(360i) Microbubbles As Non-Invasive Targets for Blood Brain Barrier Disruption: An in silico investigation

Neurological disorders are the second leading cause of death globally; the four largest contributors are stroke, migraine, dementias such as Alzheimer’s Disease, and meningitis [1]. In order to safely and effectively treat such neurological conditions, therapeutic agents targeting the central nervous system (CNS) must achieve passage through the blood-brain barrier (BBB). The BBB is a highly selective and semipermeable sheath of endothelial cells and tight junctions that regulates the movement of ions, molecules, and cells from the blood to the CNS [2]. Efflux transporters imbedded in the BBB also influence the rapid clearance of drugs from the CNS and impede drug localization in the brain [3]. The BBB is therefore a tremendous mechanical and chemical obstacle to the entry of therapeutic agents into the brain [4]. One promising method to transport drugs across the BBB and into the brain is to disrupt the structure of the BBB, temporarily and reversibly, via physical and chemical approaches. However, current methods of blood-brain barrier disruption (BBBD) and drug delivery to the CNS are evidenced with scarring, limited drug distribution, and potential mortality from cerebral edema [4]. Herein, we describe the use of molecular dynamics (MD) simulations to investigate the underlying mechanisms and utility of a novel and noninvasive approach to BBBD—microbubble (MB)-assisted focused-ultrasound (MB+FUS)—allowing for efficient, targeted delivery of drugs into the brain microenvironment.

MBs are one to ten microns in diameter and are composed of a lipid shell encapsulating a hydrophobic gas. MBs transiently permeabilize the BBB by cavitating under ultrasound, which leads to mechanofluidic intrusion of nearby tissue. Despite their promising development for BBBD, the exact underlying mechanisms of MB cavitation have yet to be understood. Recent experiments have shown that after undergoing compression via ultrasound shock waves, MBs experience rapid expansion from internal pressurized gas, leading to intriguing “patterning” behavior of MB surface lipids. We employed MD, coupled with enhanced sampling, to explore the origins of this behavior at the atomistic level. Specifically, we describe simulations of flat lipid monolayers—representing a magnified portion of the curved MB surface at the nanoscale—at a gas/solvent interface, and the application of an applied external force to mimic the effects of ultrasound-induced compression and expansion. Our results provide new insights into how MB surface lipids are able to hydrodynamically expand into their surrounding environment without destabilizing their shell structure, thereby minimizing damage to the BBB. These results thus demonstrate the utility of MBs for safely and effectively treating neurological disorders via BBBD.

[1] Daneman, R., & Prat, A. “The blood-brain barrier”, Cold Spring Harb Perspect Biol, 2015, 7, a020412.

[2] Pardridge WM. “The blood-brain barrier: bottleneck in brain drug development”, NeuroRx, 2005, 2, 3–14.

[3] Löscher W and Potschka H. “Drug resistance in brain diseases and the role of drug efflux transporters”, Nat Rev Neurosci, 2005, 6, 591–602.

[4] Song KH, Harvey BK, and Borden MA. “State-of-the-art of microbubble-assisted blood-brain barrier disruption”, Theranostics, 2018, 8, 4393-4408.