Targeted and Reduction-Sensitive Cross-Linked 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 cross-linked nanotherapeutics based on a 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 a cRGD surface density of 48% exhibited the best cellular uptake in αvβ3 overexpressing B16F10 cells and delivered DOX into the cell nuclei after 6 h of incubation, in contrast to nontargeted 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 nontargeted DOX-sPLGA XNPs. Interestingly, DOX-cRGD-sPLGA XNPs achieved a great melanoma accumulation of 10.96% ID/g and significantly better suppression of B16F10 melanoma than DOX-sPLGA XNPs and Lipo-DOX. DOX-cRGD-sPLGA XNPs brought about marked improvement of the survival rate of B16F10 melanoma-bearing mice at 20 mg of DOX equiv/kg. Smart nanotherapeutics based on the star PLGA-lipoic acid conjugate have emerged as an appealing nanoplatform for targeted tumor therapy.