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 and tumors were also 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.