Biodegradable Implants Combined with Immunogenic Chemotherapy and Immune Checkpoint Therapy for Peritoneal Metastatic...

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.