title: Safety assessment in rats and dogs of Acoustic Cluster Therapy, a novel concept for ultrasound mediated, targeted drug delivery.
abstract: Acoustic Cluster Therapy (ACT) represents a novel concept for targeted drug delivery. Ultrasound is applied to activate intravenously administered free-flowing clusters of microbubbles and microdroplets within the target pathology, depositing 20-30μm large bubbles in the microvasculature for 5-10 min. Further application of ultrasound induces biomechanical effects which increase vascular permeability and enhance localized extravasation of coadministered drugs. Herein we report investigations done to assess the preclinical safety of ACT, using doses up to 1 mL/kg (3μL perfluoromethyl-cyclopentane/kg). In dogs, half the animals were exposed to ultrasound activation in the heart for 1 min, no ultrasound was applied in the other half. Posttreatment observation time was 24 h. Clinical signs, ophthalmoscopy, clinical pathology, macro-, and microscopy were used as endpoints. No differences between groups with and without ultrasound activation were observed. Short-lasting leukopenia and thrombocytopenia, possibly secondary to a slight and short-lasting increase in plasma histamine and complement split products, were the only effects noted. In rats ACT was activated in the liver for 5 min. Histopathology and clinical chemistry parameters remained unchanged. Lastly, rats were treated with ACT activated in the heart and thereafter placed on a rotarod for evaluation of motor coordination. No differences were observed between animals treated with ACT and controls. In conclusion, ACT appeared safe at dose-levels up to 1 mL/kg and with activation either in the heart or the liver. These results, together with positive efficacy data upon coinjection with cytotoxic compounds encourage further preclinical safety studies with the objective of entering subsequent clinical trials.
authors.affiliation: Norwegian Institute of Public Health Oslo Norway.
authors.forename: Oddvar
authors.initials: O
authors.lastname: Myhre
authors.affiliation: Yara International AS Oslo Norway.
authors.forename: Marie
authors.initials: M
authors.lastname: Bjørgan
authors.affiliation: Bayer Healthcare AS Oslo Norway.
authors.forename: Derek
authors.initials: D
authors.lastname: Grant
authors.affiliation: Pronova BioPharma Norge AS Oslo Norway.
authors.forename: Svein-Olaf
authors.initials: SO
authors.lastname: Hustvedt
authors.affiliation: Phoenix Solutions AS Oslo Norway.
authors.forename: Per C
authors.initials: PC
authors.lastname: Sontum
authors.affiliation: Norwegian Institute of Public Health Oslo Norway.
authors.forename: Hubert
authors.initials: H
authors.lastname: Dirven
keywords: Acoustic Cluster Therapy; drug delivery; microbubbles; ultrasound