UZH-Logo

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


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.

Abstract

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.

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.

Citations

23 citations in Web of Science®
22 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

0 downloads since deposited on 15 Mar 2012
0 downloads since 12 months

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2011
Deposited On:15 Mar 2012 07:42
Last Modified:05 Apr 2016 15:41
Publisher:Springer
ISSN:0949-8257
Publisher DOI:10.1007/s00775-010-0697-z
Permanent URL: http://doi.org/10.5167/uzh-60366

Download

[img]
Content: Published Version
Filetype: PDF - Registered users only
Size: 676kB
View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations