1932

Abstract

Brain disease remains a significant health, social, and economic burden with a high failure rate of translation of therapeutics to the clinic. Nanotherapeutics have represented a promising area of technology investment to improve drug bioavailability and delivery to the brain, with several successes for nanotherapeutic use for central nervous system disease that are currently in the clinic. However, renewed and continued research on the treatment of neurological disorders is critically needed. We explore the challenges of drug delivery to the brain and the ways in which nanotherapeutics can overcome these challenges. We provide a summary and overview of general design principles that can be applied to nanotherapeutics for uptake and penetration in the brain. We next highlight remaining questions that limit the translational potential of nanotherapeutics for application in the clinic. Lastly, we provide recommendations for ongoing preclinical research to improve the overall success of nanotherapeutics against neurological disease.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-chembioeng-092220-030853
2022-06-07
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/chembioeng/13/1/annurev-chembioeng-092220-030853.html?itemId=/content/journals/10.1146/annurev-chembioeng-092220-030853&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    van Middendorp JJ, Sanchez GM, Burridge AL. 2010. The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries. Eur. Spine J. 19:1815–23
    [Google Scholar]
  2. 2.
    Finger S. 2005. Minds Behind the Brain: A History of the Pioneers and Their Discoveries Oxford, UK: Oxford Univ. Press
  3. 3.
    Lackland DT, Roccella EJ, Deutsch AF, Fornage M, George MG et al. 2014. Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke 45:315–53
    [Google Scholar]
  4. 4.
    Wingerchuk DM, Carter JL. 2014. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin. Proc. 89:225–40
    [Google Scholar]
  5. 5.
    UN Dep. Econ. Soc. Aff. Popul. Div 2019. World population ageing 2019: highlights Publ., ST/ESA/SER.A/430 United Nat. New York:
  6. 6.
    Robinson MD. 2019. The Market in Mind: How Financialization Is Shaping Neuroscience, Translational Medicine, and Innovation in Biotechnology Cambridge, MA: MIT Press
  7. 7.
    Pankevich DE, Altevogt BM, Dunlop J, Gage FH, Hyman SE. 2014. Improving and accelerating drug development for nervous system disorders. Neuron 84:546–53
    [Google Scholar]
  8. 8.
    Randall TS, Sam C, Tartar A, Murray P, Cannon C. 2021. More than 6.59 billion shots given: COVID-19 tracker. Bloomberg Nov. 4
    [Google Scholar]
  9. 9.
    Mikulic M. 2021. COVID-19 vaccinations administered in the U.S. as of October 2021, by manufacturer. Statista Nov. 4. https://www.statista.com/statistics/1198516/covid-19-vaccinations-administered-us-by-company/
    [Google Scholar]
  10. 10.
    Yang G, Liu Y, Wang H, Wilson R, Hui Y et al. 2019. Bioinspired core–shell nanoparticles for hydrophobic drug delivery. Angew. Chem. 131:14495–502
    [Google Scholar]
  11. 11.
    Owens DE 3rd, Peppas NA. 2006. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 307:93–102
    [Google Scholar]
  12. 12.
    Biedl A, Kraus R. 1898. Über eine bisher unbekannte toxische Wirkung der Gallensäuren auf das Zentralnervensystem. Zentralbl. Inn. Med. 19:1185–200
    [Google Scholar]
  13. 13.
    Lewandowsky M. 1909. Zur Lehre der Cerebrospinalflüssigkeit. Z. Klin. Med. 40:480–94
    [Google Scholar]
  14. 14.
    Ribatti D, Nico B, Crivellato E, Artico M. 2006. Development of the blood-brain barrier: a historical point of view. Anat. Rec. B 289:3–8
    [Google Scholar]
  15. 15.
    Bors LA, Erdő F. 2019. Overcoming the blood–brain barrier. Challenges and tricks for CNS drug delivery. Sci. Pharm. 87:6
    [Google Scholar]
  16. 16.
    Pardridge WM. 2005. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2:3–14
    [Google Scholar]
  17. 17.
    Pardridge WM. 2012. Drug transport across the blood-brain barrier. J. Cereb. Blood Flow Metab. 32:1959–72
    [Google Scholar]
  18. 18.
    Profaci CP, Munji RN, Pulido RS, Daneman R. 2020. The blood-brain barrier in health and disease: important unanswered questions. J. Exp. Med. 217:e20190062
    [Google Scholar]
  19. 19.
    Dityatev A, Seidenbecher CI, Schachner M. 2010. Compartmentalization from the outside: the extracellular matrix and functional microdomains in the brain. Trends Neurosci 33:503–12
    [Google Scholar]
  20. 20.
    Logsdon AF, Rhea EM, Reed M, Banks WA, Erickson MA. 2021. The neurovascular extracellular matrix in health and disease. Exp. Biol. Med. 246:835–44
    [Google Scholar]
  21. 21.
    Bruckner G, Hartig W, Kacza J, Seeger J, Welt K, Brauer K. 1996. Extracellular matrix organization in various regions of rat brain grey matter. J. Neurocytol. 25:333–46
    [Google Scholar]
  22. 22.
    Benarroch EE. 2015. Extracellular matrix in the CNS: dynamic structure and clinical correlations. Neurology 85:1417–27
    [Google Scholar]
  23. 23.
    Kim TW, Kim Y, Jung W, Kim DE, Keum H et al. 2021. Bilirubin nanomedicine ameliorates the progression of experimental autoimmune encephalomyelitis by modulating dendritic cells. J. Control. Release 331:74–84
    [Google Scholar]
  24. 24.
    de la Flor R, Robertson J, Shevchenko RV, Alavijeh M, Bickerton S et al. 2021. Multiple sclerosis: LIFNano-CD4 for Trojan Horse delivery of the neuro-protective biologic “LIF” into the brain: preclinical proof of concept. Front. Med. Technol. 3: https://doi.org/10.3389/fmedt.2021.640569
    [Crossref] [Google Scholar]
  25. 25.
    Heckman KL, DeCoteau W, Estevez A, Reed KJ, Costanzo W et al. 2013. Custom cerium oxide nanoparticles protect against a free radical mediated autoimmune degenerative disease in the brain. ACS Nano 7:10582–96
    [Google Scholar]
  26. 26.
    Pei W, Wan X, Shahzad KA, Zhang L, Song S et al. 2018. Direct modulation of myelin-autoreactive CD4+ and CD8+ T cells in EAE mice by a tolerogenic nanoparticle co-carrying myelin peptide-loaded major histocompatibility complexes, CD47 and multiple regulatory molecules. Int. J. Nanomed. 13:3731–50
    [Google Scholar]
  27. 27.
    Carnasciali A, Amoriello R, Bonechi E, Mazzoni A, Ravagli C et al. 2021. T cell delivery of nanoparticles-bound anti-CD20 monoclonal antibody: successful B cell depletion in the spinal cord during experimental autoimmune encephalomyelitis. J. Neuroimmune Pharmacol. 16:376–89
    [Google Scholar]
  28. 28.
    Casey LM, Pearson RM, Hughes KR, Liu JMH, Rose JA et al. 2018. Conjugation of transforming growth factor beta to antigen-loaded poly(lactide-co-glycolide) nanoparticles enhances efficiency of antigen-specific tolerance. Bioconjug. Chem. 29:813–23
    [Google Scholar]
  29. 29.
    Hunter Z, McCarthy DP, Yap WT, Harp CT, Getts DR et al. 2014. A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease. ACS Nano 8:2148–60
    [Google Scholar]
  30. 30.
    Sharma R, Kambhampati SP, Zhang Z, Sharma A, Chen S et al. 2020. Dendrimer mediated targeted delivery of sinomenine for the treatment of acute neuroinflammation in traumatic brain injury. J. Control. Release 323:361–75
    [Google Scholar]
  31. 31.
    Kumthekar P, Ko CH, Paunesku T, Dixit K, Sonabend AM et al. 2021. A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma. Sci. Transl. Med. 13:eabb3945
    [Google Scholar]
  32. 32.
    Curley CT, Mead BP, Negron K, Kim N, Garrison WJ et al. 2020. Augmentation of brain tumor interstitial flow via focused ultrasound promotes brain-penetrating nanoparticle dispersion and transfection. Sci. Adv. 6:eaay1344
    [Google Scholar]
  33. 33.
    Fisher DG, Price RJ. 2019. Recent advances in the use of focused ultrasound for magnetic resonance image-guided therapeutic nanoparticle delivery to the central nervous system. Front. Pharmacol. 10:1348
    [Google Scholar]
  34. 34.
    Carpentier A, Canney M, Vignot A, Reina V, Beccaria K et al. 2016. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci. Transl. Med. 8:343re2
    [Google Scholar]
  35. 35.
    Idbaih A, Canney M, Belin L, Desseaux C, Vignot A et al. 2019. Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin. Cancer Res. 25:3793–801
    [Google Scholar]
  36. 36.
    Lipsman N, Meng Y, Bethune AJ, Huang Y, Lam B et al. 2018. Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Nat. Commun. 9:2336
    [Google Scholar]
  37. 37.
    Mainprize T, Lipsman N, Huang Y, Meng Y, Bethune A et al. 2019. Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci. Rep. 9:321
    [Google Scholar]
  38. 38.
    Joseph A, Wood T, Chen C-C, Corry K, Snyder JM et al. 2018. Curcumin-loaded polymeric nanoparticles for neuroprotection in neonatal rats with hypoxic-ischemic encephalopathy. Nano Res 11:5670–88
    [Google Scholar]
  39. 39.
    Joseph A, Nyambura CW, Bondurant D, Corry K, Beebout D et al. 2021. Formulation and efficacy of catalase-loaded nanoparticles for the treatment of neonatal hypoxic-ischemic encephalopathy. Pharmaceutics 13:1131
    [Google Scholar]
  40. 40.
    Kulikova OI, Berezhnoy DS, Stvolinsky SL, Lopachev AV, Orlova VS, Fedorova TN. 2018. Neuroprotective effect of the carnosine–α-lipoic acid nanomicellar complex in a model of early-stage Parkinson's disease. Regul. Toxicol. Pharmacol. 95:254–59
    [Google Scholar]
  41. 41.
    Hashemian M, Ghasemi-Kasman M, Ghasemi S, Akbari A, Moalem-Banhangi M et al. 2019. Fabrication and evaluation of novel quercetin-conjugated Fe3O4-β-cyclodextrin nanoparticles for potential use in epilepsy disorder. Int. J. Nanomed. 14:6481–95
    [Google Scholar]
  42. 42.
    Del Grosso A, Galliani M, Angella L, Santi M, Tonazzini I et al. 2019. Brain-targeted enzyme-loaded nanoparticles: a breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease. Sci. Adv. 5:eaax7462
    [Google Scholar]
  43. 43.
    Joshi HP, Kumar H, Choi UY, Lim YC, Choi H et al. 2020. CORM-2-solid lipid nanoparticles maintain integrity of blood-spinal cord barrier after spinal cord injury in rats. Mol. Neurobiol. 57:2671–89
    [Google Scholar]
  44. 44.
    Mo Y, Duan L, Yang Y, Liu W, Zhang Y et al. 2021. Nanoparticles improved resveratrol brain delivery and its therapeutic efficacy against intracerebral hemorrhage. Nanoscale 13:3827–40
    [Google Scholar]
  45. 45.
    Mittal G, Carswell H, Brett R, Currie S, Kumar MN. 2011. Development and evaluation of polymer nanoparticles for oral delivery of estradiol to rat brain in a model of Alzheimer's pathology. J. Control. Release 150:2220–28
    [Google Scholar]
  46. 46.
    So PW, Ekonomou A, Galley K, Brody L, Sahuri-Arisoylu M et al. 2019. Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke. Int. J. Nanomed. 14:1979–91
    [Google Scholar]
  47. 47.
