Construction of Actively Targeted and High Drug Content Polyprodrug Amphiphiles to Perform Synergistic Chemo-Photo-Anti-Tumor Therapy and Immune-Activated Investigation

Chemotherapy is one of the most employed strategies inclinicaltreatment of cancer, but the low content of drug molecules causedby the inadequate accumulation of drug carriers in the lesion locationshas an adverse impact on the therapeutic effect. To solve this issue,a kind of high drug content prodrug monomers with topological structuresof AB(2) and AB(3) were designed and utilized toconstruct a series of polyprodrug amphiphiles, P[GMA(-l-RGD/-PEG)-CPT n ] (n =2 or 3), with both targeting peptides (l-RGD) andhigh drug content. Depending on the structure of prodrug monomers,the content of drug molecules could be achieved as high as 60 wt %(n = 2) and 65 wt % (n = 3), respectively.These polyprodrug amphiphiles could self-assemble with photothermalconversion reagents (IR780) in water to form spherical nanoparticles,which could expose original hidden l-RGD throughthe removal of hydrophilic PEG coronas under the trigger of a tumormicroenvironment and thus promote the endocytosis of nanoparticles.Once in the presence of intracellular glutathione (GSH), high contentdrug molecules could be efficiently released by a cascade amplificationreaction to kill cancer cells, this process could be further enhancedby the synergistic effect of local hyperthermia induced by near-infraredlight irradiation. The results from in vitro simulation and in vivomouse solid tumor models showed that these nanoreagents had a highlyinhibitory effect on the tumor. Not only that, the immune responseafter chemical-optical synergistic therapy was also systematicallyconducted, the results demonstrated that the maturation of dendriticcells and proliferation of T cells could be successfully activated,accompanied by the increase of high mobility group protein B1 anddecrease of immunosuppressive regulatory T cells. We believe thisproof-of-concept could effectively solve the bottleneck problem inchemotherapy and provide a continuous immune protection to the bodyafter anti-tumor treatment.