Development and technical validation of an ultrasound nebulizer to deliver intraperitoneal pressurized aerosols in a rat colon cancer peritoneal metastases model

Abstract

Background/aim To develop and validate a nebulizer device for anti-cancer research on pressurized intraperitoneal aerosol supply in a preclinical peritoneal metastases (PM) rat model. Material and methods For aerosol generation, an ultrasonic nebulizer (USN) was modified. Aerosol analyses were performed ex-vivo by laser diffraction spectrometry (LDS). Intraperitoneal (IP) 99mtechnetium sodium pertechnetate (99mTc) aerosol distribution and deposition were quantified by in-vivo single photon emission computed tomography (SPECT/CT) and compared to liquid IP instillation of equivalent volume/doses of 99mTc with and without capnoperitoneum. PM was induced by IP injection of HCT116-Luc2 human colon cancer cells in immunosuppressed RNU rats. Tumor growth was monitored by bioluminescence imaging (BLI), 18F-FDG positron emission tomography (PET) and tissues examination at necropsy. Results The USN was able to establish a stable and reproducible capnoperitoneum at a pressure of 8 to 10 mmHg. LDS showed that the USN provides a polydisperse and monomodal aerosol with a volume-weighted diameter of 2.6 μm. At a CO2 flow rate of 2 L/min with an IP residence time of 3.9 s, the highest drug deposition efficiency was found to be 15 wt.-%. In comparison to liquid instillation, nebulization showed the most homogeneous IP spatial drug deposition. Compared to BLI, 18F-FDG-PET was more sensitive to detect smaller PM nodules measuring only 1–2 mm in diameter. BLI, 18F-FDG PET and necropsy analyses showed relevant PM in all animals. Conclusions The USN together with the PM rat model are suitable for robust and species-specific preclinical pharmacological studies regarding intraperitoneal delivery of pressurized aerosolized drugs and cancer research.

Performance of different nebulizers in clinical use for Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

“…For PIPAC nebulizers, such standards should ideally be set by a panel of experts through consensus conferences. Moreover, nebulizers with significant technical and granulometric differences from the standard technology should undergo first ex- and in-vivo animal testing before their first clinical use [ 26 – 34 ]. Manufacturers should be obliged to have the bioequivalence of the cytostatic drugs administered independently certified in comparison to standard nebulizer systems, analogous to drugs and their generics.…”

Intraoperative parameters and postoperative follow-up of foam-based intraperitoneal chemotherapy (FBIC)

“…The local instillation of chemotherapeutic solution increases cell toxicity when it is in direct contact with the cancer nodules of the peritoneal cavity. Even though extensive attempts have been made to improve IPC delivery ( Mikolajczyk et al, 2020 ; Buggisch et al, 2022 ; Khosrawipour et al, 2023a ) limitations still exist in both liquid instillations as well as aerosol-based systems ( Dedrick and Flessner, 1997 ; Sugarbaker and Ryan, 2012 ; Khosrawipour et al, 2016a ; Bellendorf et al, 2018 ). These limitations include inhomogeneous drug distribution and limited penetration into PM.…”

“…Novel substances have also been used for intraperitoneal delivery however some show limited drug tissue penetration ( Mikolajczyk et al, 2018b ). Therefore, new delivery methods have been presented to improve IPC ( Buggisch et al, 2022 ; Hwang et al, 2022 ). For the patients to have a better outcome, new physical methods of drug delivery have been used to enhance the antitumoral effect of IPC ( Khosrawipour et al, 2016b ; Khosrawipour et al, 2023a ).…”