    Polania Gutierrez JJ, Munakomi S. 2021. Intramuscular Injection Treasure Island, FL: StatPearls Publ.
  48. 48.
    Davies N, Hovdal D, Edmunds N, Nordberg P, Dahlen A et al. 2021. Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein. Mol. Ther. Nucleic Acids 24:369–84
    [Google Scholar]
  49. 49.
    Al-Ghobashy MA, ElMeshad AN, Abdelsalam RM, Nooh MM, Al-Shorbagy M, Laible G. 2017. Development and pre-clinical evaluation of recombinant human myelin basic protein nano therapeutic vaccine in experimental autoimmune encephalomyelitis mice animal model. Sci. Rep. 7:46468
    [Google Scholar]
  50. 50.
    Shyam R, Ren Y, Lee J, Braunstein KE, Mao HQ, Wong PC. 2015. Intraventricular delivery of siRNA nanoparticles to the central nervous system. Mol. Ther. Nucleic Acids 4:e242
    [Google Scholar]
  51. 51.
    Tarumi T, Yamabe T, Fukuie M, Zhu DC, Zhang R et al. 2021. Brain blood and cerebrospinal fluid flow dynamics during rhythmic handgrip exercise in young healthy men and women. J. Physiol. 599:1799–813
    [Google Scholar]
  52. 52.
    Helakari H, Korhonen V, Holst S, Piispala J, Kallio M et al. 2020. Sleep-specific changes in physiological brain pulsations. bioRxiv 280479 https://doi.org/10.1101/2020.09.03.280479
    [Crossref]
  53. 53.
    Stanton EH, Persson NDA, Gomolka RS, Lilius T, Sigurethsson B et al. 2021. Mapping of CSF transport using high spatiotemporal resolution dynamic contrast-enhanced MRI in mice: effect of anesthesia. Magn. Reson. Med. 85:3326–42
    [Google Scholar]
  54. 54.
    Plog BA, Mestre H, Olveda GE, Sweeney AM, Kenney HM et al. 2018. Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI Insight 3:e120922
    [Google Scholar]
  55. 55.
    Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ et al. 2009. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73:1662–69
    [Google Scholar]
  56. 56.
    Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P et al. 2007. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet 369:2097–105
    [Google Scholar]
  57. 57.
    LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW et al. 2011. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 10:309–19
    [Google Scholar]
  58. 58.
    Bourdenx M, Daniel J, Genin E, Soria FN, Blanchard-Desce M et al. 2016. Nanoparticles restore lysosomal acidification defects: implications for Parkinson and other lysosomal-related diseases. Autophagy 12:472–83
    [Google Scholar]
  59. 59.
    Abbasi S, Uchida S, Toh K, Tockary TA, Dirisala A et al. 2021. Co-encapsulation of Cas9 mRNA and guide RNA in polyplex micelles enables genome editing in mouse brain. J. Control. Release 332:260–68
    [Google Scholar]
  60. 60.
    Frey WH 2nd 1991. Neurologic agents for nasal administration to the brain WO Patent 1991/007947
  61. 61.
    Lombardo R, Musumeci T, Carbone C, Pignatello R. 2021. Nanotechnologies for intranasal drug delivery: an update of literature. Pharm. Dev. Technol. 26:824–45
    [Google Scholar]
  62. 62.
    Tang S, Wang A, Yan X, Chu L, Yang X et al. 2019. Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson's disease. Drug Deliv 26:700–7
    [Google Scholar]
  63. 63.
    Pu H, Ma C, Zhao Y, Wang Y, Zhang W et al. 2021. Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury. J. Cereb. Blood Flow Metab. 41:2870–86
    [Google Scholar]
  64. 64.
    Chung K, Ullah I, Kim N, Lim J, Shin J et al. 2020. Intranasal delivery of cancer-targeting doxorubicin-loaded PLGA nanoparticles arrests glioblastoma growth. J. Drug Target. 28:617–26
    [Google Scholar]
  65. 65.
