Ultrasound-induced Cavitation enhances the efficacy of Chemotherapy in a 3D Model of Pancreatic Ductal Adenocarcinoma with its microenvironment.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is supported by a complex microenvironment whose physical contribution to chemoresistance could be overcome by ultrasound (US) therapy. This study aims to investigate the ability of US-induced inertial cavitation in association with chemotherapy to alter tumor cell viability via microenvironment disruption. For this purpose, we used a 3D-coculture PDAC model partially mimicking the tumor and its microenvironment. Coculture spheroids combining DT66066 cells isolated from KPC-transgenic mice and murine embryonic fibroblasts (iMEF) were obtained by using a magnetic nanoshuttle method. Spheroids were exposed to US with incremental inertial cavitation indexes. Conditions studied included control, gemcitabine, US-cavitation and US-cavitation + gemcitabine. Spheroid viability was assessed by the reduction of resazurin and flow cytometry. The 3D-coculture spheroid model incorporated activated fibroblasts and produced type 1-collagen, thus providing a partial miniature representation of tumors with their microenvironment. Main findings were: (a) Gemcitabine (5 μM) was significantly less cytotoxic in the presence of KPC/iMEFs spheroids compared with KPC (fibroblast-free) spheroids; (b) US-induced inertial cavitation combined with Gemcitabine significantly decreased spheroid viability compared to Gemcitabine alone; (c) both cavitation and chemotherapy affected KPC cell viability but not that of fibroblasts, confirming the protective role of the latter vis-à-vis tumor cells. Gemcitabine toxicity is enhanced when cocultured spheroids of KPC and iMEF are exposed to US-cavitation. Although the model used is only a partial representation of PDAC, this experience supports the hypothesis that US-inertial cavitation can enhance drug penetration and cytotoxicity by disrupting PDAC microenvironment.

• Authors: R Leenhardt, M Camus, J L Mestas, M Jeljeli, E Abou Ali, S Chouzenoux, B Bordacahar, C Nicco, F Batteux, C Lafon, F Prat
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 18916 (12 12 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31831785 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Carcinoma, Pancreatic Ductal (metabolism, pathology, therapy)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, pharmacology)
• Mice
• Mice, Transgenic
• Neoplasms, Experimental (metabolism, pathology, therapy)
• Pancreatic Neoplasms (metabolism, pathology, therapy)
• Spheroids, Cellular (metabolism, pathology)
• Tumor Microenvironment (drug effects)
• Ultrasonic Therapy
• Gemcitabine
• Pancreatic Neoplasms