CO2-Driven Nebulization of pH-Sensitive Supramolecular Polymers for Intraperitoneal Hydrogel Formation and the Treatment of Peritoneal Metastasis

Because peritoneal metastasis (PM) from ovarian cancer is characterized by non-specific symptoms, it is often diagnosed at advanced stages. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) can be considered a promising drug delivery method for unresectable PM. Currently, the efficacy of intraperitoneal (IP) drug delivery is limited by the off-label use of IV chemotherapeutic solutions, which are rapidly cleared from the IP cavity. Hence, this research aimed to improve PM treatment by evaluating a nanoparticle-loaded, pH-switchable supramolecular polymer hydrogel as a controlled release drug delivery system that can be IP nebulized. Moreover, a multidirectional nozzle was developed to allow nebulization of viscous materials such as hydrogels and to reach an even IP gel deposition. We demonstrated that acidification of the nebulized hydrogelator solution by carbon dioxide, used to inflate the IP cavity during laparoscopic surgery, stimulated the in situ gelation, which prolonged the IP hydrogel retention. In vitro experiments indicated that paclitaxel nanocrystals were gradually released from the hydrogel depot formed, which sustained the cytotoxicity of the formulation for 10 days. Finally, after aerosolization of this material in a xenograft model of PM, tumor progression could successfully be delayed, while the overall survival time was significantly increased compared to non-treated animals.

Automated summary

This study aimed to improve the treatment of peritoneal metastasis from ovarian cancer by evaluating a nanoparticle-loaded, pH-switchable supramolecular polymer hydrogel as a controlled release drug delivery system. The research demonstrated that acidifying the nebulized hydrogel solution with carbon dioxide stimulated in situ gelation, prolonging the retention of the hydrogel in the peritoneal cavity. In vitro experiments showed that the drug was gradually released from the hydrogel and maintained cytotoxicity for 10 days. Furthermore, aerosolization of the hydrogel delayed tumor progression and significantly increased overall survival time in a xenograft model of peritoneal metastasis.