Establishment of a rat ovarian peritoneal metastasis model to study pressurized intraperitoneal aerosol chemotherapy (PIPAC)

Abstract

Background pressurized intraperitoneal aerosol chemotherapy (PIPAC), with or without electrostatic precipitation (ePIPAC), was recently introduced in the treatment of peritoneal metastases (PM) from ovarian cancer (OC). Preliminary clinical data are promising, but several methodological issues as well the anticancer efficacy of PIPAC remain unaddressed. Here, we propose a rat ePIPAC model that allows to study these issues in a clinically relevant, reproducible, and high throughput model. Methods laparoscopy and PIPAC were established in healthy Wistar rats. Aerosol properties were measured using laser diffraction spectrometry based granulometric analyses. Electrostatic precipitation was accomplished using a commercially available generator (Ultravision™). A xenograft model of ovarian PM was created in athymic rats using intraperitoneal (IP) injection of SKOV-3 luciferase positive cells. Tumor growth was monitored weekly by in vivo bioluminescence imaging. Results PIPAC and electrostatic precipitation were well tolerated using a capnoperitoneum of 8 mmHg. All rats survived the (e)PIPAC procedure and no gas or aerosol leakage was observed over the entire procedure. With an injection pressure of 20 bar, granulometry showed a mean droplet diameter (D(v,0.5)) of 47 μm with a flow rate of 0.5 mL/s, and a significantly lower diameter (30 μm) when a flow rate of 0.8 mL/s was used. Experiments using IP injection of SKOV-3 luciferase positive cells showed that after IP injection of 20 × 10 6 cells, miliary PM was observed in all animals . PIPAC was feasible and well supported in these tumor bearing animals. Conclusions we propose a reproducible and efficient rodent model to study PIPAC and ePIPAC in OC xenografts with widespread PM. This model allows to characterize and optimize pharmacokinetic and biophysical parameters, and to evaluate the anti-cancer efficacy of (e)PIPAC treatment.

Establishment of a Mouse Ovarian Cancer and Peritoneal Metastasis Model to Study Intraperitoneal Chemotherapy

“…In addition, we identified the optimum time frame within which distribution of intraperitoneal compounds reached their optimum. Of note, we found that PIPAC had the best distribution pattern among the three different forms of IPC studies, which is consistent with data found in the rat model [ 13 ] and in humans [ 20 ]. This suggests that our mouse model is an adequate surrogate for studying human IPC.…”

“…Thus, animal models allowing for rapid, reproducible, and inexpensive study of different forms of IPC are warranted. Recently, van de Sande et al developed an animal model of IPC using Wistar rats undergoing laparoscopy with capnoperitoneum, aerosolized chemotherapy, and electroprecipitation [ 13 ]. This tumor model used a xenograft of ovarian PM based on SKOV-3 luciferase-positive cells.…”

Synergy between Intraperitoneal Aerosolization (PIPAC) and Cancer Nanomedicine: Cisplatin-Loaded Polyarginine-Hyaluronic Acid Nanocarriers Efficiently Eradicate Peritoneal Metastasis of Advanced Human Ovarian Cancer

“…Therefore, the feasibility and added benefits of the PIPAC therapy with nanoparticles still largely remain to be elucidated. In this study, we explored the in vivo potency of cisplatin-loaded pARG-HA NPs in a rat model of intraperitoneally disseminated human ovarian cancer [56][57] , with a special focus on the potential advantage of formulating cisplatin into a nanoparticle system and whether or not liquid aerosolization is beneficial compared to liquid injection of NPs into the peritoneal cavity. Tumor-bearing rats were dosed either with free cisplatin (5 mg/kg) or cisplatin-loaded pARG-HA NPs (at 5 mg/kg doseequivalent level of Pt) through a single injection or nebulization (PIPAC) (Figure 3A).…”

Enhanced Intraperitoneal Delivery of Charged, Aerosolized Curcumin Nanoparticles by Electrostatic Precipitation

“…It has also been suggested that adding electrostatic loading and following precipitation of the therapeutic aerosol might optimize tissue effects of PIPAC [22]. This hypothesis was confirmed in an animal model [14,28], and ePIPAC has successfully entered clinical practice [29,30].…”