Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study.

Wenbo Zhan

doi:10.3390/pharmaceutics12010069

Abstract

Focused ultrasound (FUS) coupled with microbubbles (MB) has been found to be a promising approach to disrupt the blood-brain barrier (BBB). However, how this disruption affects drug transport remains unclear. In this study, drug transport in combination therapy of liposomes and FUS-MB-induced BBB disruption (BBBD) was investigated based on a multiphysics model. A realistic 3D brain tumour model extracted from MR images was applied. The results demonstrated the advantage of liposomes compared to free doxorubicin injection in further improving treatment when the BBB is opened under the same delivery conditions using burst sonication. This improvement was mainly due to the BBBD-enhanced transvascular transport of free doxorubicin and the sustainable supply of the drug by long-circulating liposomes. Treatment efficacy can be improved in different ways. Disrupting the BBB simultaneously with liposome bolus injection enables more free drug molecules to cross the vessel wall, while prolonging the BBBD duration could accelerate liposome transvascular transport for more effective drug release. However, the drug release rate needs to be well controlled to balance the trade-off among drug release, transvascular exchange and elimination. The results obtained in this study could provide suggestions for the future optimisation of this FUS-MB–liposome combination therapy against brain cancer.

Highlights

Malignant glioma is highly invasive and aggressive, with a high mortality rate and short survival time [1]
The present study offers some new insight into the enhancement of liposome-mediated drug delivery into brain tumour via Focused ultrasound (FUS) and MB; there were several assumptions involved. (I) FUS sonication is usually performed using an ultrasound transducer with its focus point swapping across the brain tumour, so the blood–brain barrier disruption (BBBD) could be non-uniform across the entire brain
Drug transport in the liposome-mediated delivery coupled with FUS- and MB-induced BBBD was investigated by means of numerical simulation in this study

Summary

Introduction

Malignant glioma is highly invasive and aggressive, with a high mortality rate and short survival time [1]. Despite recovering gradually after the sonication ends [5], the temporary blood–brain barrier disruption (BBBD) can successfully enable intravenously administrated drugs to enter brain tumours for cell killing. This enhanced transvascular transport could be more significant for drugs like doxorubicin, to which the BBB is normally nearly impermeable [6,7]. Given that its clinical use is highly limited by serious adverse effects, especially cardiotoxicity, doxorubicin in a liposome-encapsulated form has been approved by the FDA as an alternative [8] It is not clear how BBBD influences drug transport in liposome-mediated delivery, which can largely determine delivery outcomes and treatment efficacy

Methods

Results

Conclusion