Journal
JOURNAL OF CONTROLLED RELEASE
Volume 341, Issue -, Pages 646-660Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2021.12.016
Keywords
Fenton reaction; Arsenic trioxide; Oxidative stress; Hydroxyl radical; Polymer micelle; Cancer therapy
Funding
- National Research Foundation of Korea (NRF) - Korea government (MSIT) [2019R1A2C1003353]
- Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Korea government (MSIPMOHW) [2017M3A9E4048170]
- National Research Foundation of Korea [2019R1A2C1003353] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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CuAS-PMs is a new class of Fenton-like catalytic nanosystems that can manipulate ROS for anticancer therapy. It can effectively kill cancer cells by releasing highly cytotoxic hydroxyl radicals and suppress solid tumor growth without systemic toxicity, showing great potential for cancer-specific therapy.
We report copper(II) arsenite (CuAS)-integrated polymer micelles (CuAS-PMs) as a new class of Fenton-like catalytic nanosystem that can display reactive oxygen species (ROS)-manipulating anticancer therapeutic activity. CuAS-PMs were fabricated through metal-catechol chelation-based formation of the CuAS complex on the core domain of poly (ethylene glycol)-b-poly(3,4-dihydroxy-L-phenylalanine) (PEG-PDOPA) copolymer micelles. CuAS-PMs maintained structural robustness under serum conditions. The insoluble state of the CuAS complex was effectively retained at physiological pH, whereas, at endosomal pH, the CuAS complex was ionized to release arsenite and cuprous Fenton catalysts (Cu+ ions). Upon endocytosis, CuAS-PMs simultaneously released hydrogen peroxide (H2O2)-generating arsenite and Fenton-like reaction-catalyzing Cu+ ions in cancer cells, which synergistically elevated the level of highly cytotoxic hydroxyl radicals (center dot OH), thereby preferentially killing cancer cells. Animal experiments demonstrated that CuAS-PMs could effectively suppress the growth of solid tumors without systemic in vivo toxicity. The design rationale of CuAS-PMs may provide a promising strategy to develop diverse oxidative stress-amplifying agents with great potential in cancer-specific therapy.
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