Biodegradable Implants Combined with Immunogenic Chemotherapy and Immune Checkpoint Therapy for Peritoneal Metastatic Carcinoma Postoperative Treatment
Xinghui Si, Guofeng Ji, Sheng Ma, Yudi Xu, Jiayu Zhao, Zichao Huang, Yu Zhang, Wantong Song, Zhaohui Tang
Abstract
Peritoneal seeding represents one of the most frequent sites of metastasis for late-stage gastrointestinal and gynecological cancer. At present, the major treatment method for peritoneal metastatic carcinoma (PMC) is the combination of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Nevertheless, the 5 year survival rate of patients after these treatments is still far from satisfactory. Here, we report a biodegradable implant co-loaded with doxorubicin (DOX) and anti-PD-1 monoclonal antibody (aPD-1) (BI@DOX+aPD-1) for a combination of immunogenic chemotherapy and immune checkpoint therapy for PMC postoperative treatment. The bio-implant is fabricated with oxidized dextran (ODEX) and 4-arm poly(ethylene glycol) amine (4-arm PEG-NH2) by Schiff’s base reaction at mild conditions, with DOX and aPD-1 loaded inside during and after the fabrication process, respectively. In vitro studies confirmed the slow and sustained release of DOX and aPD-1 from the bio-implants. In vivo studies showed that the bio-implants could be gradually degraded and maintain relatively high concentrations of therapeutic agents in the mouse abdomen. In a murine CT26 PMC model, the BI@DOX+aPD-1 resulted in a 89.7% tumor-suppression rate after peritoneal implantation. Importantly, the combination therapy of DOX and aPD-1 in the bio-implant showed an excellent synergistic effect with a Q value of 2.35. This easy-fabricated bio-implant combined with DOX and aPD-1 should be promising for clinical PMC postoperative treatment.