Cell and Tissue Research

, Volume 375, Issue 1, pp 287–293 | Cite as

Penetration of the blood-brain barrier by peripheral neuropeptides: new approaches to enhancing transport and endogenous expression

  • M. R. LeeEmail author
  • R. D. JayantEmail author


The blood-brain barrier (BBB) is a structural and functional barrier between the interstitial fluid of the brain and the blood; the barrier maintains the precisely controlled biochemical environment that is necessary for neural function. This constellation of endothelial cells, macrophages, pericytes, and astrocytes forms the neurovascular unit which is the structural and functional unit of the blood-brain barrier. Peptides enter and exit the CNS by transport systems expressed by the capillary endothelial cells of the neurovascular unit. Limiting the transport of peptides and proteins into the brain are efflux transporters like P-gp are transmembrane proteins present on the luminal side of the cerebral capillary endothelium and their function is to promote transit and excretion of drugs from the brain to the blood. Nanocarrier systems have been developed to exploit transport systems for enhanced BBB transport. Recent approaches for enhancing endogenous peptide expression are discussed.


Neuropeptides Oxytocin Blood-brain barrier (BBB) Receptor mediated transcytosis (RMT) CRISPR/Cas9-gRNA 


Funding information

This work was supported by the Bench-to-Bedside (B2B) Grant (PI: Lee) and grant #R03DA044887-02 (PI- Jayant) funded by the National Institutes of Health (NIH).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Aktaş Y, Yemisci M, Andrieux K, Gürsoy RN, Alonso MJ, Fernandez-Megia E, Novoa-Carballal R, Quiñoá E, Riguera R, Sargon MF (2005) Development and brain delivery of chitosan− PEG nanoparticles functionalized with the monoclonal antibody OX26. Bioconjug Chem 16:1503–1511CrossRefGoogle Scholar
  2. Althammer F, Grinevich V (2017) Diversity of oxytocin neurons: behyond mango- and parvocellular cell types? J Neuroendocrinol.
  3. Aly AEE, Waszczak BL (2015) Intranasal gene delivery for treating Parkinson’s disease: overcoming the blood–brain barrier. Expert Opin Drug Deliv 12:1923–1941CrossRefGoogle Scholar
  4. Bak A, Leung D, Barrett SE, Forster S, Minnihan EC, Leithead AW, Cunningham J, Toussaint N, Crocker LS (2015) Physicochemical and formulation developability assessment for therapeutic peptide delivery—a primer. AAPS J 17:144–155CrossRefGoogle Scholar
  5. Banks WA (2015) Peptides and the blood-brain barrier. Peptides 72:16–19CrossRefGoogle Scholar
  6. Banks WA, Kastin AJ (1984) A brain-to-blood carrier-mediated transport system for small, N-tyrosinated peptides. Pharmacol Biochem Behav 21:943–946CrossRefGoogle Scholar
  7. Banks W, Kastin A, Horvath A, Michals E (1987) Carrier-mediated transport of vasorpressin across the blood-brain barrier of the mouse. J Neurosci Res 18:326–332CrossRefGoogle Scholar
  8. Banks WA, Schally AV, Barrera CM, Fasold MB, Durham DA, Csernus VJ, Groot K, Kastin AJ (1990) Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin. Proc Natl Acad Sci 87:6762–6766CrossRefGoogle Scholar
  9. Banks WA, Kastin AJ, Komaki G, Arimura A (1993) Passage of pituitary adenylate cyclase activating polypeptide1-27 and pituitary adenylate cyclase activating polypeptide1-38 across the blood-brain barrier. J Pharmacol Exp Ther 267:690–696Google Scholar
  10. Barrera CM, Kastin AJ, Banks WA (1987) D-[Ala1]-peptide T-amide is transported from blood to brain by a saturable system. Brain Res Bull 19:629–633CrossRefGoogle Scholar
  11. Barrera CM, Kastin AJ, Fasold MB, Banks WA (1991) Bidirectional saturable transport of LHRH across the blood-brain barrier. Am J Physiol Endocrinol Metab 261:E312–E318CrossRefGoogle Scholar
