Development of Novel Therapeutics Targeting the Blood–Brain Barrier: From Barrier to Carrier

Abstract

The blood–brain barrier (BBB) is a highly specialized neurovascular unit, initially described as an intact barrier to prevent toxins, pathogens, and potentially harmful substances from entering the brain. An intact BBB is also critical for the maintenance of normal neuronal function. In cerebral vascular diseases and neurological disorders, the BBB can be disrupted, contributing to disease progression. While restoration of BBB integrity serves as a robust biomarker of better clinical outcomes, the restrictive nature of the intact BBB presents a major hurdle for delivery of therapeutics into the brain. Recent studies show that the BBB is actively engaged in crosstalk between neuronal and the circulatory systems, which defines another important role of the BBB: as an interfacing conduit that mediates communication between two sides of the BBB. This role has been subject to extensive investigation for brain‐targeted drug delivery and shows promising results. The dual roles of the BBB make it a unique target for drug development. Here, recent developments and novel strategies to target the BBB for therapeutic purposes are reviewed, from both barrier and carrier perspectives.

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“…Restoration of BBB structure and function is increasingly the subject of investigations as a therapeutic target to prevent or limit the outcome of neurological disorders [52]. Conversely, temporary FUS-induced BBB disruption is also regarded as a potential therapeutic strategy in various CNS diseases.…”

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“…A significant advantage of nano drug delivery vehicles is their ability to pass through biological barriers, especially important for the CNS and gastrointestinal tract [243] , [244] , [245] , [246] . Growing tumors release angiogenic factors and build new vasculature inside them with often abnormal extracellular matrix.…”

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“…For instance, decreased cadherin expression or loss of cadherin has been observed in stroke, TBI, and brain tumors, with BBB integrity loss. In contrast, the restoration of their expression resulted in tight junction repair and disease regression [332]. However, the options that are currently available to restore ADs expression are limited.…”