Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier

Abstract

The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

Fig. (1)

Strategies for delivering therapeutic agents across the BBB. Therapeutic agents are transported from the vessel lumen across the BBB via osmotic or chemical disruption of tight junctions, receptor-mediated transcytosis, nanoparticle-based carriers (including targeted nanoparticles), cell-mediated delivery, and FUS-mediated oscillation of microbubbles causing disruption of tight junctions and enhanced transcytosis. Interstitial wafers and microchips, in addition to catheter-based CED, bypass the BBB and deliver therapeutic agents directly to the brain parenchyma.

Fig. (2)

MRgFUS produces transient and localized BBBD. (A) Axial contrast-enhanced T1-weighted MRI sequences (top) and permeability maps generated via dynamic contrast-enhanced imaging (bottom) were obtained at four time points following sonication of a rat brain. Locations #1 and #2 were treated at 0.72 and 0.68 MPa, respectively. K_trans values (min^-1) are indicated by the color bar. (B) Mean K_trans values as a function of time in sonicated and non-sonicated regions. Modified with permission from Park et al. [127].

Fig. (3)

Distribution of gadolinium-labeled anionic liposomes following CED. (A) 3D axial T1-weighted gradient echo scans demonstrate the gadolinium in the nanocomplexes. (B) The data was reconstructed to provide a 3D model of the liposome distribution following CED into the striatum (green) and corpus callosum (purple). (C) Fluorescence microscopy was performed to visualize the anionic liposome distribution in the striatum (left) and corpus callosum (right) by using the incorporated rhodamine label. Scale bars = 500 µm. Modified with permission from Kenny et al. [236].