    Erdo F, Bors LA, Farkas D, Bajza A, Gizurarson S. 2018. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res. Bull. 143:155–70
    [Google Scholar]
  66. 66.
    Helmbrecht H, Joseph A, McKenna M, Zhang M, Nance E 2020. Governing transport principles for nanotherapeutic application in the brain. Curr. Opin. Chem. Eng. 30:112–19
    [Google Scholar]
  67. 67.
    Joseph A, Simo GM, Gao T, Alhindi N, Xu N et al. 2021. Surfactants influence polymer nanoparticle fate within the brain. Biomaterials 277:121086
    [Google Scholar]
  68. 68.
    Nance E, Zhang F, Mishra MK, Zhang Z, Kambhampati SP et al. 2016. Nanoscale effects in dendrimer-mediated targeting of neuroinflammation. Biomaterials 101:96–107
    [Google Scholar]
  69. 69.
    Zhang M, Bishop BP, Thompson NL, Hildahl K, Dang B et al. 2019. Quantum dot cellular uptake and toxicity in the developing brain: implications for use as imaging probes. Nanoscale Adv 1:3424–42
    [Google Scholar]
  70. 70.
    Nance EA, Woodworth GF, Sailor KA, Shih TY, Xu Q et al. 2012. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci. Transl. Med. 4:149ra19
    [Google Scholar]
  71. 71.
    Godin AG, Varela JA, Gao Z, Danne N, Dupuis JP et al. 2017. Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain. Nat. Nanotechnol. 12:238–43
    [Google Scholar]
  72. 72.
    Thorne RG, Nicholson C. 2006. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. PNAS 103:5567–72
    [Google Scholar]
  73. 73.
    Amani H, Arzaghi H, Bayandori M, Dezfuli AS, Pazoki-Toroudi H et al. 2019. Controlling cell behavior through the design of biomaterial surfaces: a focus on surface modification techniques. Adv. Mater. Interfaces 6:1900572
    [Google Scholar]
  74. 74.
    Modena MM, Rühle B, Burg TP, Wuttke S. 2019. Nanoparticle characterization: What to measure?. Adv. Mater. 31:1901556
    [Google Scholar]
  75. 75.
    Brown TD, Habibi N, Wu D, Lahann J, Mitragotri S. 2020. Effect of nanoparticle composition, size, shape, and stiffness on penetration across the blood-brain barrier. ACS Biomater. Sci. Eng. 6:4916–28
    [Google Scholar]
  76. 76.
    Curtis C, Toghani D, Wong B, Nance E 2018. Colloidal stability as a determinant of nanoparticle behavior in the brain. Colloids Surf. B 170:673–82
    [Google Scholar]
  77. 77.
    van Rooy I, Cakir-Tascioglu S, Hennink WE, Storm G, Schiffelers RM, Mastrobattista E. 2011. In vivo methods to study uptake of nanoparticles into the brain. Pharm. Res. 28:456–71
    [Google Scholar]
  78. 78.
    Bickel U. 2005. How to measure drug transport across the blood-brain barrier. NeuroRx 2:15–26
    [Google Scholar]
  79. 79.
    Alqahtani F, Chowdhury EA, Bhattacharya R, Noorani B, Mehvar R, Bickel U. 2018. Brain uptake of [13C] and [14C]sucrose quantified by microdialysis and whole tissue analysis in mice. Drug Metab. Dispos. 46:1514–18
    [Google Scholar]
  80. 80.
    Collins JM, Dedrick RL. 1983. Distributed model for drug delivery to CSF and brain tissue. Am. J. Physiol. 245:R303–10
    [Google Scholar]
  81. 81.
    Miller HA, Magsam AW, Tarudji AW, Romanova S, Weber L et al. 2019. Evaluating differential nanoparticle accumulation and retention kinetics in a mouse model of traumatic brain injury via Ktrans mapping with MRI. Sci. Rep. 9:16099
    [Google Scholar]
  82. 82.
