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

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) ((PEO_2K)₂-b-PFMA) miktoarm amphiphilic block copolymers by coupling alkyne-functionalized PEO (PEO_2K-C≡H) and diazide-functionalized poly(furfuryl methacrylate) ((N₃)₂-PFMA) via click chemistry. (PEO_2K)₂-b-PFMA self-assembled to form nanosized micelles (mikUCL) with hydrodynamic radii in the range of 25∼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 (PEO_2K)₂-b-PFMA 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.