The effect of electrostatic high pressure nebulization on the stability, activity and ex vivo distribution of ionic self-assembled nanomedicines

Helena Braet; Valentina Andretto; Remco Mariën; Beyza Yücesan; Stefan van der Vegte; Ragna Haegebaert; Giovanna Lollo; Stefaan C De Smedt; Katrien Remaut

doi:10.1016/j.actbio.2023.08.027

The effect of electrostatic high pressure nebulization on the stability, activity and ex vivo distribution of ionic self-assembled nanomedicines

Acta Biomater. 2023 Oct 15:170:318-329. doi: 10.1016/j.actbio.2023.08.027. Epub 2023 Aug 19.

Authors

Helena Braet¹, Valentina Andretto², Remco Mariën³, Beyza Yücesan³, Stefan van der Vegte⁴, Ragna Haegebaert¹, Giovanna Lollo², Stefaan C De Smedt¹, Katrien Remaut⁵

Affiliations

¹ Department of Pharmaceutics, Ghent University, Ghent, Belgium; CRIG - Cancer Research Institute Ghent, Ghent, Belgium.
² Laboratoire d'Automatique, de Génie des Procédés et de Génie Pharmaceutique (LAGEPP), Université Claude Bernard Lyon 1, Lyon, France.
³ Department of Pharmaceutics, Ghent University, Ghent, Belgium.
⁴ Medspray b.v., Enschede, the Netherlands.
⁵ Department of Pharmaceutics, Ghent University, Ghent, Belgium; CRIG - Cancer Research Institute Ghent, Ghent, Belgium. Electronic address: katrien.remaut@ugent.be.

PMID: 37598790
DOI: 10.1016/j.actbio.2023.08.027

Abstract

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is applied to treat unresectable peritoneal metastasis (PM), an advanced, end-stage disease with a poor prognosis. Electrostatic precipitation of the aerosol (ePIPAC) is aimed at improving the intraperitoneal (IP) drug distribution and tumor penetration. Also, the combination of nanoparticles (NPs) as drug delivery vehicles and IP aerosolization as administration method has been proposed as a promising tool to treat PM. There is currently limited knowledge on how electrostatic precipitation (ePIPAC) and high pressure nebulization (PIPAC) affects the performance of electrostatically formed complexes. Therefore, the stability, in vitro activity and ex vivo distribution and tissue penetration of negatively charged cisPt-pArg-HA NPs and positively charged siRNA-RNAiMAX NPs was evaluated following PIPAC and ePIPAC. Additionally, a multidirectional Medspray® nozzle was developed and compared with the currently used Capnopen® nozzle. For both NP types, PIPAC and ePIPAC did not negatively influence the in vitro activity, although limited aggregation of siRNA-RNAiMAX NPs was observed following nebulization with the Capnopen®. Importantly, ePIPAC was linked to a more uniform distribution and higher tissue penetration of the NPs aerosolized by both nozzles, independent on the NPs charge. Finally, compared to the Capnopen®, an increased NP deposition was observed at the top of the ex vivo model following aerosolization with the Medspray® nozzle, which indicates that this device possesses great potential for IP drug delivery purposes. STATEMENT OF SIGNIFICANCE: Aerosolized drug delivery in the peritoneal cavity holds great promise to treat peritoneal cancer. In addition, electrostatic precipitation of the aerosol to the peritoneal tissue is aimed at improving the drug distribution and tumor penetration. The combination of nanoparticles (NPs), which are nano-sized drug delivery vehicles, and aerosolization has been proposed as a promising tool to treat peritoneal cancer. However, there is currently limited knowledge on how electrostatic precipitation and aerosolization affect the performance of electrostatically formed NPs. Therefore, the stability, activity, distribution and penetration of negatively and positively charged NPs was evaluated after aerosolization and electrostatic precipitation. Additionally, to further optimize the local drug distribution, a multidirectional spray nozzle was developed and compared with the currently used nozzle.

Keywords: Drug delivery; Intraperitoneal; Lipid nanoparticles; Nebulization; Polymeric nanoparticles; ePIPAC.