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Background  Modifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an outstanding tumor-targeting modification of synergistic drug conjugate for effective anti-tumor treatment. However, the combination regimen of coupling PD-L1 polypeptide with chemotherapeutic drug in tumoricidal treatment has not been reported thus far.    Methods  We developed a novel synergistic strategy by conjugating PPA1 to doxorubicin (DOX) with a pH sensitive linker that can trigger the release of DOX near acidic tumor tissues. The binding affinity of PPA1-DOX with PD-L1 and the acid-sensitive cleavage of PPA1-DOX were investigated. A mouse xenograft model of colon cancer was used to evaluate the biodistribution, cytotoxicity and anti-tumor activity of PPA1-DOX.    Results  PPA1-DOX construct showed high binding affinity with PD-L1  in vitro  and specifically enriched within tumor when administered  in vivo . PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity  in vivo , as compared with free PPA1, random polypeptide-DOX conjugate, DOX, or 5-FU, respectively. Moreover, increased infiltration of both CD4 +  and CD8 +  T cells was found in tumors from PPA1-DOX treated mice.    Conclusions  We describe here for the first time that the dual-functional conjugate PPA1-DOX, which consist of the PD-L1-targeted polypeptide that renders both the tumor-specific drug delivery and inhibitory PD-1/PD-L1 immune checkpoint inhibition, and a cytotoxic agent that is released and kills tumor cells once reaching tumor tissues, thus representing a promising therapeutic option for colon cancer with improved efficacy and reduced toxicity.

A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer