title: Inertial cavitation to non-invasively trigger and monitor intratumoral release of drug from intravenously delivered liposomes.
abstract: The encapsulation of cytotoxic drugs within liposomes enhances pharmacokinetics and allows passive accumulation within tumors. However, liposomes designed to achieve good stability during the delivery phase often have compromised activity at the target site. This problem of inefficient and unpredictable drug release is compounded by the present lack of low-cost, non-invasive methods to measure such release. Here we show that focused ultrasound, used at pressures similar to those applied during diagnostic ultrasound scanning, can be utilised to both trigger and monitor release of payload from liposomes. Notably, drug release was influenced by liposome composition and the presence of SonoVue® microbubbles, which provided the nuclei for the initiation of an event known as inertial cavitation. In vitro studies demonstrated that liposomes formulated with a high proportion of 1,2 distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) released up to 30% of payload following ultrasound exposure in the presence of SonoVue®, provided that the exposure created sufficient inertial cavitation events, as characterised by violent bubble collapse and the generation of broadband acoustic emissions. In contrast a 'Doxil'-like liposome formulation gave no such triggered release. In pre-clinical studies, ultrasound was used as a non-invasive, targeted stimulus to trigger a 16-fold increase in the level of payload release within tumors following intravenous delivery. The inertial cavitation events driving this release could be measured remotely in real-time and were a reliable predictor of drug release.
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Graham
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK. Electronic address: robert.carlisle@eng.ox.ac.uk.
authors.forename: Robert
authors.initials: R
authors.lastname: Carlisle
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: James J
authors.initials: JJ
authors.lastname: Choi
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: Apurva R
authors.initials: AR
authors.lastname: Shah
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Myers
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Fisher
authors.affiliation: Institut d'Investigacio Biomedica de Bellvitge, Gran Via 199, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
authors.forename: Miriam-Bazan
authors.initials: MB
authors.lastname: Peregrino
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: Len
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
authors.forename: Constantin C
authors.initials: CC
authors.lastname: Coussios
mesh_terms: D000818:Animals; D005260:Female; D049454:Firefly Luciferin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D045423:Microbubbles; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010743:Phospholipids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013459:Sulfur Hexafluoride / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014464:Ultrasonic Therapy
chemical_list: D008081:Liposomes; D010714:Phosphatidylethanolamines; D010743:Phospholipids; C420843:contrast agent BR1; C038089:1,2-distearoylphosphatidylethanolamine; D049454:Firefly Luciferin; D013459:Sulfur Hexafluoride
keywords: Cancer; Drug delivery; Inertial cavitation; Liposomes; Ultrasound