Technology development of hyperthermic pressurized intraperitoneal aerosol chemotherapy (hPIPAC)

Abstract

Background: Optimized drug delivery systems are needed for intraperitoneal chemotherapy. The aim of this study was to develop a technology for applying pressurized intraperitoneal aerosol chemotherapy (PIPAC) under hyperthermic conditions (hPIPAC).

Methods: This is an ex-vivo study in an inverted bovine urinary bladder (IBUB). Hyperthermia was established using a modified industry-standard device (Humigard). Two entry and one exit ports were placed. Warm-humid CO₂ was insufflated in the IBUB placed in a normothermic bath to simulate body thermal inertia. The temperature of the aerosol, tissue, and water bath was measured in real-time.

Results: Therapeutic hyperthermia (target tissue temperature 41-43 °C) could be established and maintained over 30 min. In the first phase (insufflation phase), tissue hyperthermia was created by insufflating continuously warm-humid CO₂. In the second phase (aerosolization phase), chemotherapeutic drugs were heated up and aerosolized into the IBUB. In a third phase (application phase), hyperthermia was maintained within the therapeutic range using an endoscopic infrared heating device. In a fourth phase, the toxic aerosol was discarded using a closed aerosol waste system (CAWS).

Discussion: We introduce a simple and effective technology for hPIPAC. hPIPAC is feasible in an ex-vivo model by using a combination of industry-standard medical devices after modification. Potential pharmacological and biological advantages of hPIPAC over PIPAC should now be evaluated.

Keywords: Aerosol; Hyperthermia; Intraperitoneal chemotherapy; Laparoscopy; Medical devices.

Fig. 1

Target tissue temperature generated by warm-humid CO₂ alone in the hyperthermic inverted bovine urinary bladder (hIBUB) model. Three phases are simulated: (1) heating the hIBUB with humid CO₂ at a flow of 6 L/min and a temperature of 46.8 °C; (2) aerosolization of 200 ml chemotherapy at RT; (3) restoring therapeutic hyperthermia with warm-humid CO₂. Warm-humid CO₂ can generate therapeutic hyperthermia in the target tissue, but hyperthermia cannot be maintained during the aerosolization phase

Fig. 2

Technology proposed for generating hyperthermic pressurized intraperitoneal aerosol chemotherapy (hPIPAC). The system consists of the following components, connected sequentially: (a) an angio-injector equipped with a heating cuff; (b) a CO₂-insufflator delivering dry CO₂ at a temperature of 33 °C; (c) a device humidifying and warming up CO₂ to an output temperature of 45 °C and (d) an endoscopic infrared Saphir coagulator inserted into the lumen of the hIBUB model

Fig. 3

Target tissue temperature profile in two hIBUB organs (blue and red lines) during hPIPAC. The therapeutic phase begins at the end of the chemotherapy administration (spraying) phase. The infrared energy source restores and maintains the temperature of the target tissue within the desired therapeutic hyperthermia range (highlighted blue area) for the time needed (30 min) (Color figure online)