    Houston ZH, Bunt J, Chen KS, Puttick S, Howard CB et al. 2020. Understanding the uptake of nanomedicines at different stages of brain cancer using a modular nanocarrier platform and precision bispecific antibodies. ACS Cent. Sci. 6:727–38
    [Google Scholar]
  83. 83.
    Smith QR, Allen DD. 2003. In situ brain perfusion technique. Methods Mol. Med. 89:209–18
    [Google Scholar]
  84. 84.
    Takasato Y, Rapoport SI, Smith QR. 1984. An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am. J. Physiol. 247:H484–93
    [Google Scholar]
  85. 85.
    Cheng R, Zhang F, Li M, Wo X, Su YW, Wang W. 2019. Influence of fixation and permeabilization on the mass density of single cells: a surface plasmon resonance imaging study. Front. Chem. 7:588
    [Google Scholar]
  86. 86.
    Shepherd TM, Thelwall PE, Stanisz GJ, Blackband SJ. 2009. Aldehyde fixative solutions alter the water relaxation and diffusion properties of nervous tissue. Magn. Reson. Med. 62:26–34
    [Google Scholar]
  87. 87.
    Tosi G, Duskey JT, Kreuter J. 2020. Nanoparticles as carriers for drug delivery of macromolecules across the blood-brain barrier. Expert Opin. Drug Deliv. 17:23–32
    [Google Scholar]
  88. 88.
    Thangudu S, Cheng FY, Su CH. 2020. Advancements in the blood-brain barrier penetrating nanoplatforms for brain related disease diagnostics and therapeutic applications. Polymers 12:3055
    [Google Scholar]
  89. 89.
    Terstappen GC, Meyer AH, Bell RD, Zhang W. 2021. Strategies for delivering therapeutics across the blood-brain barrier. Nat. Rev. Drug Discov. 20:362–83
    [Google Scholar]
  90. 90.
    D'Souza A, Dave KM, Stetler RA, Manickam DS. 2021. Targeting the blood-brain barrier for the delivery of stroke therapies. Adv. Drug Deliv. Rev. 171:332–51
    [Google Scholar]
  91. 91.
    Timbie KF, Mead BP, Price RJ. 2015. Drug and gene delivery across the blood-brain barrier with focused ultrasound. J. Control. Release 219:61–75
    [Google Scholar]
  92. 92.
    Saunders NR, Liddelow SA, Dziegielewska KM. 2012. Barrier mechanisms in the developing brain. Front. Pharmacol. 3:46
    [Google Scholar]
  93. 93.
    Ek CJ, Dziegielewska KM, Stolp H, Saunders NR. 2006. Functional effectiveness of the blood-brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica). J. Comp. Neurol. 496:13–26
    [Google Scholar]
  94. 94.
    Millen JW, Hess A. 1958. The blood-brain barrier: an experimental study with vital dyes. Brain 81:248–57
    [Google Scholar]
  95. 95.
    Dobbing J. 1961. The blood-brain barrier. Physiol. Rev. 41:130–88
    [Google Scholar]
  96. 96.
    Donahue S, Pappas GD. 1961. The fine structure of capillaries in the cerebral cortex of the rat at various stages of development. Am. J. Anat. 108:331–47
    [Google Scholar]
  97. 97.
    Saunders NR, Dreifuss JJ, Dziegielewska KM, Johansson PA, Habgood MD et al. 2014. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front. Neurosci. 8:404
    [Google Scholar]
  98. 98.
    Penta P. 1932. Sulla colorazione vitale del sistema nervosa negli centrale animali neonati. Riv. Neurol. 5:62–80
    [Google Scholar]
  99. 99.
    Stern L, Rapoport J, Lokschina E. 1929. Le fonctionnement de la barrière hémato-encéphalique chez les nouveau nés. CR Soc. Biol. 100:231–23
    [Google Scholar]
  100. 100.
    Moos T, Mollgard K. 1993. Cerebrovascular permeability to azo dyes and plasma proteins in rodents of different ages. Neuropathol. Appl. Neurobiol. 19:120–27
    [Google Scholar]
  101. 101.
