Tumor pH and intracellular reduction responsive polypeptide nanomedicine with a sheddable PEG corona and a disulfide-cross-linked core†
To overcome the tumor and cellular barriers in cancer chemotherapy, the construction of biodegradable polymeric nanomedicine with pathological stimuli-responsivity is still challenging. In this work, a new class of polypeptide copolymer nanoparticles with a sheddable PEG corona and a dynamic disulfide bond cross-linked core was fabricated in aqueous solution, which can respond to tumor pH and intracellular reductive milieu. The polypeptide block copolymer (i.e., PEG-D-PC) composed of hydrophilic poly(ethylene glycol) (PEG) and thiol-pendant poly(L-cysteine) (PC) was synthesized via the primary amine terminated PEG dimethylmaleic anhydride derivative initiated ring-opening polymerization of α-amino acid N-carboxyanhydride and a sequential photocleavage reaction. The size and zeta potential change of the core-cross-linked (CCL) nanoparticles was monitored by on-line dynamic light scattering at pH 6.5, 10 mM DTT, and pH 6.5 + 10 mM DTT, respectively. In a similar manner, the anticancer drug camptothecin (CPT)-loaded CCL nanoparticles exhibited dual-stimuli-triggered drug release profiles. The CPT-loaded CCL79 nanoparticles facilitated the cellular internalization and CPT release inside the HeLa cells at pH 6.5, as confirmed by flow cytometry and fluorescence microscopy. The half maximal inhibitory concentration of CPT-loaded CCL79 nanoparticles at pH 6.5 was greatly lowered 31.8 fold to 0.61 μg CPT equiv. per mL compared to that at pH 7.4 + 0.1 mM BSO inhibitor, presenting dual stimuli-triggered cytotoxicity.