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

Background: Chemotherapy is most commonly used for treating colon cancer. However, the destruction to normal cells and resistance to chemical therapeutics still remain as clinical challenges. Methods We developed a novel synergistic strategy coupling PD-L1 polypeptide with chemotherapeutic reagent for colon cancer. Results A proteolysis resistant PD-L1-targeted peptide (PPA1) was conjugated to doxorubicin (DOX) with a pH sensitive linker, which could trigger the release of DOX near acidic tumor tissues. We found that PPA1-DOX construct showed high binding affinity with PD-L1 in vitro and specifically enriched within tumor when administered in vivo . Conclusions 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, indicating that PPA1-DOX enhanced immune response. Delivery of chemical regimen guided by PD-L1 polypeptide represents a potential targeted treatment strategy of colon cancer with improved efficacy and reduced toxicity.