X-Ray activated pharmaceutical therapy is highly sought after as it provides deep tissue, synergistic method of treating cancers in which the standard method of care involves radiotherapy. Traditional drugs utilized as neoadjuvant chemotherapy have significant side effects and a lack of selectivity, leaving a dire need for targeted drug delivery methods. We have recently developed a unique delivery platform whereby the drug is conjugated to an alkylcobalamin vitamin B12 scaffold, and these alkylcobalamins are actively transported into cells by transcobalamin receptors (TCblR). A large number of cancer types have enhanced expression of these receptors; therefore, the drug-cobalamin conjugate could be effectively ferried into the tumor selectively via the TCblR pathway. This delivery system provides light-activatable release of chemotherapeutics. Due to the drug becoming active at the specific site that it is needed, such as a tumor, the potential side effects of that drug in organs at risk are mitigated. As a proof of concept, we have found that a fluorescent cobalamin derivative localized within xenograft tumors in mice, demonstrating the effectiveness of the vitamin B12 scaffold as a theranostic targeting agent. In addition, this derivative is also activated with clinical X-ray doses from a linear accelerator. We explored the ability of a variety of cobalamin drug conjugates to be used in combination with radiotherapy to elicit an enhanced reduction in tumor margins in pancreatic adenocarcinoma models.
Light-responsive compounds can be utilized to control spatially and temporally the initiation of biochemical processes. This has the potential to improve the treatment of diseases, such as cancers, by controlling the location of drug activity at the site of disease rather than the drug acting systemically. This would reduce side-effects as well as the overall systemic dose of anticancer agents. Until recently light-responsive molecules that released active compounds in a stoichiometric manner required the use of short wavelength, high energy ultraviolet light (UV). These compounds cannot be used to treat disease because the required light wavelengths are readily absorbed by biological molecules preventing the light from penetrating tissue to an appreciable extent. Recently, we have a developed a platform technology that combines Vitamin B12 and a near infrared (NIR) absorbing fluorophore that converts an inactivated drug into an active form when exposed to NIR. In contrast to UV, NIR is poorly absorbed by biological tissues. Therefore, NIR penetrates tissue and can be used for photochemotherapeutic treatment of disease. In addition to targeting diseased tissue based on controlling drug activity by regulating light exposure, these compounds target cancer cells due to the Vitamin B12 moiety because rapidly dividing cancer cells have an increased demand for Vitamin B12 in comparison to normal, healthy cells. The reported technology could improve treatment of certain by diseases by affording effective treatment while reducing side effects.
The discovery of new tumor targeting agents is desirable to expand imaging and drug delivery platforms. Cobalamins, vitamin B12 derivatives, selectively accumulate in tumor versus benign tissue due to overexpression of transcobalamin receptors in a variety of cancer types. Multiple forms of this vitamin are taken into cells via transport through transcobalamin receptors on the cell surface. Alkylcobalamins are light-activatable, and we have discovered that the wavelength of this light activation is tunable via appendage of a fluorophore. We have been able to harness this cobalamin platform to release drugs with a variety of wavelengths of light, including those within the optical window of tissue. This cobalamin drug delivery platform provides selective spatiotemporal activation of drug only where needed, thereby diminishing side effects of traditional chemotherapy.
A Bodipy650-cobalamin was synthesized and utilized to study the tumor targeting ability of cobalamin derivatives in athymic nude mice with subcutaneous MCF-7 and MIA PaCa-2 tumors, which have been demonstrated to overexpress transcobalamin receptors. The fluorescently labeled cobalamin was injected intravenously into the mice and allowed to incubate for a series of time points. Fluorescence imaging revealed that this cobalamin conjugate selectively accumulated in both tumor types. We utilized this cobalamin platform for tumor selective, light-activated delivery of the pancreatic cancer drugs erlotinib and SN38. We determined light-induced apoptosis in MIA PaCa-2 cells in vitro and explored the reduction of MIA PaCa-2 tumors in vivo utilizing these cobalamin drug conjugates. This cobalamin platform provides potential for development of new theranostic tools for drug delivery.