Tumor pH and intracellular reduction responsive polypeptide nanomedicine with a sheddable PEG corona and a disulfide-cross-linked core

Abstract

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.