Advertisement

Approaches in Barriers, Modifications, Route of Administrations, and Formulations of Therapeutic Agents for Brain Delivery

  • Arun Kumar Kotha
  • Saikat Ghosh
  • Neeraja Komanduri
  • Rui Wang
  • Subhas Bhowmick
  • Mahavir Bhupal ChouguleEmail author
Chapter
  • 33 Downloads

Abstract

The barriers in the delivery of the therapeutic agent to brain diseases are blood–brain barrier (BBB), blood-cerebrospinal fluid barrier, and cellular barriers. The above mentioned barriers limit the distribution of the therapeutic agent or drug delivery system, thereby affects the therapeutic efficacy. The route of administration is also an important factor in the drug delivery to the brain diseases. Therefore, there is unmet need for the development of drug delivery systems which will overcome the barriers and delivers the therapeutic agent to the brain diseases. This chapter is focused on various strategies used to overcome the barriers in drug delivery to the brain diseases. The application of energy and chemical substances such as osmotic agent and permeation enhancers has been studied. Other strategies, such as developing the prodrug and inclusion complex of therapeutic agents, have been explained. The application and limitations of the different routes of administration such as intravenous, intra-arterial, intranasal, intracerebral, and intracerebroventricular have been described. The drug delivery system in the nanoscale such as liposomes, nanoemulsion, polymeric nanoparticles, and dendrimer have been explored to overcome the limitations associated with drug delivery to the brain diseases. Specific examples are described in this chapter. Lastly, various ongoing clinical trials for drug targeting to the brain are listed.

Keywords

Blood brain barrier Brain drug delivery Nanocarrier systems 

Notes

Acknowledgments

The authors would like to acknowledge the Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, USA, for providing start-up support to Dr. Chougule’s lab.