  12. Beard R, Singh N, Grundschober C, Gee AD, Tate EW (2018) High-yielding (18)F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo. Chem Commun 54:8120–8123CrossRefGoogle Scholar
  13. Blanchette M, Fortin D (2011) Blood-brain barrier disruption in the treatment of brain tumors. The Blood-Brain and Other Neural Barriers Springer, pp 447–463Google Scholar
  14. Bodor N, Farag HH, Brewster ME (1981) Site-specific, sustained release of drugs to the brain. Science 214:1370–1372CrossRefGoogle Scholar
  15. Bruno BJ, Miller GD, Lim CS (2013) Basics and recent advances in peptide and protein drug delivery. Ther Deliv 4:1443–1467CrossRefGoogle Scholar
  16. Burgess A, Shah K, Hough O, Hynynen K (2015) Focused ultrasound-mediated drug delivery through the blood–brain barrier. Expert Rev Neurother 15:477–491CrossRefGoogle Scholar
  17. Chang J, Jallouli Y, Kroubi M, Yuan X-B, Feng W, Kang C-S, Pu P-Y, Betbeder D (2009) Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood–brain barrier. Int J Pharm 379:285–292CrossRefGoogle Scholar
  18. Chen F, Zhang X, Ma K, Madajewski B, Benezra M, Zhang L, Phillips E, Turker MZ, Gallazzi F, Penate-Medina O (2018) Melanocortin-1 receptor-targeting ultrasmall silica nanoparticles for dual-modality human melanoma imaging. ACS Appl Mater Interfaces 10:4379–4393CrossRefGoogle Scholar
  19. Costantino L, Gandolfi F, Tosi G, Rivasi F, Vandelli MA, Forni F (2005) Peptide-derivatized biodegradable nanoparticles able to cross the blood–brain barrier. J Control Release 108:84–96CrossRefGoogle Scholar
  20. Dhuria SV, Hanson LR, Frey WH (2010) Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 99:1654–1673CrossRefGoogle Scholar
  21. Dufes C (2011) Brain delivery of peptides and proteins. In Peptide and Protein Delivery. Elsevier, pp 105–122.
  22. Dwibhashyam V, Nagappa A (2008) Strategies for enhanced drug delivery to the central nervous system. Indian J Pharm Sci 70:145CrossRefGoogle Scholar
  23. Engert V, Koester AM, Riepenhausen A, Singer T (2016) Boosting recovery rather than buffering reactivity: higher stress-induced oxytocin secretion is associated with increased cortisol reactivity and faster vagal recovery after acute psychosocial stress. Psychoneuroendocrinology 74:111–120CrossRefGoogle Scholar
  24. Fenstermacher J, Gross P, Sposito N, Acuff V, Pettersen S, Gruber K (1988) Structural and functional variations in capillary systems within the brain. Ann N Y Acad Sci 529:21–30CrossRefGoogle Scholar
  25. Gainer H (1998) Cell-specific gene expression in oxytocin and vasopressin magnocellular neurons. In: Zingg HH, Bourque CW, Bichet DG (eds) Vasopressin and Oxytocin. Springer, Boston, pp 15–27Google Scholar
  26. Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, Meier PJ (2000) Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 294:73–79Google Scholar
  27. Gao X, Wu B, Zhang Q, Chen J, Zhu J, Zhang W, Rong Z, Chen H, Jiang X (2007) Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration. J Control Release 121:156–167CrossRefGoogle Scholar
  28. Han IK, Kim MY, Byun HM, Hwang TS, Kim JM, Hwang KW, Park TG, Jung WW, Chun T, Jeong GJ, Oh YK (2007) Enhanced brain targeting efficiency of intranasally administered plasmid DNA: an alternative route for brain gene therapy. J Mol Med (Berl) 85:75–83CrossRefGoogle Scholar
  29. Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185CrossRefGoogle Scholar
  30. Jayant RD, Atluri VS, Agudelo M, Sagar V, Kaushik A, Nair M (2015) Sustained-release nanoART formulation for the treatment of neuroAIDS. Int J Nanomedicine 10:1077CrossRefGoogle Scholar
  31. Jayant RD, Kuehl P, Chand H, Nair M (2018) Intranasal nanodelivery of oxytocin to treat drug addiction in HIV patients using CRISPR gene editing. J Neuroimmune Pharmacol 13. Springer 233 Spring St, New York, NY 10013 USA:S39–S39CrossRefGoogle Scholar
