Acidity-Triggered Ligand-Presenting Nanoparticles To Overcome Sequential Drug Delivery Barriers to Tumors.

The success of cancer chemotherapy is impeded by poor drug delivery efficiency due to the existence of a series of pathophysiological barriers in the tumor. In this study, we reported a tumor acidity-triggered ligand-presenting (ATLP) nanoparticle for cancer therapy. The ATLP nanoparticles were composed of an acid-responsive diblock copolymer as a sheddable matrix and an iRGD-modified polymeric prodrug of doxorubicin (iPDOX) as an amphiphilic core. A PEG corona of the polymer matrix protected the iRGD ligand from serum degradation and nonspecific interactions with the normal tissues while circulating in the blood. The ATLP nanoparticles specifically accumulated at the tumor site through the enhanced permeability and retention (EPR) effect, followed by acid-triggered dissociation of the polymer matrix within the tumoral acidic microenvironment (pH ∼ 6.8) and subsequently exposing the iRGD ligand for facilitating tumor penetration and cellular uptake of the PDOX prodrug. Additionally, the acid-triggered dissociation of the polymer matrix induced a 4.5-fold increase of the fluorescent signal for monitoring nanoparticle activation in vivo. Upon near-infrared (NIR) laser irradiation, activation of Ce6-induced significant reactive oxygen species (ROS) generation, promoted drug diffusion inside the tumor mass and circumvented the acquired drug resistance by altering the gene expression profile of the tumor cells. The ATLP strategy might provide a novel insight for cancer nanomedicine.