Particle stability and structure on the peritoneal surface in pressurized intra‑peritoneal aerosol chemotherapy (PIPAC) analysed by electron microscopy: First evidence of a new physical concept for PIPAC

Abstract

Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has been introduced to the clinical setting as a novel approach for the treatment of peritoneal metastasis. The local interaction of chemoaerosol droplets with the peritoneal surface as well as their distribution pattern is considered the main advantage over conventional liquid intraperitoneal chemotherapy. The aim of the present study was to investigate the behavior of these aerosol particles during PIPAC application via electron microscopy. Solutions of doxycycline, liposomal doxorubicin and macrophage cells were aerosolized using an established ex-vivo model. PIPAC was performed on peritoneum samples via microcatheter (MC) at a pressure of 12 mmHg C0 2 at 27°C. Following PIPAC the surface structure of applied particles was measured via electron microscopy. The aerosol particle contact of doxycyclin created a nanofilm of ~200 nm height on the peritoneal surface, and this height was revealed to be independent of the size of the initial particle hitting. These nanofilm blocks of ‘cylinders’ are of different diameters depending on the initial aerosol particle hitting that spot. Diameters of these ‘cylinders’ are far wider than the original diameter of the initial aerosol particle. However, coated particles such as liposomal doxorubicin and macrophages remained intact following contact with the peritoneal surface. Based on this and other data, the concept that aerosol particles exhibit a gas-like behavior in the abdomen creating a therapeutic capnoperitoneum should be revised. Fluid aerosol particles collide with the peritoneum creating a nanofilm. The interaction of pressurized intraperitoneal aerosol on the peritoneum is therefore closer to the distribution of a liquid film than to that of a gas. Further studies are required to further analyze the interaction of this nanofilm on the peritoneum.

Creating nanocrystallized chemotherapy: the differences in pressurized aerosol chemotherapy (PAC) via intracavitary (IAG) and extracavitary aerosol generation (EAG) regarding particle generation, morphology and structure

“…While there are many clinical PIPAC studies, research on transport of aerosol particles remains limited. Although attempts have been made to analyze the microstructure and behavior of chemoparticles [11,21], these efforts have been partially obstructed due to challenges in size detection technology.…”

“…EAG produces a smaller particle outburst than PIPAC via intracavitary aerosol generator (IAG) [15]. These smaller particles supposedly create a smaller drug coating and hence result in lower in-tissue drug penetration rates, which have already been shown for PIPAC with IAG [11]. However, the opposite is the case.…”

“…This phenomenon has been recently attributed to a "hyperconcentrated drug nanolayer" formed by aerosols which is believed to increase diffusion effects by creating a high concentration gradient on the drug surface and its underlying tissues [11]. Interestingly, this effect can be achieved while total drug dosage is reduced compared to liquid intraperitoneal chemotherapy (IPC).…”

Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC): Does increased intraperitoneal pressure change distribution patterns and penetration depth of doxorubicin in a sheep model?

“…These experiments suggest that peritoneal cells may be less permeable to doxorubicin that other cell types, as also observed in the present study. The formation of a liquid lm on the peritoneum after PIPAC may also contribute to the poorer effects of increased intra-abdominal pressure pressure on the peritoneum [23].…”

Increased Tissue Penetration of Doxorubicin in Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) after High-Intensity Ultrasound (HIUS)

“…Data on electrostatic augmentation is scarce, and the potential of electrostatic PIPAC is unknown. Analyzing the effects of electrostatic precipitation combined with the applied aerosol itself is quite a challenge, and while ongoing studies present new locations and various applications for chemoaerosol [39,40], there is an ongoing effort to understand the applied chemoaerosol itself [39,41]. e application of heat in IPC is well studied.…”