    Weber CM, Clyne AM. 2021. Sex differences in the blood-brain barrier and neurodegenerative diseases. APL Bioeng. 5:011509
    [Google Scholar]
  102. 102.
    Parrado-Fernández C, Blennow K, Hansson M, Leoni V, Cedazo-Minguez A, Björkhem I. 2018. Evidence for sex difference in the CSF/plasma albumin ratio in ∼20 000 patients and 335 healthy volunteers. J. Cell. Mol. Med. 22:5151–54
    [Google Scholar]
  103. 103.
    Moon Y, Lim C, Kim Y, Moon WJ. 2021. Sex-related differences in regional blood-brain barrier integrity in non-demented elderly subjects. Int. J. Mol. Sci. 22:2860
    [Google Scholar]
  104. 104.
    Wilson AC, Clemente L, Liu T, Bowen RL, Meethal SV, Atwood CS. 2008. Reproductive hormones regulate the selective permeability of the blood-brain barrier. Biochim. Biophys. Acta 1782:401–7
    [Google Scholar]
  105. 105.
    Cipolla MJ, Godfrey JA, Wiegman MJ. 2009. The effect of ovariectomy and estrogen on penetrating brain arterioles and blood-brain barrier permeability. Microcirculation 16:685–93
    [Google Scholar]
  106. 106.
    Robison LS, Gannon OJ, Salinero AE, Zuloaga KL. 2019. Contributions of sex to cerebrovascular function and pathology. Brain Res 1710:43–60
    [Google Scholar]
  107. 107.
    Kucharz K, Kristensen K, Johnsen KB, Lund MA, Lonstrup M et al. 2021. Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles. Nat. Commun. 12:4121
    [Google Scholar]
  108. 108.
    Nance E, Porambo M, Zhang F, Mishra MK, Buelow M et al. 2015. Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury. J. Control. Release 214:112–20
    [Google Scholar]
  109. 109.
    Kirschbaum K, Sonner JK, Zeller MW, Deumelandt K, Bode J et al. 2016. In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis. PNAS 113:13227–32
    [Google Scholar]
  110. 110.
    Shetty AK, Zanirati G. 2020. The interstitial system of the brain in health and disease. Aging Dis 11:200–11
    [Google Scholar]
  111. 111.
    Hladky SB, Barrand MA. 2014. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11:26
    [Google Scholar]
  112. 112.
    Joseph A, Liao R, Zhang M, Helmbrecht H, McKenna M et al. 2020. Nanoparticle-microglial interaction in the ischemic brain is modulated by injury duration and treatment. Bioeng. Transl. Med. 5:e10175
    [Google Scholar]
  113. 113.
    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W et al. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4:147ra11
    [Google Scholar]
  114. 114.
    Brinker T, Stopa E, Morrison J, Klinge P. 2014. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS 11:10
    [Google Scholar]
  115. 115.
    Kiviniemi V, Wang X, Korhonen V, Keinanen T, Tuovinen T et al. 2016. Ultra-fast magnetic resonance encephalography of physiological brain activity—glymphatic pulsation mechanisms?. J. Cereb. Blood Flow Metab. 36:1033–45
    [Google Scholar]
  116. 116.
    Eide PK, Vinje V, Pripp AH, Mardal KA, Ringstad G. 2021. Sleep deprivation impairs molecular clearance from the human brain. Brain 144:863–74
    [Google Scholar]
  117. 117.
    Ringstad G, Valnes LM, Dale AM, Pripp AH, Vatnehol SS et al. 2018. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 3:e121537
    [Google Scholar]
  118. 118.
    Sykova E, Nicholson C. 2008. Diffusion in brain extracellular space. Physiol. Rev. 88:1277–340
    [Google Scholar]
  119. 119.
    Fenstermacher J, Kaye T. 1988. Drug “diffusion” within the brain. Ann. N.Y. Acad. Sci. 531:29–39
    [Google Scholar]
  120. 120.
