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.
Highlights
Delivering pharmaceutical agents to specific retinal locations may greatly improve treatment of degenerative retinopathies, including age-related macular degeneration, diabetic retinopathy, and hereditary retinal disorders such as Norrie disease
Delivery of most therapeutic agents to the retina from the peripheral circulation is limited by the membrane impermeability of blood-retinal barrier (BRB) [1], which is formed by complex tight junctions of the endothelium of retinal blood vessels and the retinal pigment epithelium [2]
Low-level BRB disruption was still observed but the level was substantially less compared to the first MRI contrast injection
Summary
Delivering pharmaceutical agents to specific retinal locations may greatly improve treatment of degenerative retinopathies, including age-related macular degeneration, diabetic retinopathy, and hereditary retinal disorders such as Norrie disease. Delivery of most therapeutic agents to the retina from the peripheral circulation is limited by the membrane impermeability of blood-retinal barrier (BRB) [1], which is formed by complex tight junctions of the endothelium of retinal blood vessels and the retinal pigment epithelium [2]. The BRB presents a functional impediment for drug delivery due to efflux transporters such as Pglycoprotein [3] that rapidly eliminate many substances from the extravascular space. An estimated 98% of clinically validated drugs, of which many are potential therapies for retinal diseases, cannot cross the BRB [4,5,6,7]
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