Vitamin B12-Mediated Transport: A Potential Tool for Tumor Targeting of Antineoplastic Drugs and Imaging Agents

Abstract

The uptake of vitamin B12 (cyanocobalamin, Cbl/VB12) in mammalian cells is mediated by specific, high-affinity receptors for the vitamin B12-binding protein, transcobalamin II, which is expressed on the plasma membrane. The receptor for vitamin B12 is overexpressed on a number of human tumors, including cancers of the ovary, kidney, uterus, testis, brain, colon, lung, and myelocytic blood cells. Furthermore, the affinity of cyanocobalamin conjugates for cell surface transcobalamin II receptors seems to be high enough so that vitamin B12 derivatization with the cytotoxic agent or carriers bearing cytotoxic drugs allows the selective delivery of diagnostic and therapeutic agents to cancer cells. Thus, conjugates of vitamin B12 enter receptor-expressing cancer cells via receptor-mediated endocytosis, and targeting may be accomplished by multiple mechanisms, depending on the drug-delivery strategy. This review summarizes the applications of vitamin B12 as a targeting ligand and highlights the various methods being developed for delivery of therapeutic and imaging agents to cancer cells in vitro and in vivo. This review reflects the potentiality of vitamin B12 for tumor targeting of chemotherapeutic and diagnostic agents.

Methionine synthase interreplacement in diatom cultures and communities: Implications for the persistence of B12 use by eukaryotic phytoplankton

“…Interestingly, human cancer cells, which are defined by their unchecked growth stage, have been found, in some cases, to be unable to convert homocysteine into methionine (the human genome contains only the B 12 -requiring MetH methionine synthase isoform; Breillout et al 1990). Additionally, B 12 transport is elevated in tumor cells (Gupta and Jain 2008;Waibel et al 2008); together these observations suggest that there may be relevant biological phenomena yet to be uncovered regarding eukaryotic cells and the interactions between their cellular growth phases and methionine and vitamin B 12 nutrition.…”

A Human Vitamin B12 Trafficking Protein Uses Glutathione Transferase Activity for Processing Alkylcobalamins

“…Furthermore, a practical application of vitamin B 12 is its potential use as a vehicle for delivery of drugs or fluorescent imaging probes and for targeting certain cancers (25) where the cell-surface receptor for the vitamin B 12 binder transcobalamin II is overexpressed (26). Therefore, to assess the latitude that MMACHC exhibits for its alkyl substrate, we assessed the reactivity of a series of alkylcobalamins (Table 1).…”

Tunable Visible and Near‐IR Photoactivation of Light‐Responsive Compounds by Using Fluorophores as Light‐Capturing Antennas

“…[9] Cobalamins offer a potentially attractive alternative since conjugates of the latter appear to be retained by endosomes. [10] There has been a herculean effort to create delivery strategies that avoid these organelles since endosomally-embedded bioactive species are unable to interact with their intracellular targets. This liability represents an opportunity for cobalamin conjugates: cell permeable bioactive species can potentially be endosomally sequestered, which should preclude their action until released by light.…”