Redox-responsive core-cross-linked micelles of miktoarm maltoheptaose-b-poly(furfuryl methacrylate) for enhanced...

The instability of nanocarriers and premature leakage of drugs during circulation in the body remain major challenges that frequently lead to undesirable side effects in the development of nanomedicines. Achieving effective drug release within the tumor microenvironment is a key goal for desirable chemotherapy. In this study, we designed a novel type of core-cross-linked micelles (CCL) formed from biocompatible oligosaccharide-based A₂B miktoarm block copolymers of (maltoheptaose)₂-b-poly(furfuryl methacrylate)_2k ((MH)₂-b-PFMA_2k). The synthesis of the copolymer involved the chemical coupling of alkyne-functionalized MH with diazide-functionalized PFMA through click-chemistry. The (MH)₂-b-PFMA_2k copolymers were self-assembled in water into micelles (Non-CCL) with a hydrodynamic radius of ca. 72 nm. To prevent undesired drug leakage and burst release, the PFMA core of the doxorubicin (DOX)-loaded micelles was cross-linked using disulfide and diselenide-containing cross-linkers via Diels-Alder reaction. The core-cross-linked micelles (S-S/CCL and Se-Se/CCL) demonstrated enhanced stability under physiological conditions. In a reduction environment, they de-cross-linked, ensuring effective drug release. The micelles exhibited no significant cytotoxicity in HEK-293 cells, while DOX-loaded micelles showed potent antitumor efficacy against HeLa cells. Interestingly, Se-Se/CCL/DOX demonstrated preferential accumulation at the tumor site and exhibited superior efficacy compared to free DOX, Non-CCL/DOX, and S-S/CCL/DOX in inhibiting tumor growth in HT-29 tumor-bearing nude mice.