Details

Autor(en) / Beteiligte

• Ruiz-Sánchez, Pilar
• König, Christiane
• Ferrari, Stefano
• Alberto, Roger

Titel

Vitamin B₁₂ as a carrier for targeted platinum delivery: in vitro cytotoxicity and mechanistic studies

Ist Teil von

• Journal of biological inorganic chemistry, 2011, Vol.16 (1), p.33-44

Ort / Verlag

Berlin/Heidelberg: Berlin/Heidelberg : Springer-Verlag

Erscheinungsjahr

2011

Link zum Volltext

Quelle

SpringerLink (Online service)

Beschreibungen/Notizen

• 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 {B₁₂-CN-PtII} conjugates are recognized by intracellular enzymes and converted to coenzyme B₁₂ in an enzymatic adenosylation assay. The reductive adenosylation of {B₁₂-CN-PtII} conjugates leads to the release of the PtII complexes; thus, {B₁₂-CN-PtII} 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 {B₁₂-CN-PtII} 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 {B₁₂-CN-PtII} 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 {B₁₂-CN-PtII} 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.