Journal
BIOMATERIALS
Volume 195, Issue -, Pages 63-74Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.12.032
Keywords
ROS-responsive; Polymer prodrug; Drug delivery; Oxidative stress; Oxidation-chemotherapy
Funding
- National Natural Science Foundation of China (NNSFC) Project [21674104, 21875234]
- Fundamental Research Funds for the Central Universities [WK3450000002]
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In tumor tissues, reactive oxygen species (ROS) level is significantly higher than that in normal tissues, which has been frequently explored as the specific stimulus to trigger drug release. However, the low intrinsic ROS concentration and heterogeneous distribution in tumor tissues hinder the applications as the stimulus for drug delivery. Herein, we developed integrated nanoparticles to remold tumor microenvironment via specific amplification of the tumor oxidative stress and simultaneously realize ROS-responsive drug release. The amphiphilic block copolymer prodrugs composed of poly(ethylene glycol) and polymerized methacrylate monomer containing thioketal-linked camptothecin (CPT) were synthesized and self-assembled to form core-shelf micelles for encapsulation of beta-lapachone (Lapa@NPs). After tumor accumulation and internalization into tumor cells post systemic administration of Lapa@NPs, Lapa can selectively induce remarkable ROS level increase via the catalysis of NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme overexpressed in cancer cells. Subsequently, enhanced ROS concentration would trigger the cleavage of thioketal linkers to release drug. The released CPT together with high ROS level achieved a synergistic therapy to suppress tumor growth. Moreover, Lapa@NPs exhibited superior biosafety due to the tumor-specific activation of the cascade reaction. Accordingly, Lapa@NPs represent a novel polymer prodrug design and drug release strategy via tumor-specific oxidative stress amplification and subsequent ROS-responsive drug release.
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