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Tirapazamine-embedded polyplatinum(iv) complex: a prodrug combo for hypoxia-activated synergistic chemotherapy

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Abstract

Despite the great advances achieved in hypoxia-associated tumor therapy, the efficacy of hypoxia-activated prodrugs alone is usually limited owing to the moderate oxygen supply at the tumor area. Herein, we develop a polymerized platinum(IV) compound-based nanogel (polyprodrug) containing a bioreductive and hypoxia-activated prodrug (tirapazamine, TPZ) as a prodrug combo (polyprodrug@TPZ) for synergistic chemotherapy. Upon exposure to the tumor microenvironment, platinum(IV) moieties in the polyprodrug are reduced to platinum(II) species, which significantly upregulates the expression of NADPH oxidases (NOXs) to accelerate oxygen (O2) depletion and promote reactive oxygen species (ROS) production, as confirmed by reverse transcription-PCR (RT-PCR) and fluorescence probes. In the exaggerated hypoxia environment, highly cytotoxic radicals are generated due to TPZ activation, which serve as second antitumor agents working together with platinum(II) species in synergistic chemotherapy. With the rational design of nanosized architecture, the platinum(IV)-based polyprodrug@TPZ complex exhibits the advantages of redox-responsive drug release, superior tumor accumulation, and long-term circulation during the synergistic antitumor treatment in a mouse model. These results indicate that combination of an oxygen depletion prodrug and hypoxia-activated antitumor agents would serve as a promising strategy to realize a better synergistic chemotherapy.

Graphical abstract: Tirapazamine-embedded polyplatinum(iv) complex: a prodrug combo for hypoxia-activated synergistic chemotherapy

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Publication details

The article was received on 14 Oct 2019, accepted on 13 Nov 2019 and first published on 15 Nov 2019


Article type: Paper
DOI: 10.1039/C9BM01640F
Biomater. Sci., 2020, Advance Article

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    Tirapazamine-embedded polyplatinum(IV) complex: a prodrug combo for hypoxia-activated synergistic chemotherapy

    D. Guo, S. Xu, W. Yasen, C. Zhang, J. Shen, Y. Huang, D. Chen and X. Zhu, Biomater. Sci., 2020, Advance Article , DOI: 10.1039/C9BM01640F

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