A novel nanodrug delivery system (NDDS) based on block copolymers of Poly(DEA)-block-Poly(PgMA) (PDPP) was developed to enhance in vitro cellular uptake and anticancer efficacy. pH-responsive doxorubicin (DOX) based small molecule prodrug (DOX-hyd-N3) and mPEG-N3 were co-conjugated onto PDPP via copper-catalyzed "Click chemistry" to give a dual pH-responsive polymeric prodrug (mPEG-g-PDPP-g-hyd-DOX), which could be self-assembled into core-shell polymeric micelles (M(DOX)) with particles size of 81 ± 1 nm in aqueous phase. Additionally, the pH-responsive charge-reversal, stability and drug release behaviour at different pHs were then evaluated. Moreover, the surface charge of M(DOX) could quickly convert from negative (-6.64 ± 3.37 mV) to positive (5.35 ± 1.33 mV) thanks to the protonation of Poly(DEA) moieties as the pH value decreased from 7.4 during blood circulation to 6.5 in extracellular of tumour tissues. Meanwhile, according to the cytotoxicity determined by CCK-8 assay, cellular uptake, flow-cytometric and apoptosis profiles of two human cancer cell lines (HeLa and SW480), we could draw the conclusion that the cellular uptake and anticancer efficacy were significantly enhanced when cells were incubated with micelles at pH 6.5 due to the charge-reversal of micelles from negative to positive. With the protonation of Poly(DEA) moieties in acidic extracellular microenvironment and the pH-responsive DOX release with hydrazone linkage in endo/lysosome pH, this dual pH-responsive-charge-reversal micelle platform might become an encouraging strategy for more effective cancer treatment.
Keywords: Charge-reversal; Dual pH-responsive; Nanodrug delivery system; Polymeric micelles; “Click chemistry”.
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