  32. Jones AR, Shusta EV (2007) Blood–brain barrier transport of therapeutics via receptor-mediation. Pharm Res 24:1759–1771CrossRefGoogle Scholar
  33. Kastin AJ, Pan W (2010) Concepts for biologically active peptides. Curr Pharm Des 16:3390–3400CrossRefGoogle Scholar
  34. Keir SD, House SB, Li J, Xiao X, Gainer H (1999) Gene transfer into hypothalamic organotypic cultures using an adeno-associated virus vector. Exp Neurol 160:313–316CrossRefGoogle Scholar
  35. Kniesel U, Wolburg H (2000) Tight junctions of the blood–brain barrier. Cell Mol Neurobiol 20:57–76CrossRefGoogle Scholar
  36. Kreuter J (2001) Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev 47:65–81CrossRefGoogle Scholar
  37. Kreuter J, Alyautdin RN, Kharkevich DA, Ivanov AA (1995) Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res 674:171–174CrossRefGoogle Scholar
  38. Lalatsa A, Garrett N, Ferrarelli T, Moger J, Schatzlein A, Uchegbu I (2012) Delivery of peptides to the blood and brain after oral uptake of quaternary ammonium palmitoyl glycol chitosan nanoparticles. Mol Pharm 9:1764–1774CrossRefGoogle Scholar
  39. Lee MR, Weerts EM (2016) Oxytocin for the treatment of drug and alcohol use disorders. Behav Pharmacol 27:640–648CrossRefGoogle Scholar
  40. Lee MR, Scheidweiler KB, Diao XX, Akhlaghi F, Cummins A, Huestis MA, Leggio L, Averbeck BB (2018a) Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiatry 23:115–122CrossRefGoogle Scholar
  41. Lee MR, Sheskier MB, Farokhnia M, Feng N, Marenco S, Lipska BK, Leggio L (2018b) Oxytocin receptor mRNA expression in dorsolateral prefrontal cortex in major psychiatric disorders: a human post-mortem study. Psychoneuroendocrinology 96:143–147CrossRefGoogle Scholar
  42. Lehrman S (1999) Virus treatment questioned after gene therapy death. Nature 401:517CrossRefGoogle Scholar
  43. Lindqvist A, Rip J, Gaillard PJ, Björkman S, Hammarlund-Udenaes M (2012) Enhanced brain delivery of the opioid peptide DAMGO in glutathione pegylated liposomes: a microdialysis study. Mol Pharm 10:1533–1541CrossRefGoogle Scholar
  44. Liu Q, Muruve DA (2003) Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther 10:935CrossRefGoogle Scholar
  45. Liu Z, Jiang M, Kang T, Miao D, Gu G, Song Q, Yao L, Hu Q, Tu Y, Pang Z (2013) Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration. Biomaterials 34:3870–3881CrossRefGoogle Scholar
  46. Lockman PR, Mumper RJ, Khan MA, Allen DD (2002) Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm 28:1–13CrossRefGoogle Scholar
  47. Lungwitz U, Breunig M, Blunk T, Göpferich A (2005) Polyethylenimine-based non-viral gene delivery systems. Eur J Pharm Biopharm 60:247–266CrossRefGoogle Scholar
  48. Mens WB, Laczi F, Tonnaer JA, de Kloet ER, van Wimersma Greidanus TB (1983a) Vasopressin and oxytocin content in cerebrospinal fluid and in various brain areas after administration of histamine and pentylenetetrazol. Pharmacol Biochem Behav 19:587–591CrossRefGoogle Scholar
  49. Mens WB, Witter A, van Wimersma Greidanus TB (1983b) Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): half-times of disappearance of these neuropeptides from CSF. Brain Res 262:143–149CrossRefGoogle Scholar
  50. Milligan KA, Winstead C, Smith J (2018) Preparation and physiochemical characterization of chitosan nanoparticles for controlled delivery of oxytocin. Int J Pharm Sci Res 9:1430–1440Google Scholar
  51. Nair M, Jayant RD, Kaushik A, Sagar V (2016) Getting into the brain: potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev 103:202–217CrossRefGoogle Scholar
  52. Oldendorf WH (1971) Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Phys 221:1629–1639Google Scholar
  53. Oviedo N, Manuel-Apolinar L, Orozco-Suárez S, Juárez-Cedillo T, Bekker Méndez VC, Tesoro-Cruz E (2017) Intranasal administration of a naked plasmid reached brain cells and expressed green fluorescent protein, a candidate for future gene therapy studies. Arch Med Res 48:616–622CrossRefGoogle Scholar
