Editing Blood–brain barrier (section)

===As a drug target===
The blood–brain barrier is formed by the brain capillary endothelium and excludes from the brain 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs.<ref name="hersh">{{cite journal|display-authors=3 |vauthors=Hersh DS, Wadajkar AS, Roberts N, Perez JG, Connolly NP, Frenkel V, Winkles JA, Woodworth GF, Kim AJ |title=Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier |journal=Current Pharmaceutical Design |volume=22 |issue=9 |pages=1177–1193 |date=2016 |pmid=26685681 |pmc=4900538 |doi=10.2174/1381612822666151221150733}}</ref> Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders.<ref name="sweeney">{{cite journal | vauthors = Sweeney MD, Sagare AP, Zlokovic BV | title = Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders | journal = Nature Reviews. Neurology | volume = 14 | issue = 3 | pages = 133–150 | date = March 2018 | pmid = 29377008 | pmc = 5829048 | doi = 10.1038/nrneurol.2017.188 }}</ref><ref>{{cite journal | vauthors = Harilal S, Jose J, Parambi DG, Kumar R, Unnikrishnan MK, Uddin MS, Mathew GE, Pratap R, Marathakam A, Mathew B | display-authors = 6 | title = Revisiting the blood-brain barrier: A hard nut to crack in the transportation of drug molecules | journal = Brain Research Bulletin | volume = 160 | pages = 121–140 | date = July 2020 | pmid = 32315731 | doi = 10.1016/j.brainresbull.2020.03.018 | s2cid = 215807970 }}</ref> In its neuroprotective role, the blood–brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts to be clinically effective.<ref name=sweeney/> To overcome this problem some peptides able to naturally cross the BBB have been widely investigated as a drug delivery system.<ref>{{cite journal | vauthors = de Oliveira EC, da Costa KS, Taube PS, Lima AH, Junior CS | title = Biological Membrane-Penetrating Peptides: Computational Prediction and Applications | journal = Frontiers in Cellular and Infection Microbiology | volume = 12 | pages = 838259 | date = 2022-03-25 | pmid = 35402305 | pmc = 8992797 | doi = 10.3389/fcimb.2022.838259 | doi-access = free }}</ref>

Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for [[drug delivery to the brain]] in [[Dosage form|unit doses]] through the BBB entail its disruption by [[osmosis|osmotic]] means, or biochemically by the use of vasoactive substances, such as [[bradykinin]],<ref>{{cite journal | vauthors = Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M | display-authors = 6 | title = Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism | journal = Blood | volume = 128 | issue = 20 | pages = 2423–2434 | date = November 2016 | pmid = 27531677 | doi = 10.1182/blood-2016-03-705384 | doi-access = free }}</ref> or even by localized exposure to [[HIFU|high-intensity focused ultrasound (HIFU)]].<ref>{{cite journal | vauthors = McDannold N, Vykhodtseva N, Hynynen K | title = Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index | journal = Ultrasound in Medicine & Biology | volume = 34 | issue = 5 | pages = 834–40 | date = May 2008 | pmid = 18207311 | pmc = 2442477 | doi = 10.1016/j.ultrasmedbio.2007.10.016 }}</ref>

Other methods used to get through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters, such as glucose and amino acid carriers, receptor-mediated [[transcytosis]] for [[insulin]] or [[transferrin]], and the blocking of [[efflux (microbiology)|active efflux transporters]] such as [[p-glycoprotein]].<ref name=sweeney/> Some studies have shown that [[Vector (molecular biology)|vectors]] targeting BBB transporters, such as the [[transferrin receptor]], have been found to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the targeted area.<ref name=sweeney/><ref>{{cite journal | vauthors = Wiley DT, Webster P, Gale A, Davis ME | title = Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 21 | pages = 8662–7 | date = May 2013 | pmid = 23650374 | pmc = 3666717 | doi = 10.1073/pnas.1307152110 | bibcode = 2013PNAS..110.8662W | doi-access = free }}</ref>

====Intranasal administration====

The brain can be targeted non-invasively via the nasal passage. The drugs that remain in the passage after mucociliary clearance, enter the brain via three pathways: (1) Olfactory nerve-olfactory bulb-brain; (2) Trigeminal nerve-brain; and (3) Lungs/ Gastrointestinal tract-blood–brain <ref>{{Cite journal |last1=Agrawal |first1=Mukta |last2=Saraf |first2=Swarnlata |last3=Saraf |first3=Shailendra |last4=Antimisiaris |first4=Sophia G. |last5=Chougule |first5=Mahavir Bhupal |last6=Shoyele |first6=Sunday A. |last7=Alexander |first7=Amit |date=2018-07-10 |title=Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs |url=https://pubmed.ncbi.nlm.nih.gov/29772289/ |journal=Journal of Controlled Release|volume=281 |pages=139–177 |doi=10.1016/j.jconrel.2018.05.011 |issn=1873-4995 |pmid=29772289}}</ref> The first and second methods involve the nerves, so they use the neuronal pathway and the third is via systemic circulation. However, these methods are less efficient to deliver drugs as they are indirect methods.

====Nanoparticles====
{{main|Nanoparticles for drug delivery to the brain}}
[[Nanotechnology]] is under preliminary research for its potential to facilitate the transfer of drugs across the BBB.<ref name=sweeney/><ref>{{cite journal | vauthors = Krol S, Macrez R, Docagne F, Defer G, Laurent S, Rahman M, Hajipour MJ, Kehoe PG, Mahmoudi M | display-authors = 6 | title = Therapeutic benefits from nanoparticles: the potential significance of nanoscience in diseases with compromise to the blood brain barrier | journal = Chemical Reviews | volume = 113 | issue = 3 | pages = 1877–903 | date = March 2013 | pmid = 23157552 | doi = 10.1021/cr200472g }}</ref><ref name="Silva">{{cite journal | vauthors = Silva GA | title = Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS | journal = BMC Neuroscience | volume = 9 | issue = Suppl 3 | pages = S4 | date = December 2008 | pmid = 19091001 | pmc = 2604882 | doi = 10.1186/1471-2202-9-S3-S4 | doi-access = free }}</ref> Capillary endothelial cells and associated [[pericytes]] may be abnormal in tumors and the blood–brain barrier may not always be intact in brain tumors.<ref name=Silva/> Other factors, such as [[astrocytes]], may contribute to the resistance of brain tumors to therapy using nanoparticles.<ref>{{cite journal | vauthors = Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM | display-authors = 6 | title = Openings between defective endothelial cells explain tumor vessel leakiness | journal = The American Journal of Pathology | volume = 156 | issue = 4 | pages = 1363–80 | date = April 2000 | pmid = 10751361 | pmc = 1876882 | doi = 10.1016/S0002-9440(10)65006-7 }}</ref> Fat soluble molecules less than 400 [[Dalton (unit)|daltons]] in mass can freely diffuse past the BBB through [[lipid]] mediated passive diffusion.<ref>{{cite journal | vauthors = Souza RM, da Silva IC, Delgado AB, da Silva PH, Costa VR | title = Focused ultrasound and Alzheimer's disease A systematic review | journal = Dementia & Neuropsychologia | volume = 12 | issue = 4 | pages = 353–359 | date = 2018 | pmid = 30546844 | pmc = 6289486 | doi = 10.1590/1980-57642018dn12-040003 }}</ref>