Targeted and Reduction-Sensitive Crosslinked PLGA Nanotherapeutics for Safer and Enhanced Chemotherapy of Malignant Melanoma

PLGA-based nanoparticles are the most studied for cancer therapy. Insufficient stability and sustained drug release, however, often lead to reduced targetability and antitumor efficacy in vivo. In this work, we report on cRGD-installed reduction-responsive crosslinked nanotherapeutics based on star PLGA-lipoic acid conjugate (cRGD-sPLGA XNPs) for potent and targeted chemotherapy of B16F10 melanoma in mice. cRGD-sPLGA XNPs exhibited nearly quantitative encapsulation of doxorubicin (DOX), giving DOX-cRGD-sPLGA XNPs with 13.2 wt.% DOX and a small size of 91.0±0.6 nm. DOX-cRGD-sPLGA XNPs with cRGD surface density of 48% exhibited the best cellular uptake in v3 overexpressing B16F10 cells and delivered DOX into the cell nuclei after 6 h incubation, in contrast to non-targeted DOX-sPLGA XNPs that delivered DOX mainly in the cytoplasm. Cell viability experiments showed that DOX-cRGD-sPLGA XNPs had about 2-fold better inhibitory activity in B16F10 cells than non-targeted DOX-sPLGA XNPs. Interestingly, DOX-cRGD-...