There is a dire need to develop more effective treatments for pancreatic ductal adenocarcinoma (PDAC), due to the unique microenvironment of the pancreas tumor, which includes lack of vascularization and high stromal pressure. Current treatment options are limited, ineffective, and suffer from severe side effects due to lack of selectivity for tumor versus healthy tissue. The cobalamin scaffold represents a new selective drug delivery and release platform that allows active receptor mediated uptake of chemotherapeutics into pancreatic tumor cells that wields maximum efficiency while minimizing side effects. A vitamin B12 targeted photopharmaceutic therapy (PPT) platform technology is proposed that allows amplified intracellular uptake and targeted release of active drug. This allows release of active drug only in the area needed, such as a tumor, which avoids the typical side effects seen with chemotherapeutics. This platform is derived from the alkylcobalamin scaffold, which is structurally related to vitamin B12 and is actively transported into cells by transcobalamin receptors (TCblR). PDAC has enhanced expression of these receptors; therefore, the drug-cobalamin conjugate could be effectively ferried into the tumor via the TCblR pathway. The cobalamin platform can be used to: a) effectively deliver drugs in an inactive form into tumors disguised as vitamin B12 derivatives b) release the drug in response to near-infrared (NIR) light at the tumor site c) be used in combination with radiotherapy to elicit an enhanced reduction in tumor margins. This work is significant in that it addresses a need for a chemotherapy that is selective for cancer cells, in that it is taken into pancreatic cancer cells utilizing a pathway that is overexpressed (TCblR), and actively can amplify the internal drug delivery. The PPT technology could be used in combination with radiation therapy, and we will examine Cherenkov-mediated release, as a way to amplify the efficacy of radiotherapy.

Vitamin B12 derivatives for photopharmaceutical therapy

256th National Meeting (2018)

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