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

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 biored...

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Bibliographic Details
Published in:Biomaterials science 2020-01, Vol.8 (2), p.694-71
Main Authors: Guo, Dongbo, Xu, Shuting, Yasen, Wumaier, Zhang, Chuan, Shen, Jian, Huang, Yu, Chen, Dong, Zhu, Xinyuan
Format: Article
Language:English
Subjects:
Anticancer properties
Chemical compounds
Chemotherapy
Depletion
Drug delivery systems
Drugs
Fluorescent indicators
Hypoxia
Oxygen
Platinum
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Summary: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 (O 2 ) 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. A polyprodrug complex containing oxygen depleting chemodrugs and hypoxia-activated antitumor agents can serve as a promising drug delivery system for synergistic chemotherapy.
ISSN:2047-4830
2047-4849
DOI:10.1039/c9bm01640f