Towards standardization of the parameters for opening the blood–brain barrier with focused ultrasound to treat glioblastoma multiforme: A systematic review of the devices, animal models, and therapeutic compounds used in rodent tumor models

Abstract

Glioblastoma multiforme (GBM) is a deadly and aggressive malignant brain cancer that is highly resistant to treatments. A particular challenge of treatment is caused by the blood–brain barrier (BBB), the relatively impermeable vasculature of the brain. The BBB prevents large molecules from entering the brain parenchyma. This protective characteristic of the BBB, however, also limits the delivery of therapeutic drugs for the treatment of brain tumors. To address this limitation, focused ultrasound (FUS) has been safely utilized to create transient openings in the BBB, allowing various high molecular weight drugs access to the brain. We performed a systematic review summarizing current research on treatment of GBMs using FUS-mediated BBB openings in in vivo mouse and rat models. The studies gathered here highlight how the treatment paradigm can allow for increased brain and tumor perfusion of drugs including chemotherapeutics, immunotherapeutics, gene therapeutics, nanoparticles, and more. Given the promising results detailed here, the aim of this review is to detail the commonly used parameters for FUS to open the BBB in rodent GBM models.

Breaking Barriers in Neuro-Oncology: A Scoping Literature Review on Invasive and Non-Invasive Techniques for Blood–Brain Barrier Disruption

“…FUS utilizes acoustic waves that pass through the skull and converge at a specific focal point within the brain [ 143 , 144 ]. Within this focal point, the FUS beam targets intravenously injected microbubbles, which subsequently respond to the rarefactions and compressions of the applied pressure wave by oscillating [ 145 , 146 ]. Such oscillation has adequate energy to exert mechanical stress onto the cells, leading to the opening of TJs between ECs of the BBB [ 145 , 146 ].…”

“…Within this focal point, the FUS beam targets intravenously injected microbubbles, which subsequently respond to the rarefactions and compressions of the applied pressure wave by oscillating [ 145 , 146 ]. Such oscillation has adequate energy to exert mechanical stress onto the cells, leading to the opening of TJs between ECs of the BBB [ 145 , 146 ]. FUS has also been shown to enhance the active transport of molecules across the BBB through various pathways, such as up-regulation of vesicles and carrier proteins or modulation of mechanosensitive ion channels [ 145 , 146 ].…”

“…Such oscillation has adequate energy to exert mechanical stress onto the cells, leading to the opening of TJs between ECs of the BBB [ 145 , 146 ]. FUS has also been shown to enhance the active transport of molecules across the BBB through various pathways, such as up-regulation of vesicles and carrier proteins or modulation of mechanosensitive ion channels [ 145 , 146 ]. Lastly, given that FUS provokes a transition from diffusive transport to convective transport in the tumor interstitial space, this method could be potentially suitable for the delivery of larger therapeutics, such as antibodies, whose transport across the BBB is largely reliant on convection [ 22 ].…”

Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review

“…Similarly, the properties of interest for the contrast agents include the shell formulation, size, dose, and half-life [ 16 ]. Careful combinations of contrast agents and FUS have allowed the noninvasive delivery of small molecules, proteins, antibodies, viral vectors, and nanoparticles across the BBB in preclinical studies [ [17] , [18] , [19] , [20] ]. Through a deep understanding of these factors, the technique of BBBO can be tailored for the predictable delivery of specific therapeutics into the brain.…”

An Overview on the Physiopathology of the Blood–Brain Barrier and the Lipid-Based Nanocarriers for Central Nervous System Delivery

“…This BBB disruption effect lasts usually for 4-6 h, but it can vary according to the patient, the intensity of US, and the size and concentration of the MBs [58,64]. In addition, these US favor the active transport of molecules across the BBB, for example, by enhancing the delivery through vesicles and carrier proteins or modulating mechanosensitive ion channels, they can cause convective flux in the tumor interstitial space, and they can remodel brain vasculature and stimulate the development of new neurons [65][66][67]. This approach is currently on clinical trials for gliomas (NCT03322813, NCT02343991, NCT03616860, and NCT03551249) [68][69][70], recurrent GBM (NCT02253212, NCT03626896, and NCT03712293) [71][72][73], amyotrophic lateral sclerosis (NCT03321487) [74], PD (NCT03608553 and NCT04370665) [75], and AD (NCT02986932, NCT03671889, NCT03739905, and NCT04118764) [76][77][78].…”