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Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier

View Article: PubMed Central

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.

No MeSH data available.


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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. Ktrans values (min-1) are indicated by the color bar. (B) Mean Ktrans values as a function of time in sonicated and non-sonicated regions. Modified with permission from Park et al. [127].
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Figure 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. Ktrans values (min-1) are indicated by the color bar. (B) Mean Ktrans values as a function of time in sonicated and non-sonicated regions. Modified with permission from Park et al. [127].

Mentions: Whereas the thermal effects of FUS predominate in the setting of continuous exposures, short pulses of focused ultrasound (pFUS) produce primarily mechanical effects, with temperature elevations of only 4-5°C. Therefore, pFUS has been used in a variety of non-ablative roles, including drug delivery – and in particular, transporting drugs across the BBB [127] (see Fig. 2). While early studies attempted to disrupt the BBB with pFUS alone [128], high intensities were required and the effects on tissue integrity were variable. The introduction of intravenous, commercially available ultrasound contrast agents (UCAs) – lipid- or protein-encased gas microbubbles that are 1-10 microns in diameter – was a critical step in enabling finer control over BBBD [129]. The microbubbles typically cluster near capillary walls, where in the presence of pulsed exposures at low frequencies and pressure amplitudes, they undergo stable cavitation. Microbubbles therefore localize the pFUS effects to the endothelial cells, and significantly reduce the energy needed for BBB disruption, enabling the use of low pressures that reduce the risk of heating of the skull.


Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier
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. Ktrans values (min-1) are indicated by the color bar. (B) Mean Ktrans values as a function of time in sonicated and non-sonicated regions. Modified with permission from Park et al. [127].
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4997920&req=5

Figure 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. Ktrans values (min-1) are indicated by the color bar. (B) Mean Ktrans values as a function of time in sonicated and non-sonicated regions. Modified with permission from Park et al. [127].
Mentions: Whereas the thermal effects of FUS predominate in the setting of continuous exposures, short pulses of focused ultrasound (pFUS) produce primarily mechanical effects, with temperature elevations of only 4-5°C. Therefore, pFUS has been used in a variety of non-ablative roles, including drug delivery – and in particular, transporting drugs across the BBB [127] (see Fig. 2). While early studies attempted to disrupt the BBB with pFUS alone [128], high intensities were required and the effects on tissue integrity were variable. The introduction of intravenous, commercially available ultrasound contrast agents (UCAs) – lipid- or protein-encased gas microbubbles that are 1-10 microns in diameter – was a critical step in enabling finer control over BBBD [129]. The microbubbles typically cluster near capillary walls, where in the presence of pulsed exposures at low frequencies and pressure amplitudes, they undergo stable cavitation. Microbubbles therefore localize the pFUS effects to the endothelial cells, and significantly reduce the energy needed for BBB disruption, enabling the use of low pressures that reduce the risk of heating of the skull.

View Article: PubMed Central

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.

No MeSH data available.


Related in: MedlinePlus