Selective drug delivery approaches to lesioned brain through blood brain barrier disruption

ABSTRACT

Introduction: The development of therapeutics for central nervous system (CNS) disorders is still considered a challenging area in drug development due to insufficient translocation through the blood-brain barrier (BBB). Under normal conditions, BBB restrict the penetration of more than 98% of blood-borne molecules including drugs to the CNS. However, recent research findings have proven that the nature of the BBB is altered in several neurological conditions. This complexity encourages revisiting drug delivery strategies to the CNS as this can give a wide range of opportunities for CNS drug development.

Areas covered: This review focuses on nanotechnology-based drug delivery platforms designed for selective recruitment into the lesioned brain by taking advantages of BBB disruption that is associated with certain neurological conditions.

Expert opinion: Current CNS therapeutic strategies do not fully address the pathophysiological adaptation of BBB in their design. The lack of selective delivery to the brain lesions has been the culprit behind the failure of many CNS therapeutics. This highlighted the need for smart designs of advanced drug delivery systems that take advantage of BBB structural changes in CNS diseases. Recently, promising examples have been reported in this area, however, more work is still required beyond the preclinical testing. 

KEYWORDS:

• Blood-brain barrier
• nanoparticles-based drug delivery
• nanomedicine
• lesioned brain

Article highlights

• The blood brain barrier (BBB) is the single most important limiting factor that restricts the access of more than 98% of pharmaceutical drugs to the brain.

• Brain endothelial cells (BECs) are unique for being interconnected by tight junctions that seal spaces between BECs and have very limited transcytotic vesicles and therefore, restrict the transport of hydrophilic molecules to the brain.

• BBB functions and structure are not fixed, but in a dynamic change to respond to CNS needs during natural development and disease conditions. Changes to BECs structural features and transporter systems are widely reported in several brain disorders and contribute to BBB hyperpermeability.

• Lesioned brain is defined as an injury or disease in an area of the brain due to infection, problems with immune system, injury, disruption in blood supply, tumor, etc.

• Despite the reported disruption to BBB in different models of lesioned brain, a little or no increase in permeability to small therapeutic molecules (< 1000 Dalton) has been observed.

• Recent studies using nanoparticles-based delivery systems showed clearly that it is possible to selectively target the lesion area in the brain when injected intravenously in preclinical animal models. These observations suggested that the selective brain accumulation is mediated by BBB hyperpermeability, a phenomenon that could be very similar to the well-known enhanced permeability and retention (EPR) effect observed in solid tumors.

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Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was funded by the Division of Pharmacy and Optometry, University of Manchester.