Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-60366
Ruiz-Sanchez, P; König, C; Ferrari , S; Alberto, R (2011). Vitamin B12 as carrier for targeted platinum delivery: in vitro cytotoxicity and mechanistic studies. Journal of Biological Inorganic Chemistry, 16(1):33-44.
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It is attractive to use vitamin B12 as a carrier for targeted delivery of cytotoxic agents such as platinum complexes owing to the high demand for vitamin B12 by fast proliferating cells. The basic conjugates are recognized by intracellular enzymes and converted to coenzyme B12 in an enzymatic adenosylation assay. The reductive adenosylation of conjugates leads to the release of the PtII complexes; thus, conjugates can be considered as prodrugs. It is important not only to elucidate the activity of the cisplatin–B12 conjugates, but also to understand the mode of action on a molecular level. Chemical reduction of conjugates with cobaltocene yielded cob(II)alamin and induced release of the corresponding PtII species. Kurnakov tests and coordination of 2′-deoxyguanosine or GMP to the released PtII complexes allowed isolation and characterization of PtII complexes as released during enzymatic adenosylation. The biological activity of these PtII complexes was evaluated. Since the cleaved PtII complexes show cytotoxicity, the conjugates can be used for specific targeting of cancer cells and therapeutic drug delivery. Preliminary in vitro cytotoxicity studies indicated lower activity (IC50 between 8 and 88 μM) than found for pure cisplatin. Since active transport and receptor-mediated uptake limits the intracellular concentration, comparison with pure cisplatin is of limited use. We could show that the PtII complexes cleaved from B12 exerted a cytotoxicity comparable to that of cisplatin itself. Cytotoxicity studies in vitamin B12 free media showed a dependence on the addition of transcobalamin II for B12–Pt(II) conjugates.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||07 Faculty of Science > Institute of Inorganic Chemistry|
|Deposited On:||15 Mar 2012 08:42|
|Last Modified:||30 Nov 2012 19:44|
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