title: Sonoporation with Acoustic Cluster Therapy (ACT®) induces transient tumour volume reduction in a subcutaneous xenograft model of pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with survival averaging only 3months if untreated following diagnosis. A major limitation in effectively treating PDAC using conventional and targeted chemotherapeutic agents, is inadequate drug delivery to the target location, predominantly due to a poorly vascularised, desmoplastic tumour microenvironment. Ultrasound in combination with ultrasound contrast agents, i.e., microbubbles, that flow through the vasculature and capillaries can be used to disrupt such mechanical barriers, potentially allowing for a greater therapeutic efficacy. This phenomenon is commonly referred to as sonoporation. In an attempt to improve the efficacy of sonoporation, novel microbubble formulations are being developed to address the limitation of commercially produced clinical diagnostic ultrasound contrast agents. In our work here we evaluate the ability of a novel formulation; namely Acoustic Cluster Therapy (ACT®) to improve the therapeutic efficacy of the chemotherapeutic agent paclitaxel, longitudinally in a xenograft model of PDAC. Results indicated that ACT® bubbles alone demonstrated no observable toxic effects, whilst ACT® in combination with paclitaxel can transiently reduce tumour volumes significantly, three days posttreatment (p=0.0347-0.0458). Quantitative 3D ultrasound validated the calliper measurements. Power Doppler ultrasound imaging indicated that ACT® in combination with paclitaxel was able to transiently sustain peak vasculature percentages as observed in the initial stages of tumour development. Nevertheless, there was no significant difference in tumour vasculature percentage at the end of treatment. The high vascular percentage correlated to the transient decrease and overall inhibition of the tumour volumes. In conclusion, ACT® improves the therapeutic efficacy of paclitaxel in a PDAC xenograft model allowing for transient tumour volume reduction and sustained tumour vasculature percentage.
authors.affiliation: National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; Department of Clinical Medicine, University of Bergen, Jonas Lies vei 65, 5021 Bergen, Norway.
authors.forename: Spiros
authors.initials: S
authors.lastname: Kotopoulis
authors.affiliation: Department of Clinical Science, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway.
authors.forename: Endre
authors.initials: E
authors.lastname: Stigen
authors.affiliation: Department of Medicine, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; KinN Therapeutics AS, Jonas Lies vei 65, 5021 Bergen, Norway.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Popa
authors.affiliation: Department of Clinical Science, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway.
authors.forename: Mireia Mayoral
authors.initials: MM
authors.lastname: Safont
authors.affiliation: Phoenix Solutions AS, Nycoveien 2, 0485 Oslo, Norway.
authors.forename: Andrew
authors.initials: A
authors.lastname: Healey
authors.affiliation: Phoenix Solutions AS, Nycoveien 2, 0485 Oslo, Norway.
authors.forename: Svein
authors.initials: S
authors.lastname: Kvåle
authors.affiliation: Phoenix Solutions AS, Nycoveien 2, 0485 Oslo, Norway.
authors.forename: Per
authors.initials: P
authors.lastname: Sontum
authors.affiliation: Department of Internal Medicine, Haematology Section, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; Department of Clinical Medicine, University of Bergen, Jonas Lies vei 65, 5021 Bergen, Norway.
authors.forename: Odd Helge
authors.initials: OH
authors.lastname: Gilja
authors.affiliation: Department of Clinical Science, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; Department of Internal Medicine, Haematology Section, Haukeland University Hospital, Jonas Lies vei 65, Bergen 5021, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.. Electronic address: Emmet.Mc.Cormack@med.uib.no.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D045423:Microbubbles; D061848:Optical Imaging; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D047368:Tumor Burden; D000069453:Ultrasonic Waves; D014463:Ultrasonography; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
keywords: Acoustic Cluster Therapy; Microbubbles; Mouse model; Pancreatic ductal adenocarcinoma; Sonoporation; Ultrasound