Drug Delivery Across the Blood–Brain Barrier with Focused Ultrasound and Microbubbles

Abstract

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood-brain barrier (BBB). Neuropeptides, proteins, and chemotherapeutic agents are notable examples of potential therapeutics where the intact BBB is the major obstacle to their use. Indeed, all large-molecule products of biotechnology such as monoclonal antibodies, recombinant proteins, antisense, or gene therapeutics do not cross the BBB.Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Recent studies suggest that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain region through transient opening of the BBB. This technique offers a unique noninvasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. Clearly, if this method could be applied for different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This chapter will review both the merits and possible harmful bioeffects of this new approach. It will assess methods used to verify disruption of the BBB with MRI and examine the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Moreover, possible interactions of this novel delivery method with brain disease as well as safety aspects of BBB disruption with ultrasound and microbubbles will be addressed.

A bibliometric analysis of micro/nano-bubble related research: current trends, present application, and future prospects

“…Moreover, the investigation of inertial cavitation in micro-tunnels has significant implications for the development of therapeutic ultrasound applications such as ultrasound-mediated drug and gene delivery (Sassaroli and Hynynen 2007). Figure 8 shows that the relationship among ''Microbubble'', ''Blood-Brain Barrier'', and ''Focused Ultrasound'' was close, which the new technique of focused ultrasound with microbubble has widely applied across bloodbrain barriers for drug delivery (McDannold et al 2012;Ting et al 2012;Meairs 2013). Interestingly, ''Echocardiography'' (117; 2.4 %) has become routinely used diagnostic …”

“…In comparison to ultrasound contrast agents, contrast-enhanced ultrasound has an inherent advantage, which is an opportunity to assess the contrast enhancement patterns in real time, with a much higher temporal resolution than is possible with other imaging modalities, so that the enhancement dynamics of lesions can be studied, without the need to predefine scan time points or to perform bolus tracking (Claudon et al 2013). The focused ultrasound related research has had the highest increment rate in the recent 5 years and ranked 1st in 2014, which is extensively developed in drugs delivery, clearly showing the importance of this technique (Ting et al 2012;Meairs 2013).…”

Protocol to Induce the Temporary Opening of the Blood–Brain Barrier with Short-Time Focused Ultrasound in Rats

“…Recently, focused ultrasound (FUS) has been presented as a procedure capable of achieving a noninvasive and targeted BBB disruption [ 11 ]. FUS techniques can allow the opening of the BBB locally and reversibly [ 12 , 13 , 14 , 15 ], causing minor damage to the surrounding tissues [ 16 , 17 , 18 ]. The efficient disruption may be influenced by variables such as work frequency [ 19 , 20 ], pulse repetition [ 21 , 22 , 23 ], time application [ 24 , 25 ], and duty cycles [ 26 ].…”