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Blood-to-Brain Drug Delivery Using Nanocarriers

  • Pieter J. Gaillard
  • Corine C. Visser
  • Marco de Boer
  • Chantal C. M. Appeldoorn
  • Jaap Rip
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 10)

Abstract

Brain and nervous system disorders represent a large, unmet medical need affecting two billion people worldwide; a number that is expected to grow with increasing life expectancy and the expanding global population. CNS drug development is hampered by the restricted transport of drug candidates across the blood-brain barrier (BBB). We will discuss blood-to-brain drug delivery strategies that make use of nanocarriers, like liposomes, albumin nanoparticles, and polymeric nanoparticles. The focus will be on the key pharmaceutical, pharmacological, and regulatory aspects towards the clinical development of nanocarriers. Clinical development of treatments employing nanocarriers is not as straightforward as for a single active moiety; therefore, we will highlight the issues that should be considered when translating basic research towards clinical development. Although it is still unrealistic to expect a magic bullet for exclusive CNS drug delivery, much progress has been made towards successful development of novel treatments for patients with devastating brain diseases.

Keywords

Encapsulation Efficiency European Medicine Agency Liposomal Doxorubicin Polymeric Nanoparticles Brain Uptake 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Ali J, Ali M, Baboota S, Sahani JK, Ramassamy C, Dao L, Bhavna (2010) Potential of nanoparticulate drug delivery systems by intranasal administration. Curr Pharm Des 16(14):1644–1653PubMedCrossRefGoogle Scholar
  2. Bankiewicz K (2014) Neurosurgical approaches: drug infusion directly into the parenchyma or cerebrospinal fluid. In: Hammarlund-Udenaes M, de Lange E, Thorne R (eds) Drug delivery to the brain—physiological concepts, methodologies and approaches. Springer, New York, Chapter 20 of this bookGoogle Scholar
  3. Banks WA (2008) Delivery of peptides to the brain: emphasis on therapeutic development. Biopolymers 90(5):589–594PubMedCrossRefGoogle Scholar
  4. Beg S, Samad A, Alam MI, Nazish I (2011) Dendrimers as novel systems for delivery of neuropharmaceuticals to the brain. CNS Neurol Disord Drug Targets 10(5):576–588PubMedCrossRefGoogle Scholar
  5. Bhaskar S, Tian F, Stoeger T et al (2010) Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging. Part Fibre Toxicol 7:3PubMedCentralPubMedCrossRefGoogle Scholar
  6. Bondi ML, Di Gesu R, Craparo EF (2012) Lipid nanoparticles for drug targeting to the brain. Methods Enzymol 508:229–251PubMedCrossRefGoogle Scholar
  7. Boraschi D, Costantino L, Italiani P (2012) Interaction of nanoparticles with immunocompetent cells: nanosafety considerations. Nanomedicine (Lond) 7(1):121–131CrossRefGoogle Scholar
  8. Brasnjevic I, Steinbusch HW, Schmitz C, Martinez-Martinez P (2009) Delivery of peptide and protein drugs over the blood-brain barrier. Prog Neurobiol 87(4):212–251PubMedCrossRefGoogle Scholar
  9. Chaurasia CS, Muller M, Bashaw ED et al (2007) AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res 24(5):1014–1025PubMedCrossRefGoogle Scholar
  10. Costantino L, Boraschi D (2012) Is there a clinical future for polymeric nanoparticles as brain-targeting drug delivery agents? Drug Discov Today 17(7–8):367–378PubMedCrossRefGoogle Scholar
  11. Dadparvar M, Wagner S, Wien S, Kufleitner J, Worek F, von Briesen H, Kreuter J (2011) HI 6 human serum albumin nanoparticles–development and transport over an in vitro blood-brain barrier model. Toxicol Lett 206(1):60–66PubMedCrossRefGoogle Scholar
  12. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Preat V (2012) PLGA-based nanoparticles: an overview of biomedical applications. J Control Release 161(2):505–522PubMedCrossRefGoogle Scholar
  13. de Lange EC, Danhof M (2002) Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain. Clin Pharmacokinet 41(10):691–703PubMedCrossRefGoogle Scholar
  14. de Lange EC, de Boer AG, Breimer DD (2000) Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev 45(2–3):125–148PubMedCrossRefGoogle Scholar
  15. de Vries NA, Beijnen JH, Boogerd W, van Tellingen O (2006) Blood-brain barrier and chemotherapeutic treatment of brain tumors. Expert Rev Neurother 6(8):1199–1209PubMedCrossRefGoogle Scholar
  16. Deguchi Y (2002) Application of in vivo brain microdialysis to the study of blood-brain barrier transport of drugs. Drug Metab Pharmacokinet 17(5):395–407PubMedCrossRefGoogle Scholar
