D 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.