Remote spatiotemporally controlled and biologically selective permeabilization of blood-brain barrier

Abstract

The blood-brain barrier (BBB), comprised of brain endothelial cells with tight junctions (TJ) between them, regulates the extravasation of molecules and cells into and out of the central nervous system (CNS). Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of a broad range of brain disorders. Current strategies for BBB opening are invasive, not specific, and lack precise control over the site and timing of BBB opening, which may limit their clinical translation. In the present report, we describe a novel approach based on a combination of stem cell delivery, heat-inducible gene expression and mild heating with high-intensity focused ultrasound (HIFU) under MRI guidance to remotely permeabilize BBB. The permeabilization of the BBB will be controlled with, and limited to where selected pro-inflammatory factors will be secreted secondary to HIFU activation, which is in the vicinity of the engineered stem cells and consequently both the primary and secondary disease foci. This therapeutic platform thus represents a non-invasive way for BBB opening with unprecedented spatiotemporal precision, and if properly and specifically modified, can be clinically translated to facilitate delivery of different diagnostic and therapeutic agents which can have great impact in treatment of various disease processes in the central nervous system.

Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3–Targeted Liposomes

“…Therefore, significant efforts are being made to design safe and sophisticated strategies to bypass such barriers for efficient drug delivery (14–17). Multiple recent studies have shown that exposure to external beam radiation enhances BTB permeability in mice bearing orthotopic GBMs (18–22).…”

Strategies to improve the migration of mesenchymal stromal cells in cell therapy

“…These disadvantages may limit their clinical translation. A novel approach has been described based on a combination of stromal cell delivery, heat-inducible gene expression, and mild heating with high-intensity focused ultrasound (HIFU) under MRI guidance to remotely permeabilize the BBB [148] . The principle of this method is to administrate stromal cells engineered to express pro-inflammatory factors that will permeabilize the BBB but only trigger their expression after heating with non-invasive imageguided HIFU.…”

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part IV: Image- Guided, Remote-Controlled Opening of the Blood–Brain Barrier for Systemic Brain Tumor Therapy

“…The biologic targeting of stem cells along with the spatial targeting of HIFU can be combined to create a remote-controlled expression platform has been leveraged to assist in locally opening up the BBB for facilitated drug delivery of systemically administered agents (41). This can be accomplished by remotely triggering expression of effector cytokines, such as TNFα, from engineered tumorhoming stem cells in response to noninvasive image-guided HIFU ( Figure 1C).…”

“…By combining stem cell delivery, heat-inducible gene expression and mild heating with HIFU, Xiong et al demonstrated that HIFU can be used to remotely control the expression of pro-inflammatory factors engineered in stem cells under the control of the HSP70 promoter ( Figure 1C). This targeted expression led to the permeabilization of the BBB with highspatiotemporal precision and biologic selectivity, allowing for penetration of systemically administered small molecular MRI contrast agent and 300-nm-sized nanoparticles into the brain ( Figure 1D, E) (41). This opening of the BBB was limited to where selected factors were secreted secondary to HIFU activation, near the engineered stem cells and consequently the infiltrating tumor cells.…”

“…One enabling technology to controlled sub-lethal HIFU activation is MR thermometry, which incorporates automated, real-time feedback control of a predefined temperature, allowing for stably controlling HIFU to heat the brain tissue to around 42-43°C for successful gene activation to open the BBB (41). Indeed, transcranial magnetic resonance-guided focused ultrasound (tsMRgFUS), which employs a phase array comprised of hundreds of transducer elements, has been used in clinical trial to precisely heat or ablate target areas in the brain (49).…”