title: Combined sonodynamic and antimetabolite therapy for the improved treatment of pancreatic cancer using oxygen loaded microbubbles as a delivery vehicle.
abstract: In this manuscript we describe the preparation of an oxygen-loaded microbubble (O2MB) platform for the targeted treatment of pancreatic cancer using both sonodynamic therapy (SDT) and antimetabolite therapy. O2MB were prepared with either the sensitiser Rose Bengal (O2MB-RB) or the antimetabolite 5-fluorouracil (O2MB-5FU) attached to the microbubble (MB) surface. The MB were characterised with respect to size, physical stability and oxygen retention. A statistically significant reduction in cell viability was observed when three different pancreatic cancer cell lines (BxPc-3, MIA PaCa-2 and PANC-1), cultured in an anaerobic cabinet, were treated with both SDT and antimetabolite therapy compared to either therapy alone. In addition, a statistically significant reduction in tumour growth was also observed when ectopic human xenograft BxPC-3 tumours in SCID mice were treated with the combined therapy compared to treatment with either therapy alone. These results illustrate not only the potential of combined SDT/antimetabolite therapy as a stand alone treatment option in pancreatic cancer, but also the capability of O2-loaded MBs to deliver O2 to the tumour microenvironment in order to enhance the efficacy of therapies that depend on O2 to mediate their therapeutic effect. Furthermore, the use of MBs to facilitate delivery of O2 as well as the sensitiser/antimetabolite, combined with the possibility to activate the sensitiser using externally applied ultrasound, provides a more targeted approach with improved efficacy and reduced side effects when compared with conventional systemic administration of antimetabolite drugs alone.
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors.forename: Conor
authors.initials: C
authors.lastname: McEwan
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors.forename: Sukanta
authors.initials: S
authors.lastname: Kamila
authors.affiliation: Institute of Biomedical Engineering, University of Oxford, OX3 7DQ, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Owen
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Nesbitt
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors.forename: Bridgeen
authors.initials: B
authors.lastname: Callan
authors.affiliation: Department of Mechanical Engineering, University of Colorado, 1111 Engineering Drive, Boulder, CO 80309, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Borden
authors.affiliation: Division of Surgery & Interventional Science, Faculty of Medical Sciences, University College London, UK.
authors.forename: Nikolitsa
authors.initials: N
authors.lastname: Nomikou
authors.affiliation: Division of Surgery & Interventional Science, Faculty of Medical Sciences, University College London, UK.
authors.forename: Rifat A
authors.initials: RA
authors.lastname: Hamoudi
authors.affiliation: Department of HPB Surgery, Mater Hospital, Belfast, Northern Ireland, BT14 6AB, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Taylor
authors.affiliation: Institute of Biomedical Engineering, University of Oxford, OX3 7DQ, UK. Electronic address: eleanor.stride@eng.ox.ac.uk.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Stride
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK. Electronic address: ap.mchale@ulster.ac.uk.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: McHale
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK. Electronic address: j.callan@ulster.ac.uk.
authors.forename: John F
authors.initials: JF
authors.lastname: Callan
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000627:therapeutic use; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D045423:Microbubbles / Q000627:therapeutic use*; D010100:Oxygen / Q000008:administration & dosage / Q000627:therapeutic use*; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012395:Rose Bengal / Q000008:administration & dosage / Q000627:therapeutic use*; D014465:Ultrasonics / Q000379:methods*
chemical_list: D000964:Antimetabolites, Antineoplastic; D005456:Fluorescent Dyes; D012395:Rose Bengal; D010100:Oxygen; D005472:Fluorouracil
keywords: 5-Flurouracil; Cancer; Hypoxia; Microbubbles; Pancreatic; Rose Bengal; SDT