On-demand combinational delivery of curcumin and doxorubicin via a pH-labile micellar nanocarrier

•Curcumin and doxorubicin were co-loaded in a pH-responsive micellar nanocarrier.•Both agents exhibited an accelerated drug release under acid conditions.•Such system would enhance the therapeutic efficacy without delay of action onset.

The combinational delivery of doxorubicin and curcumin in a physically loaded nanocarrier offers the benefits of enhanced therapeutic efficacy and reduced adverse effects, but this strategy often suffers from the slow drug release followed by delayed onset of pharmacological action. This work reported the hydrazone-linked polymer-curcumin conjugate micelles containing physically loaded doxorubicin to address this problem; the ester-linked conjugate micelles were produced as the control. The pH-labile spherical micelles were less than 100 nm with a loading at 9.3 ± 0.5% (w/w, Curcumin) and 2.5 ± 0.1(w/w, Doxorubicin). Both agents were released at a faster rate in the pH-labile micelles compared to the control. The confocal laser scanning microscopy revealed a time-dependent co-localization of both agents in HepG2 cells. The IC50 of pH-labile conjugate micelles without doxorubicin in HepG2 cells was 27.7 ± 5.3 (μM), whereas the co-loaded micelles was lowered to 10.8 ± 3.4 (μM) (Cur-equivalent dose). The combination index calculation demonstrated a synergistic action of both agents in the co-loading nanocarrier. The current work provided an efficient nanocarrier system to achieve rapid on-demand drug release without onset delay of therapeutic action, which might add value to the clinical translation of the combinational delivery systems.

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