Hyperthermic Pressurized IntraPeritoneal Aerosol Chemotherapy (hPIPAC) – A pharmacological study ex vivo

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dc.contributor.advisor Königsrainer, Alfred (Prof. Dr.)
dc.contributor.author Held, Felicitas Giuliana
dc.date.accessioned 2023-02-20T10:27:33Z
dc.date.available 2023-02-20T10:27:33Z
dc.date.issued 2023-02-20
dc.identifier.uri http://hdl.handle.net/10900/136670
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1366700 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-78021
dc.description.abstract Peritoneal metastasis is relatively resistant to systemic chemotherapy and has a poor prognosis. The therapy remains palliative with the aim of prolonging life and preserving its quality. There is a need to develop improved new therapeutic approaches. An example for a new drug delivery system that addresses systemically the known limitations of intraperitoneal chemotherapy for treating peritoneal metastasis has been pressurized intraperitoneal aerosol chemotherapy (PIPAC). Preclinical experiments, patient cohorts, and controlled clinical studies suggest that PIPAC might be a significant step forward to improve the efficacy of intraperitoneal chemotherapy. Prior scientific research showed that the addition of hyperthermia to chemotherapy can increase its cytotoxic efficacy. Our research hypothesized that the addition of hyperthermia would further improve the pharmacological properties of PIPAC. In this study, we used a validated prototype for establishing and maintaining tissue temperature within a range of 41 – 43 °C in an ex-vivo organ model. The specific aim was to determine whether hyperthermia can increase drug tissue concentration as well as the depth of tissue penetration, as compared to normothermic PIPAC. The drugs cisplatin and doxorubicin were aerosolized into a test group (hyperthermia) and a control group (normothermia) of fresh inverted bovine urinary bladders (IBUB) obtained from the slaughterhouse. The CO2 filled IBUB has an equivalent volume to the expanded human abdominal cavity, and then its inner surface is overlaid with peritoneum. Altogether, 108 biopsies were taken at standardized locations and prepared for further analysis. Pharmacological measures were performed in a GLP-certified laboratory. There, doxorubicin concentration was measured by high-performance liquid chromatography and cisplatin concentration was quantified by atomic absorption spectroscopy. The depth of tissue penetration of doxorubicin was determined using a fluorescence microscope in our laboratory. All analyses were blinded. Surprisingly, results showed no significant pharmacological advantage of hPIPAC over PIPAC. Neither the tissue concentration of doxorubicin nor cisplatin was enhanced by therapeutic hyperthermia. Doxorubicin did not penetrate the tissue more deeply under hyperthermic conditions. A possible explanation for this negative result is a significant liquid uptake by the target tissue during the warming phase preceding the application of chemotherapy. We confirmed this liquid uptake by histology. As a result, we hypothesize that interstitial fluid pressure increases within the peritoneum and the retroperitoneal tissue, which is an obstacle to drug tissue uptake. The interpretation of these results should be done cautiously. First, we only evaluated the pharmacological effects and not the biological impact of hyperthermia on the target tissue. Second, we used ex-vivo, post-mortem tissue. Finally, although the model used simulated heat loss, there was no blood circulation. Further studies are needed before it is possible to conclude that hPIPAC has no pharmacological or biological advantage over PIPAC. These experiments should include measurements in a living animal model. Possibly, other drug delivery technologies might overcome current limitations and allow physicians to exploit the full potential of hyperthermia in combination with PIPAC. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.ddc 610 de_DE
dc.subject.other PIPAC de_DE
dc.subject.other Pressurized IntraPeritoneal Chemotherapy en
dc.subject.other hPIPAC de_DE
dc.subject.other hyperthermic en
dc.subject.other Hyperthermie de_DE
dc.subject.other peritoneale Metastasen de_DE
dc.subject.other pharmacological study en
dc.subject.other hPIPAC en
dc.subject.other Peritonealkarzinose de_DE
dc.subject.other Experimente de_DE
dc.subject.other peritoneal metastasis en
dc.subject.other peritoneal carcinomatosis en
dc.subject.other PIPAC en
dc.subject.other experiments en
dc.subject.other experimental research en
dc.title Hyperthermic Pressurized IntraPeritoneal Aerosol Chemotherapy (hPIPAC) – A pharmacological study ex vivo en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2023-01-26
utue.publikation.fachbereich Medizin de_DE
utue.publikation.fakultaet 4 Medizinische Fakultät de_DE
utue.publikation.noppn yes de_DE

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