Abstract
In this study, diselenide (Se-Se) and disulfide (S-S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)(2k)-b-poly(furfuryl methacrylate)(1.5k) (PEO(2k)-b-PFMA(1.5k)), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO(2k)-b-PFMA(1.5k) from FMA monomers and PEO(2k)-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(2)O(2,) while the Se-Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO(2k)-b-PFMA(1.5k)-Se)(2) micelles varied more significantly in response to changes in the redox environment than (PEO(2k)-b-PFMA(1.5k)-S)(2) 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(2k)-b-PFMA(1.5k-)Se)(2) micelles can be more sensitive drug carriers than (PEO(2k)-b-PFMA(1.5k)-S)(2) micelles.