Pressurized intraperitoneal cold atmospheric plasma as a novel therapeutic strategy for peritoneal metastatic carcinoma.

[INTRODUCTION] Peritoneal metastatic carcinoma (PMC) faces limited therapeutic efficacy due to the peritoneal-plasma barrier and heterogeneous drug distribution. Current standard therapy (cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy, CRS + HIPEC) carries high complication rates. While pressurized intraperitoneal aerosol chemotherapy (PIPAC) improves distribution, its penetration depth remains suboptimal. Cold atmospheric plasma (CAP) induces tumor cell apoptosis via reactive oxygen and nitrogen species (RONS) but has not been applied in intraperitoneal therapy.

[OBJECTIVE] This study aimed to develop Pressurized Intraperitoneal Cold Atmospheric Plasma (PICAP), integrating CAP's RONS-mediated antitumor effects with pressure-enhanced permeation technology. We sought to overcome limitations of conventional intraperitoneal therapies (uneven distribution, inadequate penetration) and evaluate PICAP's therapeutic and prophylactic potential against peritoneal metastasis.

[METHODS] An in vitro peritoneal cavity model (carbon quantum dot tracers) and murine peritoneal metastasis models (MC38 colon cancer/ID8 ovarian cancer cells) compared permeability and efficacy among PICAP, PIPAC, and HIPEC. Mice received PICAP treatment (16 kV, 0.8 L/min He gas) for 0/5/10/15 min. Tumor burden, apoptosis, ROS levels, and mitochondrial function were analyzed via laparoscopy, histopathology, immunofluorescence, and flow cytometry. Prophylactic efficacy was also assessed.

[RESULTS] PICAP achieved full-thickness peritoneal penetration in vitro with significantly superior distribution uniformity versus PIPAC and HIPEC (p < 0.001). In murine models, 15-minute PICAP significantly reduced ascites volume and tumor burden, while markedly prolonging survival (p < 0.0001). Mechanistically, pressure-enhanced RONS delivery induced mitochondrial dysfunction (confirmed by JC-1 and MitoSOX assays), promoting tumor cell apoptosis and suppressing anoikis resistance. Prophylactic PICAP reduced surgically induced tumor implantation, achieving 100 % 90-day survival.

[CONCLUSION] PICAP effectively overcomes peritoneal drug delivery barriers through pressure-enhanced RONS penetration and mitochondrial apoptosis pathways, significantly inhibiting peritoneal metastasis progression and demonstrating prophylactic potential. Its innovative design synergizing physical and biochemical effects offers a superior therapeutic strategy for PMC beyond existing modalities.