Cobalamin conjugates as drug delivery devices

Most of the front-line chemotherapeutic drugs such as doxorubicin, taxol, etopo-side and the alkylating agents have a dose-limiting toxicity that arises from interaction of the drug with an organ system that is remote from the site of cancer. If these cytotoxic drugs could be delivered selectively to cancer cells, their therapeutic index would be greatly increased and the serious side-effects such as bone marrow suppression, cardiotoxicity, nephrotoxicity, hepatotoxicity, neuro-toxicity, hair loss and nausea might be eliminated, or at least reduced.

Cobalamin (Figure 11.7) is an essential micronutrient that is required for human health and, more importantly, is required in large quantities by cells that are replicating DNA prior to cell division. Cancer cells have an increased ability to transport and to sequester cobalamin in large excess over the amount required for normal cellular metabolism and cell replication.84,85 In some patients with tumors, up to a 50-fold increase in the major cobalamin transport proteins has been observed. Collins and Hogenkamp also showed that rapidly dividing cells up-regulate cobalamin-binding receptors during DNA replica-tion.10,86,87 By taking advantage of the body's own machinery to concentrate and to maintain cobalamin levels in vivo, combined with the up-regulation of cobalamin-binding receptors in neoplastic cells, cobalamin has the potential to be a site-selective drug delivery vehicle for the treatment, imaging, and diagnosis of cancer.

Numerous bioconjugate derivatives of cobalamin with chemotherapeutic agents and radionuclides have been synthesized and some of them have shown promise in initial biological tests. For instance, Hogenkamp et al. reported tumor imaging via indium 111-labeled diethylenetriaminepentaacetate adenosylcobal-amin.10,87 The same group also used vitamin B12 (cyanocobalamin) to deliver a boron-rich nido-carborane to tumors.88 In their study, the biological activity of cyanocobalamin-nido-carborane derivatives is relatively high - 92.93%, when compared with 57Co cyanocobalamin. These 11B cobalamin conjugates might be useful agents in treating malignant tumors via neutron capture therapy. Recently, Grissom etal. have prepared some fluorescent derivatives of cobalamin by linking corrin ring system

H2C h3

H2C h3

CH2 CH2

N OH

,CH3

cobalt O

H2C^ CH3

H0CH2

5,6-di-methylbenzimidazole ribonucleotide

Figure 11.7 Chemical structure of cobalamin

fluorophores to cobalamin through a propylamide spacer (Figure 11.8).89 Unlike the cryptofluorescent and profluorescent cobalamin conjugates synthesized previously, the compounds reported herein exhibit less quenching of the fluorophore excited state by cobalamin. The CobalaFluors are overtly fluorescent molecules

Figure 11.8 Fluorescent derivatives of cobalamin

that are potentially suitable for the in vitro and in vivo imaging of transcobalamin receptors on cancer cells.

Due to the light sensitivity of the carbon—cobalt bond,90 the inert cobala-min-drug bioconjugate can be activated to cleave the Co—C bond by visible or near-UV light, thereby releasing the active drug in the irradiated tissue. Coba-lamin bioconjugates can also be activated by ultrasound to cleave the Co—C bond, allowing release of the drug deep within a tissue that is not as easily accessible with red light.91 Sonolysis of aqueous solutions produces a high concentration of hydroxyl radicals and hydrogen atoms. These, respectively, reactive oxidizing and reducing species are responsible for initiating most reactions in aqueous solvents, including cleavage of the Co—C bond and activation of the prodrug to release the active chemotherapeutic agent.

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