Abstract
The human eye being a highly privileged organ with complex barriers, reaching the posterior part of the eye via systemic routes, is still a major clinical challenge. The most critical of these cellular barriers is the blood–retinal barrier (BRB) formed by the retinal pigment epithelium (RPE) and the retinal endothelium. In this chapter, we comprehensively review the interplay of tight junctions, carrier-mediated transport proteins, influx/efflux transporters and the molecular interactions involved in controlling biomolecular transport across BRB. An effort is made to elucidate how these cellular machineries synergistically form very tight protective barricade against the entry of drugs administered through the systemic route. Thus, we have emphasized the need to identify and understand the complexity of BRB which is key to achieving effective drug delivery to the posterior part of the eye via systemic route. Next, we have comprehensively reviewed the role of drug-immobilized nanostructures and smart prodrugs in overcoming BRB and transient modulation of BRB. So far, very few formulations have reached bedside, and the reasons for such poor rate of clinical translation have been identified and critically analyzed and potential solutions discussed. Deeper investigations of the pathophysiology and understanding of BRB leading to the development of efficient drug delivery systems are warranted. Finally, we provide futuristic perspectives to achieving clinical translation of systemic therapies to the posterior eye via development of state-of-the-art and precise diagnosis tools fortified by AI and nanocontrast agents, innovative drug delivery systems based on biomolecule immobilization to overcome BRB, realistic preclinical models and rationally designed clinical trials.
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