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.

Tumor targeting vitamin B12 derivatives for X-ray induced treatment of pancreatic adenocarcinoma.

BACKGROUND: X-Ray induced phototherapy is highly sought after as it provides a deep tissue, synergistic method of treating cancers via standard-of-care radiotherapy. When this is combined with releasable chemotherapy agents, it can provide high target selectivity, with reduced off-target organ effects that limit current systemic therapies. We have recently developed a unique light-activated drug delivery system whereby the drug is conjugated to an alkylcobalamin scaffold. Alkylcobalamins are actively transported into cells by transcobalamin receptors (TCblR), which are overexpressed in a variety of cancer types. We hope to utilize this cobalamin scaffold technology for drug delivery in pancreatic adenocarcinoma (PDAC) cancer. METHODS: The ability of the cobalamin scaffold to selectively target PDAC was investigated by treating mice that had MIA PaCa-2 xenografts with an alkylcobalamin labeled with the fluorophore Bodipy650 (Bodipy650-cobalamin). The mice were imaged alive and organs as well as tumors were subsequently imaged ex vivo. In addition, we examined the potential of the cobalamin scaffold to deliver drugs to orthotopic pancreas MIA PaCa-2 tumors with Bodipy650-cobalamin. We determined the light dose required for release of cargo from the cobalamin scaffold by examining the fluorescence increase of Bodipy650-cobalamin in response to red light (650 nm). Finally, we probed the ability of the cobalamin scaffold to release cargo with increasing X-ray doses from a clinical linear accelerator. RESULTS: We have found that Bodipy650-cobalamin was shown to localize in MIA PaCa-2 tumors, both in flank and orthotopic models. We quantified a light dose for red light release from the cobalamin scaffold that is within normal clinical doses required for photodynamic therapy. This derivative was also activated with clinical X-ray doses from a linear accelerator. CONCLUSIONS: Tumor selectivity combined with fluorescence detection demonstrates the effectiveness of the vitamin B12 scaffold as a theranostic targeting agent. The activation of this scaffold with radiation from a linear accelerator shows potential for action as radiation-induced chemotherapy.