    Pantazopoulos H, Berretta S. 2016. In sickness and in health: perineuronal nets and synaptic plasticity in psychiatric disorders. Neural Plast 2016:9847696
    [Google Scholar]
  121. 121.
    Wolak DJ, Thorne RG. 2013. Diffusion of macromolecules in the brain: implications for drug delivery. Mol. Pharm. 10:1492–504
    [Google Scholar]
  122. 122.
    Wood T, Nance E 2019. Disease-directed engineering for physiology-driven treatment interventions in neurological disorders. APL Bioeng 3:040901
    [Google Scholar]
  123. 123.
    Schwarz JM, Sholar PW, Bilbo SD. 2012. Sex differences in microglial colonization of the developing rat brain. J. Neurochem. 120:948–63
    [Google Scholar]
  124. 124.
    Hanamsagar R, Bilbo SD. 2016. Sex differences in neurodevelopmental and neurodegenerative disorders: focus on microglial function and neuroinflammation during development. J. Steroid Biochem. Mol. Biol. 160:127–33
    [Google Scholar]
  125. 125.
    McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. 2005. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J. Cereb. Blood Flow Metab. 25:502–12
    [Google Scholar]
  126. 126.
    Demarest TG, McCarthy MM. 2015. Sex differences in mitochondrial (dys)function: implications for neuroprotection. J. Bioenerg. Biomembr. 47:173–88
    [Google Scholar]
  127. 127.
    Wickens MM, Bangasser DA, Briand LA. 2018. Sex differences in psychiatric disease: a focus on the glutamate system. Front. Mol. Neurosci. 11:197
    [Google Scholar]
  128. 128.
    Good M, Day M, Muir JL. 1999. Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region. Eur. J. Neurosci. 11:4476–80
    [Google Scholar]
  129. 129.
    Warren SG, Humphreys AG, Juraska JM, Greenough WT. 1995. LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats. Brain Res 703:26–30
    [Google Scholar]
  130. 130.
    Hill CA, Fitch RH. 2012. Sex differences in mechanisms and outcome of neonatal hypoxia-ischemia in rodent models: implications for sex-specific neuroprotection in clinical neonatal practice. Neurol. Res. Int. 2012:867531
    [Google Scholar]
  131. 131.
    Prendergast BJ, Onishi KG, Zucker I. 2014. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 40:1–5
    [Google Scholar]
  132. 132.
    Benavente-Fernández I, Synnes A, Grunau RE, Chau V, Ramraj C et al. 2019. Association of socio-economic status and brain injury with neurodevelopmental outcomes of very preterm children. JAMA Netw. Open. 2:e192914
    [Google Scholar]
  133. 133.
    Kim HJ, Magrane J, Starkov AA, Manfredi G. 2012. The mitochondrial calcium regulator cyclophilin D is an essential component of oestrogen-mediated neuroprotection in amyotrophic lateral sclerosis. Brain 135:2865–74
    [Google Scholar]
  134. 134.
    Minghetti L, Greco A, Zanardo V, Suppiej A. 2013. Early-life sex-dependent vulnerability to oxidative stress: the natural twining model. J. Matern.-Fetal Neonatal Med. 26:259–62
    [Google Scholar]
  135. 135.
    Bayir H, Marion DW, Puccio AM, Wisniewski SR, Janesko KL et al. 2004. Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients. J. Neurotrauma 21:1–8
    [Google Scholar]
  136. 136.
    Khalsa DS. 2015. Stress, meditation, and Alzheimer's disease prevention: where the evidence stands. J. Alzheimer's Dis. 48:1–12
    [Google Scholar]
  137. 137.
    Helmbrecht H, Xu N, Liao R, Nance E 2021. Data management schema design for effective nanoparticle formulation for neurotherapeutics. AIChE J 67:e17459
    [Google Scholar]
/content/journals/10.1146/annurev-chembioeng-092220-030853
Loading
/content/journals/10.1146/annurev-chembioeng-092220-030853
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error