| Summary: | In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)<sub>2k</sub>-<i>b</i>-poly(furfuryl methacrylate)<sub>1.5k</sub> (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub> from FMA monomers and PEO<sub>2k</sub>-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels–Alder reaction. Under physiological conditions, the structural stability of both S–S and Se–Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S–S and Se–Se bonds. In contrast, the S–S bond was intact in the presence of 100 mM H<sub>2</sub>O<sub>2,</sub> while the Se–Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-Se)<sub>2</sub> micelles varied more significantly in response to changes in the redox environment than (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-S)<sub>2</sub> micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S–S/Se–Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k-</sub>Se)<sub>2</sub> micelles can be more sensitive drug carriers than (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-S)<sub>2</sub> micelles.
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