Study On The Delivery Of Liposomal Drugs Into The Brain Using Low-frequency Focused Ultrasound With Microbubbles

Blood-brain barrier prevents most drugs entering the brain tissue, which is the bottleneck problem of the treatments of many diseases in the brain. Glioma is considered as the most common type of primary brain tumor. After surgical resection, the patients suffer from high rate of recurrence. In addition, the efficacy of chemotherapy is poor due to the existence of blood-brain barrier. Recently, focused ultrasound combined with microbubbles can open the blood-brain barrier noninvasively, reversibly and temporarily to deliver drugs to the targeted location, providing unique advantages over other traditional methods. Paclitaxel is a natural drug with good anti-cancer effect. Ergo, the present study utilizes low-frequency focused ultrasound with microbubbles to deliver liposomal paclitaxel in order to treat human glioma cell intracranial xenografts implanted in nude mice andevaluate the treatment efficacy.The present work established an ultrasound treatment platform suitable for mice. The characteristics of rhodamine-labeled liposomes with different diameters were investigated. Subsequently, the human glioma orthotopic transplantation nude mouse model was established. After delivery of liposomal paclitaxel using low-frequency focused ultrasound with microbubbles, tumor progressions were monitored using MRI and the survival rate data were obtained. Results showed that blood-brain barrier could be opened safely with peakrarefactional acoustic pressure under 0.64 MPa and microbubble dosage within 1.0 × 106 / g body weight. It was noted that the distribution pattern of liposomes with diameters above 50 nm was characterized by spots. Moreover, liposomes with smaller diameters could enter the brain tissue more easily than liposomes with larger diameters after blood-brain barrier opened by ultrasound with microbubbles. When paclitaxel dose was 10 mg/kg, the brain tumor progression was inhibited significantly using delivery method of ultrasound with microbubbles. The median survival time was increased by 18.8% higher than the control group.The originalities of the present work are elaborated in two aspects. For openers, it is the first time to investigate the effect of liposome sizes on delivery outcomes after blood-brain barrier opened by ultrasound with microbubbles. Results have been published online by Ultrasound in Medicine and Biology on April 25 th, 2016. Secondly, using human glioma orthotopic transplantation nude mouse model, the investigation on the treatment efficacy of paclitaxel liposomes delivered by focused ultrasound and microbubbles has not been reported yet.