Electrostatic Intraperitoneal Aerosol Delivery of Nanoparticles: Proof of Concept and Preclinical Validation

Abstract

There is an increasing interest in intraperitoneal delivery of chemotherapy as an aerosol in patients with peritoneal metastasis. The currently used technology is hampered by inhomogenous drug delivery throughout the peritoneal cavity because of gravity, drag, and inertial impaction. Addition of an electrical force to aerosol particles, exerted by an electrostatic field, can improve spatial aerosol homogeneity and enhance tissue penetration. A computational fluid dynamics model shows that electrostatic precipitation (EP) results in a significantly improved aerosol distribution. Fluorescent nanoparticles (NPs) remain stable after nebulization in vitro, while EP significantly improves spatial homogeneity of NP distribution. Next, pressurized intraperitoneal chemotherapy with and without EP using NP albumin bound paclitaxel (Nab‐PTX) in a novel rat model is examined. EP does not worsen the effects of CO2 insufflation and intraperitoneal Nab‐PTX on mesothelial structural integrity or the severity of peritoneal inflammation. Importantly, EP significantly enhances tissue penetration of Nab‐PTX in the anatomical regions not facing the nozzle of the nebulizer. Also, the addition of EP leads to more homogenous peritoneal tissue concentrations of Nab‐PTX, in parallel with higher plasma concentrations. In conclusion, EP enhances spatial homogeneity and tissue uptake after intraperitoneal nebulization of anticancer NPs.

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

“…With regard to NPs delivered via IP injection, both tumor nodules harvested from random locations in the peritoneal space (namely region e and f), showed identical results regarding tumor accumulation and fluorescence signal intensity of pARG-HA NPs (with average fluorescence intensities between 100 and 150 a.u). Our findings are consistent with previous studies indicating that the intra-abdominal drug distribution after PIPAC is not as homogeneous as expected but varies between different regions of the peritoneal cavity 58 . As validated by granulometric analysis, about 97.5 vol.…”

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

“…The main finding of our study is that both a positive charge and the electrostatic precipitation increase the depth of tissue penetration of CUR-PLGA-NPs. Our results are in line with prior data [13,27].…”

“…The proof-of-principle of combining PIPAC, electrostatic precipitation and nanoparticle formulation for enhancing tissue delivery was recently delivered. Simulations in silico showed that ePIPAC improved the spatial distribution of nanoparticles [13]. In a rodent model, ePIPAC significantly increased tissue penetration and provided a more homogeneous delivery of Nab-paclitaxel into the peritoneal tissue.…”

“…An objective histological response was reported in the majority of cases treated [12]. However, drug delivery throughout the peritoneal cavity with the current PIPAC technology is still not homogeneous because of inertial impaction and gravitational forces [13]. Thus, there is a need for further optimization of PIPAC.…”

“…One possible approach is the electrostatic loading of the therapeutic aerosol, followed by precipitation. This enhanced technique, electrostatic precipitation PIPAC (ePIPAC), has been shown to improve spatial aerosol homogeneity and enhance tissue penetration [13,14]. A second approach is to deliver chemotherapeutics in nanoparticles (NPs) -for example, with curcumin (CUR) [15][16][17].…”