Low-Intensity Focused Ultrasound Technique in Glioblastoma Multiforme Treatment

Abstract

Glioblastoma is one of the central nervous system most aggressive and lethal cancers with poor overall survival rate. Systemic treatment of glioblastoma remains the most challenging aspect due to the low permeability of the blood-brain barrier (BBB) and blood-tumor barrier (BTB), limiting therapeutics extravasation mainly in the core tumor as well as in its surrounding invading areas. It is now possible to overcome these barriers by using low-intensity focused ultrasound (LIFU) together with intravenously administered oscillating microbubbles (MBs). LIFU is a non-invasive technique using converging ultrasound waves which can alter the permeability of BBB/BTB to drug delivery in a specific brain/tumor region. This emerging technique has proven to be both safe and repeatable without causing injury to the brain parenchyma including neurons and other structures. Furthermore, LIFU is also approved by the FDA to treat essential tremors and Parkinson’s disease. It is currently under clinical trial in patients suffering from glioblastoma as a drug delivery strategy and liquid biopsy for glioblastoma biomarkers. The use of LIFU+MBs is a step-up in the world of drug delivery, where onco-therapeutics of different molecular sizes and weights can be delivered directly into the brain/tumor parenchyma. Initially, several potent drugs targeting glioblastoma were limited to cross the BBB/BTB; however, using LIFU+MBs, diverse therapeutics showed significantly higher uptake, improved tumor control, and overall survival among different species. Here, we highlight the therapeutic approach of LIFU+MBs mediated drug-delivery in the treatment of glioblastoma.

Low‐intensity pulsed ultrasound alleviates doxorubicin‐induced cardiotoxicity via inhibition of S100a8/a9‐mediated cardiac recruitment of neutrophils

“…However, effective and safe strategies remain limited. As a safe and non‐invasive approach, LIPUS has shown great potential in tissue repair and resolution of inflammation in various diseases 32–35 . Of note, the therapeutic effects of LIPUS on cardiovascular diseases have been reported in recent years 10–14 .…”

Focused ultrasound for treatment of peripheral brain tumors

“…However, other proposed options include FITC-Dextran, Trypan blue, Nile blue, and sodium fluorescein [ 28 – 34 ]. Because of the narrow and precise aperture of the converging LIFU wave, many different targeting methods have been developed to cover the entirety of the target tissue volume and associated areas [ 19 ]. This can be achieved using a grid system to target specific points that utilize the additive effect of merging waves to produce the intended therapeutic effect [ 35 – 38 ].…”

“…HIFU is a direct treatment approach that directly induces tissue necrosis ( Figure 1 ), while LIFU induces BBB disruption for a more effective administration of pharmaceutical treatments ( Figure 2 ) [ 17 , 18 ]. The mechanism of HIFU treatment of peripheral brain tumors is through thermoablation and mechanical destruction while the mechanism of LIFU treatment of brain tumors is through the induction of functional and mechanical changes to the BBB and blood tumor barriers [ 19 ].…”

Regulation of P-glycoprotein and Breast Cancer Resistance Protein Expression Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption: A Pilot Study

“…The acoustic treatment consisted of 3 ms bursts, every 100 ms, over a period of one minute, with an estimated focal PNP in the brain of 0.8 MPa, taking into account skull transmission factor based on [ 33 ]. An AP of 0.8 MPa was chosen since it is a typical level used to permeabilize the BBB in brain tumors in preclinical and clinical trials [ 25 , 26 ]. The treatment was performed with an MR-compatible FUS transducer (1.5 MHz central frequency, diameter: 25 mm, focal depth: 20 mm, Imasonic, Voray-sur-l′Ognon, France) connected to a therapeutic programmable FUS generator (Image-Guided Therapy, Pessac, France).…”

“…Few studies have suggested that BBB opening by FUS may also cause the temporary down-expression of P-gp on vessel walls, the duration of which was dependent on acoustic pressure (AP). P-gp was shown to fully recover three days after FUS application at low AP (e.g., peak negative pressure—PNP of 0.5 MPa, in situ) [ 23 , 24 ] whereas, at a higher AP of 0.8 MPa (similar to levels used in brain tumors trials [ 25 , 26 ]), P-gp does not return to baseline after three days [ 24 ]. However, despite these early findings, very little is known about the joint dynamics of the FUS-induced regulation of efflux transporters expressed at the BBB, and more data are needed to compare the dynamics of the expression of P-gp and BCRP over a longer time after FUS.…”