A real-time ex vivo model (eIBUB) for optimizing intraperitoneal drug delivery as an alternative to living animal models

Iaroslav Sautkin; Wiebke Solass; Frank-Jürgen Weinreich; Alfred Königsrainer; Martin Schenk; Karolin Thiel; Marc A Reymond

doi:10.1515/pp-2019-0017

A real-time ex vivo model (eIBUB) for optimizing intraperitoneal drug delivery as an alternative to living animal models

Pleura Peritoneum. 2019 Aug 15;4(3):20190017. doi: 10.1515/pp-2019-0017. eCollection 2019 Sep 1.

Authors

Iaroslav Sautkin¹, Wiebke Solass², Frank-Jürgen Weinreich³, Alfred Königsrainer⁴, Martin Schenk⁵, Karolin Thiel⁴, Marc A Reymond¹

Affiliations

¹ National Center for Pleura and Peritoneum, University of Tübingen, Tübingen, Germany.
² Institute of Pathology, University of Tübingen, Tübingen, Germany.
³ University of Tübingen, Tübingen, Germany.
⁴ Department of General and Transplant Surgery, University of Tübingen, Tübingen, Germany.
⁵ Experimental Surgical Oncology, Eberhard-Karls-Universitat Tubingen Medizinische Fakultat, Tübingen, Germany.

Abstract

Background: Optimization of intraperitoneal drug delivery systems requires functional models. We proposed the Inverted Bovine Urinary Bladder Model (IBUB), but IBUB does not allow repeated measurements over time and there is a significant biological variability between organs.

Methods: A further development of IBUB is presented, based on the physical principle of communicating vessels. Fresh bovine bladders were inverted so that the peritoneum lines up the inner surface. The IBUB and a second vessel were then interconnected under the same CO₂ pressure and placed on two scales. The therapeutic solution (Doxorubicin 2.7 mg and Cisplatin 13.5 mg) was delivered via an aerosolizer. All experiments were in triplicate and blinded to the origin of samples, measurements in a GLP-certified laboratory.

Results: The enhanced IBUB (eIBUB) model allows measurements of tissue drug concentration, depth of tissue penetration and spatial distribution. The homogeneous morphology of the peritoneum enables standardized, multiple tissue sampling. eIBUB minimizes biological variability between different bladders and eliminates the bias caused by the liquid collecting at the bottom of the model. Concentration of doxorubicin in the eIBUB (mean ± STDV: 18.5 ± 22.6 ng/mg) were comparable to clinical peritoneal biopsies (19.2 ± 38.6 ng/mg), as was depth of drug penetration (eIBUB: mean (min-max) 433 (381-486) µm, clinical ~ 500 µm).

Conclusions: The eIBUB model is a simple and powerful ex vivo model for optimizing intraperitoneal drug delivery and represents an attractive alternative to animal models. Results obtained are similar to those obtained in the human patient.

Keywords: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC); aerosol; alternative to animal models; cisplatin; doxorubicin; intraperitoneal chemotherapy; pressure.