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Issue 3, 2017
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An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo

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Abstract

The design of targeted platinum(IV) prodrugs is a very promising approach to enhance the low selectivity of platinum(II) drugs towards cancerous tissue in order to reduce the impact on healthy tissue and, consequently, the often severe side-effects. Herein, we report a set of mono-functionalized cis- and oxaliplatin-based platinum(IV) complexes bearing a maleimide moiety, which allows selective binding to serum albumin in the bloodstream. This leads not only to a prolonged plasma half-life by avoidance of fast renal clearance, but also to preferential accumulation of the drug in the tumor tissue due to the EPR-effect. Additionally, analogous succinimide-functionalized derivatives were prepared to verify the influence of the maleimide moiety. First experiments showed that all the maleimide compounds are stable and also possess good albumin-binding properties in whole serum. Further analytical studies on in vivo samples proved the highly increased plasma half-life, as well as tumor accumulation of the maleimide-functionalized substances. In vivo antitumor experiments with CT-26-bearing mice showed that, in contrast to the cisplatin derivatives, the oxaliplatin-based complexes had exceptionally better activity than the free drug resulting in the cure of the majority of treated mice. Subsequent analysis suggested that a distinctly faster reduction as well as reduced tumor accumulation of the cisplatin derivative might explain the worse performance compared to the oxaliplatin(IV) complexes. Taken together, a novel lead platinum(IV) complex with outstanding antitumor activity is presented, which will now be further developed towards clinical phase I trials.

Graphical abstract: An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo

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Publication details

The article was received on 29 Aug 2016, accepted on 02 Dec 2016 and first published on 15 Dec 2016


Article type: Edge Article
DOI: 10.1039/C6SC03862J
Citation: Chem. Sci., 2017,8, 2241-2250
  • Open access: Creative Commons BY license
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    An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo

    J. Mayr, P. Heffeter, D. Groza, L. Galvez, G. Koellensperger, A. Roller, B. Alte, M. Haider, W. Berger, C. R. Kowol and B. K. Keppler, Chem. Sci., 2017, 8, 2241
    DOI: 10.1039/C6SC03862J

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