References

  1. 1.
    Abbott NJ, Romero IA (1996) Transporting therapeutics across the blood-brain barrier. Mol Med Today 2:106–113PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Kibiuk LV, Stuart D, Miller M (2008) Brain facts: a primer on the brain and nervous system. The Society for NeuroscienceGoogle Scholar
  3. 3.
    Banks WA (2016) From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discov 15:275PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Pardridge WM (1988) Recent advances in blood-brain barrier transport. Annu Rev Pharmacol Toxicol 28:25–39PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Burke M, Langer R, Brim H (1999) Central nervous system: drug delivery to treat. The Encyclopedia of controlled drug delivery. Wiley, New York, pp 184–212Google Scholar
  6. 6.
    Nordal RA, Wong CS (2005) Molecular targets in radiation-induced blood-brain barrier disruption. Int J Radiat Oncol Biol Phys 62:279–287PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    O’Reilly MA, Hynynen K (2012) Ultrasound enhanced drug delivery to the brain and central nervous system. Int J Hyperth 28:386–396CrossRefGoogle Scholar
  8. 8.
    Park J, Aryal M, Vykhodtseva N, Zhang YZ, McDannold N (2017) Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption. J Control Release 250:77–85PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Murrell DH, Zarghami N, Jensen MD, Chambers AF, Wong E, Foster PJ (2016) Evaluating changes to blood-brain barrier integrity in brain metastasis over time and after radiation treatment. Transl Oncol 9:219–227PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Gonzales-Portillo GS, Sanberg PR, Franzblau M, Gonzales-Portillo C, Diamandis T, Staples M et al (2014) Mannitol-enhanced delivery of stem cells and their growth factors across the blood–brain barrier. Cell Transplant 23:531–539PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Rapoport SI (2000) Osmotic opening of the blood–brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol 20:217–230PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bellavance M-A, Blanchette M, Fortin D (2008) Recent advances in blood–brain barrier disruption as a CNS delivery strategy. AAPS J 10:166–177PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Azad TD, Pan J, Connolly ID, Remington A, Wilson CM, Grant GA (2015) Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurg Focus 38:E9PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Emerich DF, Snodgrass P, Pink M, Bloom F, Bartus RT (1998) Central analgesic actions of loperamide following transient permeation of the blood brain barrier with Cereport™ (RMP-7)1Published on the World Wide Web on 30 June 1998.1. Brain Res 801:259–266PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Hülper P, Veszelka S, Walter FR, Wolburg H, Fallier-Becker P, Piontek J et al (2013) Acute effects of short-chain alkylglycerols on blood-brain barrier properties of cultured brain endothelial cells. Br J Pharmacol 169:1561–1573PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Erdlenbruch B, Alipour M, Fricker G, Miller DS, Kugler W, Eibl H et al (2003) Alkylglycerol opening of the blood–brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. Br J Pharmacol 140:1201–1210PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Prokai-Tatrai K, Prokai L (2011) Prodrug design for brain delivery of small-and medium-sized neuropeptides. In: Merighi A (eds) Neuropeptides. Methods in molecular biology (Methods and Protocols), vol 789. Humana Press, New York CityGoogle Scholar
  18. 18.
    Li Y, Zhou Y, Jiang J, Wang X, Fu Y, Gong T et al (2015) Mechanism of brain targeting by Dexibuprofen prodrugs modified with ethanolamine-related structures. J Cereb Blood Flow Metab 35:1985–1994PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Tirucherai GS, Yang C, Mitra AK (2001) Prodrugs in nasal drug delivery. Expert Opin Biol Ther 1:49–66PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Gambaryan PY, Kondrasheva IG, Severin ES, Guseva AA, Kamensky AA (2014) Increasing the efficiency of Parkinson’s disease treatment using a poly(lactic-co-glycolic acid) (PLGA) based L-DOPA delivery system. Exp Neurobiol 23:246–252PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Buchwald P, Bodor N (2016) Brain-targeting chemical delivery systems and their Cyclodextrin-based formulations in light of the contributions of Marcus E. Brewster. J Pharm Sci 105:2589–2600PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Muankaew C, Loftsson T (2018) Cyclodextrin-based formulations: a non-invasive platform for targeted drug delivery. Basic Clin Pharmacol Toxicol 122:46–55PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Lisnyak YV, Martynov AV, Baumer VN, Shishkin OV, Gubskaya AV (2007) Crystal and molecular structure of β-cyclodextrin inclusion complex with succinic acid. J Incl Phenom Macrocycl Chem 58:367–375CrossRefGoogle Scholar
  24. 24.
    Zhang Y (2018) Enhancing antidepressant effect of Poloxamer/chitosan thermosensitive gel containing Curcumin-Cyclodextrin inclusion complex. Int J Polym Sci 2018:1–8Google Scholar
  25. 25.
    Chen Y, Liu L (2012) Modern methods for delivery of drugs across the blood–brain barrier. Adv Drug Deliv Rev 64:640–665PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Jiang Y, Lv L, Shi H, Hua Y, Lv W, Wang X et al (2016) PEGylated Polyamidoamine dendrimer conjugated with tumor homing peptide as a potential targeted delivery system for glioma. Colloids Surf B: Biointerfaces 147:242–249PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Soni S, AK B, Rk S, Maitra A (2006) Delivery of hydrophobised 5-fluorouracil derivative to brain tissue through intravenous route using surface modified nanogels. J Drug Target 14:87–95PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Yadav S, Gattacceca F, Panicucci R, Amiji MM (2015) Comparative biodistribution and pharmacokinetic analysis of cyclosporine-a in the brain upon intranasal or intravenous Administration in an oil-in-water nanoemulsion formulation. Mol Pharm 12:1523–1533PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L (2016) Nanoparticle-mediated brain drug delivery: overcoming blood–brain barrier to treat neurodegenerative diseases. J Control Release 235:34–47PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Chen Z-L, Huang M, Wang X-R, Fu J, Han M, Shen