Reversibly core cross-linked polymeric micelles with pH- and reduction-sensitivities: effects of cross-linking degree on particle stability, drug release kinetics, and anti-tumor efficacy

A doxorubicin-conjugated disulfide cross-linked PEG-b-P[Asp(Hyd-DOX)] micelle drug delivery system was employed in this study to investigate the effects of cross-linking degree on particle stability, pH-dependent drug release, and in vivo anti-tumor efficacy. Cross-linked polymeric micelles demonstrated superior particle stability and slower drug release kinetics compared with the non-cross-linked counterparts in the absence of reducing agents in a cross-linking level-dependent manner. Once the cross-links were cleaved due to the action of dithiothreitol, both cross-linked and non-cross-linked polymeric micelles behaved similarly in terms of stability and drug release. In vitro cytotoxicity of doxorubicin-conjugated micelles was observed to decrease gradually with increasing degree of cross-linking. While both crosslinked and non-cross-linked polymeric micelles caused tumor regression in mice bearing subcutaneous 4T1 breast tumors, polymeric micelles with a 25% cross-linking degree increased the tolerated dose of doxorubicin by 33%. These findings suggest that reversible core cross-linking of polymeric micelles through disulfide linkages is beneficial to the control of drug release and reduction in systemic toxicity caused by doxorubicin.