Development and validation of an ex vivo model for optimizing intraperitoneal drug delivery

Abstract

Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a minimally invasive treatment mode for local chemotherapy of Peritoneal Metastasis (PM). PIPAC has demonstrated promising results in the first clinical studies. Optimization of the current drug-devices combinations requires functional models. The currently used in vivo, in vitro and ex vivo models cannot deliver real-time information on tissue drug uptake. Moreover, alternatives should be developed to limit research on living animals. This study focuses on the development and validation of an ex vivo model for optimizing intraperitoneal drug delivery, the enhanced Inverted Bovine Urinary Bladder Model (eIBUB). The research builds up on the IBUB model proposed by Schnelle et al in 2017, by connecting a second vessel to the bladder. A list of specifications and requirements for an ex-vivo model was created. The eIBUB model takes advantage of the principle of communicating vessels by connecting the base of the bladder to a second, hermetic container kept under an identical pressure. This design allows continuous collection of the aerosol falling down, and real-time assessment of the tissue liquid uptake (i.e., the portion of the therapeutic aerosol effectively taken up by the tissue) vs. the liquid falling down (which, by definition, can only have a limited therapeutic effect). This study details the technical setup of the eIBUB model and its feasibility, in particular concerning real-time measurements. The verification process showed that the eIBUB model meets the majority of the specifications. The usability and safety of the eIBUB model was confirmed under real laboratory conditions using toxic drugs. The validation process, involving two drugs commonly used during PIPAC (doxorubicin and cisplatin), showed that the depth of tissue penetration and the tissue drug concentration are in line with the gold standard (measurements in the human patient) and available comparators (ex-vivo and animal models). The variability of the results was at least comparable to the comparators. The eIBUB model meets the ARRIVE criteria (replacement, reduction, refinement) in animal research. Thus, the eIBUB model is a significant advance in peritoneal pharmacological research.