Dual stimuli-responsive polypeptide-calcium phosphate hybrid nanoparticles for co-delivery of multiple drugs in cancer therapy.

Abstract

In this study, a new type of polypeptide, crosslinked methoxy poly(ethylene glycol)-g-poly(aspartic acid)-g-tyrosine (CPPT), was synthesized via a green and simple one-pot polymerization method. With the disulfide-crosslinked interlayer and the CaP shell, the pH and redox dual-sensitive polypeptide-based organic-inorganic hybrid nanoparticles encapsulated curcumin (Cur) into the hydrophobic core of micelles and loaded doxorubicin hydrochloride (DOX) on the hydrophilic segment of micelles as well as CaP shell. The spherical Cur- and DOX-loaded nanoparticles (CPPT@CaP-CD) showed a hydrodynamics size of about 157.9\u2009±\u20093.9\u2009nm. The premature leakage of drugs from the nanoparticles at physiological pH was efficiently restrained because of the enhanced structure integrity, whereas at acidic and hypoxia microenvironment the release of both drugs was promoted due to the rapid dissolution of the CaP shell and the break of the disulfide crosslinked network, facilitating the stimuli-responsive controllable drugs release. In vitro anticancer activity evaluation revealed that the co-loaded nanoparticles presented higher cytotoxicity against A549 cells compared with that of the free combination of Cur\u2009+\u2009DOX. Confocal laser scanning microscopy observation indicated that more DOX and Cur were released into the nucleus triggered by the up-regulated intracellular glutathione (GSH) concentration and decreased pH, displaying enhanced cell uptake. The self-assembling polypeptide-based dual-sensitive drug co-delivery system could be a promising platform for efficient chemotherapy.