Y-Q et al (2016) Transferrin-modified liposome promotes α-mangostin to penetrate the blood–brain barrier. Nanomedicine 12:421–430PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Wang Y, Xia Z, Xu J-R, Wang Y-X, Hou L-N, Qiu Y et al (2012) α-Mangostin, a polyphenolic xanthone derivative from mangosteen, attenuates β-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation. Neuropharmacology 62:871–881PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Rotman M, Welling MM, Bunschoten A, de Backer ME, Rip J, Nabuurs RJA et al (2015) Enhanced glutathione PEGylated liposomal brain delivery of an anti-amyloid single domain antibody fragment in a mouse model for Alzheimer’s disease. J Control Release 203:40–50PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Joshi S, Ellis JA, Emala CW (2014) Revisiting intra-arterial drug delivery for treating brain diseases or is it “déjà-vu, all over again”? J Neuroanaesthesiol Crit Care 1:108–115CrossRefGoogle Scholar
  34. 34.
    Marcos-Contreras OA, Brenner JS, Kiseleva RY, Zuluaga-Ramirez V, Greineder CF, Villa CH et al (2019) Combining vascular targeting and the local first pass provides 100-fold higher uptake of ICAM-1-targeted vs untargeted nanocarriers in the inflamed brain. J Control Release 301:54–61PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Lesniak W, Chu C, Jablonska A, Azad BB, Pomper M, Walczak P et al (2019) PET-CT shows advantage of Intra-arterial vs. Intravenous delivery of PAMAM Dendrimers for targeting the brain but their accumulation is transient. J Nucl Med 60:116CrossRefGoogle Scholar
  36. 36.
    Argibay B, Trekker J, Himmelreich U, Beiras A, Topete A, Taboada P et al (2017) Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Sci Rep 7:40758PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Zheng X, Shao X, Zhang C, Tan Y, Liu Q, Wan X et al (2015) Intranasal H102 peptide-loaded liposomes for brain delivery to treat Alzheimer’s disease. Pharm Res 32:3837–3849PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Pashirova TN, Zueva IV, Petrov KA, Lukashenko SS, Nizameev IR, Kulik NV et al (2018) Mixed cationic liposomes for brain delivery of drugs by the intranasal route: the acetylcholinesterase reactivator 2-PAM as encapsulated drug model. Colloids Surf B: Biointerfaces 171:358–367PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Pandey YR, Kumar S, Gupta BK, Ali J, Baboota S (2015) Intranasal delivery of paroxetine nanoemulsion via the olfactory region for the management of depression: formulation, behavioural and biochemical estimation. Nanotechnology 27:025102PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Gupta S, Kesarla R, Chotai N, Misra A, Omri A (2017) Systematic approach for the formulation and optimization of solid lipid nanoparticles of efavirenz by high pressure homogenization using design of experiments for brain targeting and enhanced bioavailability. Biomed Res Int 2017:5984014PubMedPubMedCentralGoogle Scholar
  41. 41.
    Huang M, Gu X, Gao X (2019) Nanotherapeutic strategies for the treatment of neurodegenerative diseases. In: Brain targeted drug delivery system. Academic Press, San Diego, pp 321–356CrossRefGoogle Scholar
  42. 42.
    Nance E, Zhang C, Shih T-Y, Xu Q, Schuster BS, Hanes J (2014) Brain-penetrating nanoparticles improve paclitaxel efficacy in malignant glioma following local administration. ACS Nano 8:10655–10664PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Bachiller S, Jiménez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T et al (2018) Microglia in neurological diseases: a road map to brain-disease dependent-inflammatory response. Front Cell Neurosci 12:488PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Han X, Li Q, Lan X, Leena E-M, Ren H, Wang J (2019) Microglial depletion with Clodronate liposomes increases Proinflammatory cytokine levels, induces astrocyte activation, and damages blood vessel integrity. Mol Neurobiol 56(9):6184–6196PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Norouzi M (2018) Recent advances in brain tumor therapy: application of electrospun nanofibers. Drug Discov Today 23:912–919PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Ashby LS, Smith KA, Stea B (2016) Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review. World J Surg Oncol 14:225PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Guerin C, Olivi A, Weingart JD, Lawson HC, Brem H (2004) Recent advances in brain tumor therapy: local intracerebral drug delivery by polymers. Investig New Drugs 22:27–37CrossRefGoogle Scholar
  48. 48.
    Finan JD, Cho FS, Kernie SG, Morrison B (2016) Intracerebroventricular administration of chondroitinase ABC reduces acute edema after traumatic brain injury in mice. BMC Res Notes 9:160PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Armbruster N, Lattanzi A, Jeavons M, Van Wittenberghe L, Gjata B, Marais T et al (2016) Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy. Mol Ther Methods Clin Dev 3:16060PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Wang Z, Zhao Y, Jiang Y, Lv W, Wu L, Wang B et al (2015) Enhanced anti-ischemic stroke of ZL006 by T7-conjugated PEGylated liposomes drug delivery system. Sci Rep 5:12651PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Boche M, Pokharkar V (2017) Quetiapine nanoemulsion for intranasal drug delivery: evaluation of brain-targeting efficiency. AAPS PharmSciTech 18:686–696PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Arun Kumar Kotha
    • 1
  • Saikat Ghosh
    • 2
    • 3
  • Neeraja Komanduri
    • 1
  • Rui Wang
    • 1
  • Subhas Bhowmick
    • 2
    • 3
  • Mahavir Bhupal Chougule
    • 1
    • 4
    • 5
    Email author
  1. 1.Department of Pharmaceutics and Drug Delivery, School of PharmacyThe University of MississippiUniversityUSA
  2. 2.Department of Pharmaceutics, Faculty of PharmacyThe Maharaja Sayajirao University of BarodaVadodaraIndia
  3. 3.Formulation Development Department- Novel Drug Delivery Systems (FDD-NDDS), Research & Development Centre-ISun Pharmaceutical Industries LimitedVadodaraIndia
  4. 4.Pii Center for Pharmaceutical Technology, Research Institute of Pharmaceutical SciencesThe University of MississippiUniversityUSA
  5. 5.National Center for Natural Products Research, Research Institute of Pharmaceutical SciencesThe University of MississippiUniversityUSA

Personalised recommendations