  54. Pang Z, Lu W, Gao H, Hu K, Chen J, Zhang C, Gao X, Jiang X, Zhu C (2008) Preparation and brain delivery property of biodegradable polymersomes conjugated with OX26. J Control Release 128:120–127CrossRefGoogle Scholar
  55. Pardridge WM (2007) Blood–brain barrier delivery. Drug Discov Today 12:54–61CrossRefGoogle Scholar
  56. Popov M, Hammad IA, Bachar T, Grinberg S, Linder C, Stepensky D, Heldman E (2013) Delivery of analgesic peptides to the brain by nano-sized bolaamphiphilic vesicles made of monolayer membranes. Eur J Pharm Biopharm 85:381–389CrossRefGoogle Scholar
  57. Purba JS, Hoogendijk WJ, Hofman MA, Swaab DF (1996) Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psychiatry 53:137–143CrossRefGoogle Scholar
  58. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281CrossRefGoogle Scholar
  59. Reddy JS, Venkateswarlu V (2004) Novel delivery systems for drug targeting to the brain. Drugs Future 29:63–83CrossRefGoogle Scholar
  60. Renukuntla J, Vadlapudi AD, Patel A, Boddu SH, Mitra AK (2013) Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 447:75–93CrossRefGoogle Scholar
  61. Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, Grauer S, Pulicicchio C, Resnick L, Rahman Z (2010) Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 58:69–77CrossRefGoogle Scholar
  62. Rout AK, Singh H, Patel S, Raghvaan V, Gautam S, Minda R, Rao BJ, Chary KVR (2018) Structural Characterization of a novel KH-domain containing plant chloroplast endonuclease. Scientific reports 8:13750Google Scholar
  63. Sanchez C, El Hajj Diab D, Connord V, Clerc P, Meunier E, Pipy B, Payré B, Tan RP, Gougeon M, Carrey J (2014) Targeting a G-protein-coupled receptor overexpressed in endocrine tumors by magnetic nanoparticles to induce cell death. ACS Nano 8:1350–1363CrossRefGoogle Scholar
  64. Strazielle N, Ghersi-Egea J (2013) Physiology of blood–brain interfaces in relation to brain disposition of small compounds and macromolecules. Mol Pharm 10:1473–1491CrossRefGoogle Scholar
  65. Tanaka A, Furubayashi T, Arai M, Inoue D, Kimura S, Kiriyama A, Kusamori K, Katsumi H, Yutani R, Sakane T (2018) Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application. Mol Pharm 15:1105–1111CrossRefGoogle Scholar
  66. Uhrig S, Hirth N, Broccoli L, von Wilmsdorff M, Bauer M, Sommer C, Zink M, Steiner J, Frodl T, Malchow B, Falkai P, Spanagel R, Hansson AC, Schmitt A (2016) Reduced oxytocin receptor gene expression and binding sites in different brain regions in schizophrenia: a post-mortem study. Schizophr Res 177:59–66CrossRefGoogle Scholar
  67. Vinzant N, Scholl JL, Wu C-M, Kindle T, Koodali R, Forster GL (2017) Iron oxide nanoparticle delivery of peptides to the brain: reversal of anxiety during drug withdrawal. Front Neurosci 11:608CrossRefGoogle Scholar
  68. Xie Y-L, Lu W, Jiang X-G (2006) Improvement of cationic albumin conjugated pegylated nanoparticles holding NC-1900, a vasopressin fragment analog, in memory deficits induced by scopolamine in mice. Behav Brain Res 173:76–84CrossRefGoogle Scholar
  69. Zaman RU, Mulla NS, Gomes KB, D’Souza C, Murnane KS, D’Souza MJ (2018) Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin. Int J Pharm 548:698–706CrossRefGoogle Scholar
  70. Zhang EY, Knipp GT, Ekins S, Swaan PW (2002) Structural biology and function of solute transporters: implications for identifying and designing substrates. Drug Metab Rev 34:709–750CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2018

Authors and Affiliations

  1. 1.Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)National Institute on Alcohol Abuse and Alcoholism (NIAAA)BethesdaUSA
  2. 2.Department of Pharmaceutical Sciences, School of PharmacyTexas Tech University Health Sciences CenterAmarilloUSA

Personalised recommendations