Application of Tumor Treating Fields (TTFields) to open the blood brain barrier (BBB) as future CNS drug delivery strategy

Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood–brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O2, 60 minutes followed by 21% O2, 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor- β (TGF- β)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF- β/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

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DDRE-49. TRANSIENT OPENING OF THE BLOOD-BRAIN BARRIER BY VASOACTIVE PEPTIDES TO INCREASE CNS DRUG DELIVERY: REALITY VERSUS WISHFUL THINKING?

Neuro-Oncology ◽

10.1093/neuonc/noab196.333 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi85-vi85

Author(s):

Matthew Smith-Cohn ◽

Nicholas Burley ◽

Stuart Grossman

Keyword(s):

Drug Delivery ◽

Blood Vessels ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Specific Information ◽

Vasoactive Peptides ◽

Cns Drug Delivery ◽

Blood Brain ◽

Bbb Permeability

Abstract BACKGROUND Drug delivery to treat neurologic disease and cancers of the central nervous system (CNS) is severely limited by the blood-brain barrier (BBB). Vasoactive peptides (VAPs) such as regadenoson, adenosine, and labradimil have been shown in animal studies to transiently open the BBB, and regadenoson is currently under investigation in humans to determine if it might improve CNS drug delivery. There is currently limited information regarding the potential for other VAPs to open the BBB transiently. METHODS We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the BBB, we devised a four-tier classification system to organize data available in the literature which factors in alterations in BBB integrity and effects on normal brain vasculature and systemic blood vessels. This data was further sorted based on whether it comes from humans, animals, or in vitro systems. RESULTS We identified 38 VAPs with potential BBB permeability-altering properties. To date, none of these has been shown to open the BBB in humans. Thirteen VAPs increased BBB permeability in rodents. The remaining 25 had favorable physiologic effects on blood vessels but lack specific information on permeability changes to the BBB. We ranked VAPs in a four-tier ranking system related to their known physiologic actions. CONCLUSION Rodent studies document that analogs of bradykinin and adenosine transiently disrupt the BBB leading to higher chemotherapy concentrations in the CNS. VAPs remain an understudied class of drugs with the potential to increase drug delivery to the CNS. Dozens of VAPs have yet to be formally evaluated for this important clinical effect. This retrospective review summarizes the available data on VAPs highlighting agents that deserve further in vitro and in vivo investigations.

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Drug Delivery to The Brain Using Polymeric Nanoparticles: A Review

International Journal of Pharmaceutical and Life Sciences ◽

10.3329/ijpls.v2i3.15457 ◽

2013 ◽

Vol 2 (3) ◽

pp. 107-132 ◽

Cited By ~ 21

Author(s):

Bhatt Neha ◽

Bhatt Ganesh ◽

Kothiyal Preeti

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Polymeric Nanoparticles ◽

Neurological Diseases ◽

Drug Carriers ◽

Brain Barrier ◽

Pharmaceutical Drugs ◽

Great Expectations ◽

Cns Drug Delivery ◽

Blood Brain

Nanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50300 nm generally). The use of minute particles as drug carriers for targeted treatment has been studied over a long period of time. A selective accumulation of active substances in target tissues has been demonstrated for certain so-called nanocarrier systems that are administered bound to pharmaceutical drugs. Great expectations are placed on nanocarrier systems that can overcome natural barriers such as the blood-brain barrier (BBB) and transport the medication directly to the desired tissue and thus heal neurological diseases that were formerly incurable. Polymeric Nanoparticle have been shown to be promising carriers for CNS drug delivery due to their potential both in encapsulating drugs, hence protecting them from excretion and metabolism, and in delivering active agents across the blood brain barrier without inflicting any damage to the barrier. Different polymers have been used and different strategies like surface modification have been done to increase the retention time of nanoparticles. DOI: http://dx.doi.org/10.3329/ijpls.v2i3.15457 International Journal of Pharmaceutical and Life Sciences Vol.2(3) 2013: 107-132

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