title: Evaluating the Effect of Micropump© Position, Internal Pressure and Doxorubicin Dosage on Efficacy of Pressurized Intra-peritoneal Aerosol Chemotherapy (PIPAC) in an Ex Vivo Model.
abstract: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel clinical approach to the treatment of peritoneal carcinomatosis. A well-established, not anatomic ex vivo PIPAC model was used to investigate the influence of changes in internal pressure, distance of the Micropump(©) (MIP) to the distributing surface and the drug concentration on the penetration depth of doxorubicin in the target tissue.
  
  
  
  Doxorubicin was aerosolized in an ex vivo PIPAC model using a hermetic container system mimicking the abdominal cavity. Fresh post-mortem swine peritoneum was cut into proportional samples. Tissue specimens were spatially placed at 4 different spots within the box: P1, on the distributing surface of the box, directly opposite to MIP; P2, on the side wall of the box; P3, on the ceiling of the box; P4, on the distributing surface with a partial cover. Impact of changes in the following parameters were analyzed and compared with clinically established values (CEVs) at our center: pressure (CEV=12 mmHg), distance of the MIP from the distributing surface (CEV=8 cm) and doxorubicin concentration (CEV=3 mg/50 ml). In-tissue doxorubicin penetration depth was measured using fluorescence microscopy on frozen thin sections.
  
  
  
  Tissue positioning in the box had a significant impact on drug penetration after PIPAC with CEV. Under CEV conditions, the highest drug penetration depth was observed in the tissue placed on the distributing surface directly opposite to the MIP (P1: 351 μm, P2: 77 μm, P3: 66 μm, P4: 34 μm). A closer positioning of the MIP lead to a significantly higher mean depth penetration of doxorubicin in the P1 in contrast to other samples in which a reduced drug penetration was observed (1 cm vs. 8 cm distance from MIP to the distributing surface, P1 at 1 cm: 469 μm vs. P1 at 8 cm: 351 μm, p<0.0001; P2 at 1 cm: 25 μm vs. P2 at 8 cm: 77 μm, p<0.0001; P3 at 1 cm: 21 μm vs. P3 at 8 cm: 66 μm, p<0.001; P4 at 1 cm: 13 μm vs. P4 at 8 cm: 39 μm, p=0.021). Higher doxorubicin concentrations led to a highly significant increase of drug penetration in P1 (1 cm vs. 8 cm, p<0.0001), but only a little significant increase in other samples. An increase of internal pressure did not show a significant increase in penetration depth of doxorubicin.
  
  
  
  Our ex vivo data suggest that a higher pressure does not increase the penetration deepness of doxorubicin. Higher drug dosage and a closer positioning of the MIP toward the target lead to a higher penetration of doxorubicin within the samples. A more homogeneous penetration within all targets cannot be achieved by changing drug concentration, position of the nozzle or pressure increase.
authors.affiliation: Department of General Surgery and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany Basic Research Laboratory, Department of Surgery, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany veria.khosrawipour@elisabethgruppe.de.
authors.forename: Veria
authors.initials: V
authors.lastname: Khosrawipour
authors.affiliation: Basic Research Laboratory, Department of Surgery, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Khosrawipour
authors.affiliation: Basic Research Laboratory, Department of Surgery, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.
authors.forename: Thomas Albert
authors.initials: TA
authors.lastname: Falkenstein
authors.affiliation: Department of Hematology and Medical Oncology, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Diaz-Carballo
authors.affiliation: Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Herne, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Förster
authors.affiliation: Basic Research Laboratory, Department of Surgery, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.
authors.forename: Aras
authors.initials: A
authors.lastname: Osma
authors.affiliation: Department of Radiation Oncology, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.
authors.forename: Irenäus Anton
authors.initials: IA
authors.lastname: Adamietz
authors.affiliation: Department of General Surgery and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany Basic Research Laboratory, Department of Surgery, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zieren
authors.affiliation: Basic Research Laboratory, Department of Surgery, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany Department of Radiation Oncology, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany.
authors.forename: Khashayar
authors.initials: K
authors.lastname: Fakhrian
mesh_terms: D000336:Aerosols; D000818:Animals; D002277:Carcinoma; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D066298:In Vitro Techniques; D010535:Laparoscopy; D008856:Microscopy, Fluorescence; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D010537:Peritoneum / Q000187:drug effects; D011312:Pressure; D013552:Swine
chemical_list: D000336:Aerosols; D004317:Doxorubicin
keywords: Local drug distribution; doxorubicin; peritoneal carcinomatosis; pressurized intra-peritoneal aerosol chemotherapy (PIPAC)