Radiation-Activated Cobalamin-Kinase Inhibitors for Treatment of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most dismal diagnoses that a patient can receive. PDAC is extremely difficult to treat, as drug delivery is challenging in part due to the lack of vascularization, high stromal content, and high collagen content of these tumors. We have previously demonstrated that attaching drugs to the cobalamin scaffold provides selectivity for tumors over benign cells due to a high vitamin demand in these rapidly growing cells and an overexpression of transcobalamin receptors in a variety of cancer types. Importantly, we have shown the ability to deliver cobalamin derivatives to orthotopic pancreas tumors. Tyrosine kinase inhibitors have shown promise in treating PDAC as well as other cancer types. However, some of these inhibitors suffer from drug resistance, and as such, their success has been diminished. With this in mind, we synthesized the tyrosine kinase inhibitors erlotinib (EGFR) and dasatinib (Src) that are attached to this cobalamin platform. Both of these cobalamin-drug conjugates cause visible light-induced apoptosis, and the cobalamin-erlotinib conjugate ( 2 ) causes X-ray-induced apoptosis in MIA PaCa-2 cells. Both visible light and X-rays provide spatial control of drug release; however, utilizing X-ray irradiation offers the advantage of deeper tissue penetration. Therefore, we explored the utilization of 2 as a synergistic therapy with radiation in athymic nude mice implanted with MIA PaCa-2 tumors. We discovered that the addition of 2 caused an enhanced reduction in tumor margins in comparison with radiation therapy alone. In addition, treatment with 2 in the absence of radiation caused no significant reduction in tumor size in comparison with the controls. The cobalamin technology presented here allows for the spatial release of drugs in conjunction with external beam radiation therapy, potentially allowing for more effective treatment of deep-seated tumors with less systemic side effects.