Development of rotational intraperitoneal pressurized aerosol chemotherapy to enhance drug delivery into the peritoneum

Abstract

This study aims to evaluate the drug distribution, tissue concentrations, penetration depth, pharmacokinetic properties, and toxicities after rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. Because relevant medical devices have not been introduced, we developed our prototype of pressurized intraperitoneal aerosol chemotherapy (PIPAC) and RIPAC by adding a conical pendulum motion device for rotating the nozzle. RIPAC and PIPAC were conducted using 150 ml of 1% methylene blue to evaluate the drug distribution and 3.5 mg of doxorubicin in 50 ml of 0.9% NaCl to evaluate the tissue concentrations and penetration depth, pharmacokinetic properties, and toxicities. All agents were sprayed as aerosols via the nozzle, DreamPen ® (Dalim Biotech, Gangwon, South Korea), with a velocity of 5 km/h at a flow rate of 30 ml/min under a pressure of 7 bars, and capnoperitoneum of 12 mmHg was maintained for 30 min. As a result, RIPAC showed a wider distribution and stronger intensity than PIPAC. Compared with PIPAC, RIPAC demonstrated high values of the tissue concentration in the central, right upper, epigastrium, left upper, left lower, right lower, and right flank regions (median, 375.5–2124.9 vs. 161.7–1240 ng/ml; p ≤ .05), and higher values of the depth of concentrated diffusion and depth of maximal diffusion (median, 232.5–392.7 vs. 116.9–240.1 μm; 291.2–551.2 vs. 250.5–362.4 μm; p ≤ .05) in all regions except for bowels. In RIPAC, the pharmacokinetic properties reflected hemodynamic changes during capnoperitoneum, and there were no related toxicities. Conclusively, RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC.

Rotational intraperitoneal pressurized aerosol chemotherapy with paclitaxel and cisplatin: pharmacokinetics, tissue concentrations, and toxicities in a pig model

“…After we developed RIPAC as a novel prototype of PIPAC for improving drug delivery, we tried to evaluate the effect and safety of RIPAC for treating EOC with PM [ 17 18 19 20 ]. In the previous report, we compared the distribution, tissue concentration, and diffusion of doxorubicin between PIPAC and RIPAC, suggesting that RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC [ 19 ].…”

“…After we developed RIPAC as a novel prototype of PIPAC for improving drug delivery, we tried to evaluate the effect and safety of RIPAC for treating EOC with PM [ 17 18 19 20 ]. In the previous report, we compared the distribution, tissue concentration, and diffusion of doxorubicin between PIPAC and RIPAC, suggesting that RIPAC may have the potential to enhance drug delivery into the peritoneum compared to PIPAC [ 19 ]. Since paclitaxel and cisplatin were the main agents for intraperitoneal chemotherapy that have been shown to improve survival in the Gynecologic Oncology Group (GOG)-172 and HIPEC trials for advanced ovarian cancer [ 6 7 ], we further investigated the pharmacokinetics, tissue concentrations, and toxicities of RIPAC with paclitaxel and cisplatin in this study.…”

“…Thus, the rotational stick moved clockwise, and when the sensor attached to the rotating stick contacted the rod of the rotating path, it moved counterclockwise to maintain repetitive rotation ( Fig. 1 ; Video S1 ) [ 17 19 ].…”

“…In previous studies, we reported the development of rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) to improve drug delivery by rotating the nozzle [ 17 18 ]. RIPAC using the new nozzle, Dreampen ® (Dreampac Corp., Wonju, Korea), enhanced drug distribution in the abdominal cavity, tissue concentration, and penetration depth of doxorubicin into the peritoneum compared with PIPAC in a pig model [ 19 20 ]. In this study, we report the pharmacokinetics, tissue concentrations, and toxicities when paclitaxel and cisplatin, the most effective drugs for treating ovarian cancer, were administered during RIPAC in a pig model.…”

Is PIPAC a Treatment Option in Upper and Lower Gastrointestinal Cancer with Peritoneal Metastasis?

“…Worldwide, several centers have developed tools for the preclinical study of intraperitoneal aerosolized drug delivery. These include computational models, in vitro models, isolated organ models such as the inverted bladder, and animal models (mouse, rat, pig, sheep) [40][41][42][43][44][45][46][47][48][49][50][51][52].…”