{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T03:42:12Z","timestamp":1792726932512,"version":"4.5.0"},"reference-count":62,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"publisher","award":["13420"],"award-info":[{"award-number":["13420"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) using the original 30 min protocol has shown limited benefits in patients with peritoneal metastasis of colorectal cancer (PMCRC), likely due to the short duration, which limits drug penetration into tumor nodules. Bevacizumab, an antiangiogenic antibody that modifies the tumor microenvironment, may improve drug delivery during HIPEC. This in silico study evaluates the availability of oxaliplatin within tumor nodules when HIPEC is performed after bevacizumab treatment. Methods: Using a computational fluid dynamics (CFD) model of HIPEC, the temperature and oxaliplatin distribution within the rat abdomen were calculated, followed by a model of drug transport within tumor nodules located at various sites in the peritoneum. The vascular normalization effect of the bevacizumab treatment was incorporated by adjusting the biophysical parameters of the tumor nodules. The effective penetration depth values, including the thermal enhancement ratio of cytotoxicity, were then compared between HIPEC alone and HIPEC combined with the bevacizumab treatment. Results: After bevacizumab treatments at doses of 0.5 mg\/kg and 5 mg\/kg, the oxaliplatin availability increased by up to 20% and 45% when HIPEC was performed during the vascular normalization phase, with the penetration depth increasing by 1.5-fold and 2.3-fold, respectively. Tumors with lower collagen densities and larger vascular pore sizes showed higher oxaliplatin enhancement after the combined treatment. Bevacizumab also enabled a reduction in the oxaliplatin dose (up to half at 5 mg\/kg bevacizumab) while maintaining effective drug levels in the tumor nodules, potentially reducing systemic toxicity. Conclusions: These findings suggest that administering oxaliplatin-based HIPEC during bevacizumab-induced vascular normalization could significantly improve drug penetration and enhance treatment efficacy.<\/jats:p>","DOI":"10.3390\/pharmaceutics17020155","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T12:24:09Z","timestamp":1737635049000},"page":"155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Computational Evaluation of Improved HIPEC Drug Delivery Kinetics via Bevacizumab-Induced Vascular Normalization"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6795-5088","authenticated-orcid":false,"given":"Pouya","family":"Namakshenas","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7474-0533","authenticated-orcid":false,"given":"Johannes","family":"Crezee","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5952-8000","authenticated-orcid":false,"given":"Jurriaan B.","family":"Tuynman","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Surgery, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3146-3310","authenticated-orcid":false,"given":"Pieter J.","family":"Tanis","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Surgery, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6936-1934","authenticated-orcid":false,"given":"Arlene L.","family":"Oei","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 1105 AZ Amsterdam, The Netherlands"},{"name":"Laboratory for Experimental Oncology and Radiobiology (LEXOR), 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8504-136X","authenticated-orcid":false,"given":"H. Petra","family":"Kok","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mendoza-Moreno, F., Diez-Alonso, M., Mat\u00edas-Garc\u00eda, B., Ovejero-Merino, E., G\u00f3mez-Sanz, R., Bl\u00e1zquez-Mart\u00edn, A., Quiroga-Valc\u00e1rcel, A., Vera-Mansilla, C., Molina, R., and San-Juan, A. (2022). Prognostic factors of survival in patients with peritoneal metastasis from colorectal cancer. J. Clin. 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