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Chemotherapy is one of the most employed strategies in clinical treatment of cancer, but the low content of drug molecules caused by the inadequate accumulation of drug carriers in the lesion locations has an adverse impact on the therapeutic effect. To solve this issue, a kind of high drug content prodrug monomers with topological structures of AB2 and AB3 were designed and utilized to construct a series of polyprodrug amphiphiles, P[GMA(-l-RGD/-PEG)-CPT n ] (n = 2 or 3), with both targeting peptides (l-RGD) and high 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 photothermal conversion reagents (IR780) in water to form spherical nanoparticles, which could expose original hidden l-RGD through the removal of hydrophilic PEG coronas under the trigger of a tumor microenvironment and thus promote the endocytosis of nanoparticles. Once in the presence of intracellular glutathione (GSH), high content drug molecules could be efficiently released by a cascade amplification reaction to kill cancer cells, this process could be further enhanced by the synergistic effect of local hyperthermia induced by near-infrared light irradiation. The results from in vitro simulation and in vivo mouse solid tumor models showed that these nanoreagents had a highly inhibitory effect on the tumor. Not only that, the immune response after chemical–optical synergistic therapy was also systematically conducted, the results demonstrated that the maturation of dendritic cells and proliferation of T cells could be successfully activated, accompanied by the increase of high mobility group protein B1 and decrease of immunosuppressive regulatory T cells. We believe this proof-of-concept could effectively solve the bottleneck problem in chemotherapy and provide a continuous immune protection to the body after anti-tumor treatment.

Highly efficient endocytosis and multi-approach integrated therapeutic tactics are important factors in oncotherapy. With the aid of thermal reversible furan-maleimide dynamic covalent bonds and “polyprodrug amphiphiles” concept, thermal- and reduction-responsive...