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

Abstract

BackgroundOptimization 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.MethodsA 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.ResultsThe 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).ConclusionsThe 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.

Enhanced Intraperitoneal Delivery of Charged, Aerosolized Curcumin Nanoparticles by Electrostatic Precipitation

“…For this purpose, CUR-PLGA-NPs were coated with chitosan to create a positive versus negative ζ-potential. We then used an established ex vivo model of the peritoneal cavity, the eIBUB model [18,19], to compare the efficacy of ePIPAC versus PIPAC for delivering these CUR-PLGA-NPs. The main finding of our study is that both a positive charge and the electrostatic precipitation increase the depth of tissue penetration of CUR-PLGA-NPs.…”

“…After insufflation with CO 2 , the eIBUB develops a volume similar to that of the human abdomen (3-5 l). Tissue concentration and depth of penetration of doxorubicin in the eIBUB have been shown to be similar to in a human patient [18]. Fresh bovine bladders were obtained from the slaughterhouse, stored on ice and delivered in the early morning to the laboratory.…”

“…To test this hypothesis, we created cationic and anionic NPs. We studied their tissue uptake in an established ex vivo model of the human peritoneal space [18] after delivery as PIPAC versus ePIPAC. Our results provide the first evidence that a combination of ePIPAC with positively charged NPs has superior pharmacological properties for intraperitoneal drug delivery.…”

Technology development of hyperthermic pressurized intraperitoneal aerosol chemotherapy (hPIPAC)

“…The IBUB model has been described elsewhere [19,20]. The bovine bladder has a volume somewhat smaller (2-3 L) than the human abdominal cavity (3-5 L).…”

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

“…Several studies have evaluated drug uptake into the target tissue after PIPAC, and some of them have compared PIPAC with other drug delivery techniques such as HIPEC and/or laparoscopic HIPEC. Therapeutic substances investigated include methylene blue [28,76], DNA [77], RNA [29,78], cisplatin [79][80][81][82], doxorubicin [75,[83][84][85], oxaliplatin [82,[86][87][88] and liposomal doxorubicin [89,90].…”