Enzyme-Triggered Disassembly of Polymeric Micelles by Controlled Depolymerization via Cascade Cyclization for Anticancer Drug Delivery

• Published in: ACS applied materials & interfaces 2021-02, Vol.13 (7), p.8060-8070
• Main Authors: Park, Jaehyun, Jo, Seokhee, Lee, Yeong Mi, Saravanakumar, Gurusamy, Lee, Junseok, Park, Dongsik, Kim, Won Jong
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Benzoquinones - chemistry; Benzoquinones - metabolism; Biological and Medical Applications of Materials and Interfaces; Cell Proliferation - drug effects; Cell Survival - drug effects; Cyclization; Doxorubicin - chemistry; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug Delivery Systems; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Hydrophobic and Hydrophilic Interactions; Lactones - chemistry; Lactones - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Micelles; Molecular Structure; NAD(P)H Dehydrogenase (Quinone) - chemistry; NAD(P)H Dehydrogenase (Quinone) - metabolism; Particle Size; Polymerization; Polymers - chemistry; Polymers - metabolism; Propionates - chemistry; Propionates - metabolism; Surface Properties; Tumor Cells, Cultured
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.0c22644

The high activity of specific enzymes in cancer has been utilized in cancer diagnosis, as well as tumor-targeted drug delivery. NAD­(P)­H:quinone oxidoreductase-1 (NQO1), an overexpressed enzyme in certain tumor types, maintains homeostasis and inhibits oxidative stress caused by elevated reactive oxygen species (ROS) in tumor cells. The activity of NQO1 in lung and liver cancer cells is increased compared to that in normal cells. Interestingly, NQO1 reacts with trimethyl-locked quinone propionic acid (QPA) and produces a lactone-based group via intramolecular cyclization. Toward this objective, we synthesized an amphiphilic block copolymer (QPA-P) composed of NQO1 enzyme-triggered depolymerizable QPA-locked polycaprolactone (PCL) and poly­(ethylene glycol) (PEG) as hydrophobic and hydrophilic constituents, respectively. This QPA-P formed self-assembled micelles in aqueous conditions. It was observed that NQO1 catalyzed the depolymerization of QPA-locked PCL via a cascade two-step cyclization process, which eventually induced the dissociation of micellar structure and triggered the release of loaded drugs at the target cancer cells. Compared to the control group, the NQO1-responsive micelle showed NQO1-triggered intracellular drug release and enhanced anticancer effects. These results indicate that the NQO1-responsive polymeric micelles present a promising potential for improving therapeutic efficacy of an anticancer drug delivery system.