Hybrid PEGylated chitosan/PLGA nanoparticles designed as pH-responsive vehicles to promote intracellular drug delivery and cancer chemotherapy

To achieve effective intracellular anticancer drug release for boosted antitumor efficacy, the acidity-responsive nanovehicles for doxorubicin (DOX) delivery were fabricated by tailor-made co-assembly of amphiphilic PEGylated chitosan(20k) and hydrophobic poly(lactic-co-glycolic acid) (PLGA) segments at pH 8.5. The attained DOX-loaded PEGylated chitosan(20k)/PLGA nanoparticles (DOX-PC(20k)PNs) were characterized to have a spherical shape composed of drug-encapsulated chitosan(20k)/PLGA-constituted solid core surrounded by hydrophilic PEG shells. Compared to non-pH-sensitive DOX-loaded PLGA nanoparticles (DOX-PNs), the DOX-PC(20k)PNs displayed outstanding colloidal stability under serum-containing condition and tended to swell in weak acidic milieu upon increased protonation of chitosan20k within hybrid cores, thus accelerating drug release. The in vitro cellular uptake and cytotoxicity studies revealed that the DOX-PC(20k)PNs after being endocytosed by prostate TRAMP-C1 cancer cells rapidly liberated drug, thus promoting drug accumulation in nuclei to enhance anticancer potency. Moreover, the hydrated PEG shells of DOX-PC(20k)PNs remarkably reduced their uptake by macrophage-like RAW264.7 cells. Importantly, in vivo animal findings showed that the DOX-PC(20k)PNs exhibited the capability of inhibiting TRAMP-C1 tumor growth superior to free hydrophobic DOX molecules and DOX-PNs, demonstrating the great potential in cancer chemotherapy.

Automated summary

In this study, acidity-responsive nanovehicles were developed for efficient intracellular drug release. The nanovehicles exhibited excellent colloidal stability and accelerated drug release, leading to enhanced anticancer efficacy in vitro and in vivo.