Optimization of intraperitoneal aerosolized drug delivery using computational fluid dynamics (CFD) modeling.

Intraperitoneal (IP) aerosolized anticancer drug delivery was recently introduced in the treatment of patients with peritoneal metastases. However, little is known on the effect of treatment parameters on the spatial distribution of the aerosol droplets in the peritoneal cavity. Here, computational fluid dynamics (CFD) modeling was used in conjunction with experimental validation in order to investigate the effect of droplet size, liquid flow rate and viscosity, and the addition of an electrostatic field on the homogeneity of IP aerosol. We found that spatial distribution is optimal with small droplet sizes (1-5 µm). Using the current clinically used technology (droplet size of 30 µm), the optimal spatial distribution of aerosol is obtained with a liquid flow rate of 0.6 mL s-1. Compared to saline, nebulization of higher viscosity liquids results in less homogeneous aerosol distribution. The addition of electrostatic precipitation significantly improves homogeneity of aerosol distribution, but no further improvement is obtained with voltages higher than 6.5 kV. The results of the current study will allow to choose treatment parameters and settings in order to optimize spatial distribution of IP aerosolized drug, with a potential to enhance its anticancer effect.

Exploring high pressure nebulization of Pluronic F127 hydrogels for intraperitoneal drug delivery.

Peritoneal metastasis is an advanced cancer type which can be treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Here, chemotherapeutics are nebulized under high pressure in the intraperitoneal (IP) cavity to obtain a better biodistribution and tumor penetration. To prevent the fast leakage of chemotherapeutics from the IP cavity, however, nebulization of controlled release formulations is of interest. In this study, the potential of the thermosensitive hydrogel Pluronic F127 to be applied by high pressure nebulization is evaluated. Therefore, aerosol formation is experimentally examined by laser diffraction and theoretically simulated by computational fluid dynamics (CFD) modelling. Furthermore, Pluronic F127 hydrogels are subjected to rheological characterization after which the release of fluorescent model nanoparticles from the hydrogels is determined. A delicate equilibrium is observed between controlled release properties and suitability for aerosolization, where denser hydrogels (20% and 25% w/v Pluronic F127) are able to sustain nanoparticle release up to 30 h, but cannot effectively be nebulized and vice versa. This is demonstrated by a growing aerosol droplet size and exponentially decreasing aerosol cone angle when Pluronic F127 concentration and viscosity increase. Novel nozzle designs or alternative controlled release formulations could move intraperitoneal drug delivery by high pressure nebulization forward.

Intraperitoneal aerosolized drug delivery: Technology, recent developments, and future outlook.

Current therapies for patients with peritoneal metastases (PM) are only moderately effective. Recently, a novel locoregional treatment method for PM was introduced, consisting of a combination of laparoscopy with intraperitoneal (IP) delivery of anticancer agents as an aerosol. This 'pressurized intraperitoneal aerosol chemotherapy' (PIPAC) may enhance tissue drug penetration by the elevated IP pressure during CO2 capnoperitoneum. Also, repeated PIPAC cycles allow to accurately stage peritoneal disease and verify histological response to treatment. This review provides an overview of the rationale, indications, and currently used technology for therapeutic IP nebulization, and discusses the basic mechanisms governing aerosol particle transport and peritoneal deposition. We discuss early clinical results in patients with advanced, irresectable PM and highlight the potential of electrostatic aerosol precipitation. Finally, we discuss promising novel approaches, including nebulization of nanoparticles and prolonged release formulations.

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

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.