Targeted and Reversible Blood-Retinal Barrier Disruption via Focused Ultrasound and Microbubbles

Abstract

The blood-retinal barrier (BRB) prevents most systemically-administered drugs from reaching the retina. This study investigated whether burst ultrasound applied with a circulating microbubble agent can disrupt the BRB, providing a noninvasive method for the targeted delivery of systemically administered drugs to the retina. To demonstrate the efficacy and reversibility of such a procedure, five overlapping targets around the optic nerve head were sonicated through the cornea and lens in 20 healthy male Sprague-Dawley rats using a 690 kHz focused ultrasound transducer. For BRB disruption, 10 ms bursts were applied at 1 Hz for 60 s with different peak rarefactional pressure amplitudes (0.81, 0.88 and 1.1 MPa). Each sonication was combined with an IV injection of a microbubble ultrasound contrast agent (Definity). To evaluate BRB disruption, an MRI contrast agent (Magnevist) was injected IV immediately after the last sonication, and serial T1-weighted MR images were acquired up to 30 minutes. MRI contrast enhancement into the vitreous humor near targeted area was observed for all tested pressure amplitudes, with more signal enhancement evident at the highest pressure amplitude. At 0.81 MPa, BRB disruption was not detected 3 h post sonication, after an additional MRI contrast injection. A day after sonication, the eyes were processed for histology of the retina. At the two lower exposure levels (0.81 and 0.88 MPa), most of the sonicated regions were indistinguishable from the control eyes, although a few tiny clusters of extravasated erythrocytes (petechaie) were observed. More severe retinal damage was observed at 1.1 MPa. These results demonstrate that focused ultrasound and microbubbles can offer a noninvasive and targeted means to transiently disrupt the BRB for ocular drug delivery.

Ultrasound-mediated blood–brain barrier disruption for targeted drug delivery in the central nervous system

“…There is data demonstrating that disruption of the blood-retinal [182] and blood-spinal cord [183] barriers can be disrupted by FUS, and that the glomerular function in the kidney can be enhanced, presumably through changes in the “blood-urine barrier” [184]. Also, using pressure amplitudes higher than are needed for FUS-induced BBB disruption, one can use microbubble-enhanced sonications for ablation [185], thrombolysis [186], or radiosensitization [187].…”

Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions

“…In addition, emerging techniques are currently being evaluated for better penetration of the nanoparticles through the sclera and to the retina. For example, transscleral delivery can A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 32 be enhanced with either iontophoresis where penetration is enhanced with a low electric current [243,244] or ultrasound [245,246]. Implants are an interesting alternative to nanoparticles for prolonged drug release.…”

Ultrasound-mediated ocular delivery of therapeutic agents: a review

“…Most of the experiments were performed either in vitro on isolated cornea or sclera or ex vivo on entire excised eyes until 2006 [6]. Between 2006 and 2013, the majority of the studies were conducted in vivo [6,7,[66][67][68]. In the last in vivo study to date which has been found, dexamethasone (a steroidal anti-inflammatory agent) has been delivered to the aqueous humor at 2.8 times the passive penetration using 5-minute continuous wave ultrasound (CWUS) with moderate intensities (0.8W/cm²) at 400kHz [69].…”