4.8 Article

Redox-Responsive Core-Cross-Linked Micelles of Miktoarm Poly(ethylene oxide)-b-poly(furfuryl methacrylate) for Anticancer Drug Delivery

Journal

ACS APPLIED MATERIALS & INTERFACES
Volume 15, Issue 10, Pages 12719-12734

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsami.2c21152

Keywords

miktoarm copolymer; Diels-Alder reaction; click chemistry; core-cross-linked micelles; redox-responsive

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Cross-linking of nanocarriers allows targeted drug release, addressing issues such as drug leakage and side effects, thereby improving the efficacy of nanomedicines.
The physiological instability of nanocarriers, premature drug leakage during blood circulation, and associated severe side effects cause compromised therapeutic efficacy, which have significantly hampered the progress of nanomedicines. The cross-linking of nanocarriers while keeping the effectiveness of their degradation at the targeted site to release the drug has emerged as a potent strategy to overcome these flaws. Herein, we have designed novel (poly(ethylene oxide))2-b-poly(furfuryl methacrylate) ((PEO2K)2-b- PFMAnk) miktoarm amphiphilic block copolymers by coupling alkyne-functionalized PEO (PEO2K-CH) and diazide-functionalized poly(furfuryl methacrylate) ((N3)2-PFMAnk) via click chemistry. (PEO2K)2-b-PFMAnk self-assembled to form nanosized micelles (mikUCL) with hydrodynamic radii in the range of 25 similar to 33 nm. The hydrophobic core of mikUCL was cross-linked by a disulfide-containing cross-linker using the Diels-Alder reaction to avoid unwanted leakage and burst release of a payload. As expected, the resulting core-cross-linked (PEO2K)2-b-PFMAnk micelles (mikCCL) exhibited superior stability under a normal physiological environment and were de-cross-linked to rapidly release doxorubicin (DOX) upon exposure to a reduction environment. The micelles were compatible with HEK-293 normal cells, while DOX-loaded micelles (mikUCL/DOX and mikCCL/DOX) induced high antitumor activity in HeLa and HT-29 cells. mikCCL/ DOX preferentially accumulated at the tumor site and was more efficacious than free DOX and mikUCL/DOX for tumor inhibition in HT-29 tumor-bearing nude mice.

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