Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier

摘要

To achieve synergistic therapeutic efficacy and prevent cancer relapse,chemotherapy and immunotherapy have been combined as a new modality for tumor treatment.In this work,we designed a redox-responsive immunostimulatory polymeric prodrug carrier,PSSN10,for programmable co-delivery of an immune checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX).NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized micelles that served as a carrier to load DOX (DOX/ PSSN10 micelles).DOX/PSSN10 micelles displayed spherical morphology with a size of ～170 nm.DOX was effectively loaded into PSSN10 micelles with a loading efficiency of 84.0％.In vitro DOX release studies showed that rapid drug release could be achieved in the highly redox environment after intracellular uptake by tumor cells.In 4T1.2 tumor-bearing mice,DOX/PSSN1O micelles exhibited greater accumulation of DOX and NLG in the tumor tissues compared with other organs.The PSSN1O carrier dose-dependently enhanced T-cell immune responses in the lymphocyte-Panc02 co-culture experiments,and significantly inhibited tumor growth in vivo.DOX/PSSN10 micelles showed potent cytotoxicity in vitro against 4T1.2 mouse breast cancer cells and PC-3 human prostate cancer cells comparable to that of DOX.In 4T1.2 tumor-bearing mice,DOX/PSSN1O mixed micelles (5 mg DOX/kg,iv) was more effective than DOXIL (a clinical formulation of liposomal DOX) or free DOX in inhibiting the tumor growth and prolonging the survival of the treated mice.In addition,a more immunoactive tumor microenvironment was observed in the mice treated with PSSN1O or DOX/ PSSN10 micelles compared with the other treatment groups.In conclusion,systemic delivery of DOX via PSSN1O nanocarrier results in synergistic anti-tumor activity.