  17. Deli MA, Abraham CS, Kataoka Y, Niwa M (2005) Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol 25(1):59–127PubMedCrossRefGoogle Scholar
  18. Duncan R, Gaspar R (2011) Nanomedicine(s) under the microscope. Mol Pharm 8(6):2101–2141PubMedCrossRefGoogle Scholar
  19. Fabel K, Dietrich J, Hau P et al (2001) Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. Cancer 92(7):1936–1942PubMedCrossRefGoogle Scholar
  20. Farrell D, Ptak K, Panaro NJ, Grodzinski P (2011) Nanotechnology-based cancer therapeutics–promise and challenge–lessons learned through the NCI Alliance for Nanotechnology in Cancer. Pharm Res 28(2):273–278PubMedCrossRefGoogle Scholar
  21. FDA (2001) Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074959.pdf
  22. FDA (2004) Guidance for Industry: Changes to an approved NDA or ANDA. http://www.fda.gov/OHRMS/DOCKETS/98fr/1999d-0529-gdl0003.pdf
  23. FDA (2006) Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Products. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126054.pdf
  24. Fernandes C, Soni U, Patravale V (2010) Nano-interventions for neurodegenerative disorders. Pharmacol Res 62(2):166–178PubMedCrossRefGoogle Scholar
  25. Fortin D (2014) Osmotic Opening of the BBB for DRug Treatment for Brain Tumors (Focus on Methodological Issues). In: Hammarlund-Udenaes M, de Lange E, Thorne R (eds) Drug delivery to the brain—physiological concepts, methodologies and approaches. Springer, New York, Chapter 21 of this bookGoogle Scholar
  26. Gabathuler R (2014) Development of new protein vecotrs for the physiologic delivery of large therapeutic compounds to the CNS. In: Hammarlund-Udenaes M, de Lange E, Thorne R (eds) Drug delivery to the brain—physiological concepts, methodologies and approaches. Springer, New York, Chapter 18 of this bookGoogle Scholar
  27. Gabizon AA (2001) Stealth liposomes and tumor targeting: one step further in the quest for the magic bullet. Clin Cancer Res 7(2):223–225PubMedGoogle Scholar
  28. Gaillard PJ (2010) Crossing barriers from blood-to-brain and academia-to-industry. Ther Deliv 1(4):495–500PubMedCrossRefGoogle Scholar
  29. Gaillard PJ, Visser CC, Appeldoorn CCM, Rip J (2011) Enhanced brain drug delivery: safely crossing the blood-brain barrier. Drug Discov Today Technol 9(2):e155–e160CrossRefGoogle Scholar
  30. Gaillard PJ, Gladdines W, Appeldoorn CCM, et al. (2012) Development of glutathione pegylated liposomal doxorubicin (2B3-101) for the treatment of brain cancer. [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 31 Mar–4 Apr; Chicago, Illinois. Philadelphia (PA): AACR; 2012. Abstract nr 5687Google Scholar
  31. Ganta S, Deshpande D, Korde A, Amiji M (2010) A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers. Mol Membr Biol 27(7):260–273PubMedCrossRefGoogle Scholar
  32. Garbayo E, Montero-Menei CN, Ansorena E, Lanciego JL, Aymerich MS, Blanco-Prieto MJ (2009) Effective GDNF brain delivery using microspheres—a promising strategy for Parkinson’s disease. J Control Release 135(2):119–126PubMedCrossRefGoogle Scholar
  33. Geldenhuys W, Mbimba T, Bui T, Harrison K, Sutariya V (2011) Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers. J Drug Target 19(9):837–845PubMedCrossRefGoogle Scholar
  34. Gilead Sciences, Inc. (2000) Press Release; http://www.gilead.com/pr_969296575
  35. Glas M, Koch H, Hirschmann B et al (2007) Pegylated liposomal doxorubicin in recurrent malignant glioma: analysis of a case series. Oncology 72(5–6):302–307PubMedCrossRefGoogle Scholar
  36. Gray D (2014) Pharmacoeconomical considerations of CNS drug development. In: Hammarlund-Udenaes M, de Lange E, Thorne R (eds) Drug delivery to the brain—physiological concepts, methodologies and approaches. Springer, New York, Chapter 15 of this bookGoogle Scholar
  37. Hammarlund-Udenaes M (2009) Active-site concentrations of chemicals—are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol 106:215–220PubMedCrossRefGoogle Scholar
  38. Hammarlund-Udenaes M (2014) PK concepts for brain drug delivery. In: Hammarlund-Udenaes M, de Lange E, Thorne R (eds) Drug delivery to the brain—physiological concepts, methodologies and approaches. Springer, New York, Chapter 6 of this bookGoogle Scholar
  39. Hau P, Fabel K, Baumgart U et al (2004) Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer 100(6):1199–1207PubMedCrossRefGoogle Scholar
  40. Helmchen F, Denk W (2005) Deep tissue two-photon microscopy. Nat Methods 2(12):932–940PubMedCrossRefGoogle Scholar
  41. Holmgaard R, Benfeldt E, Nielsen JB et al (2012) Comparison of open-flow microperfusion and microdialysis methodologies when sampling topically applied fentanyl and benzoic acid in human dermis ex vivo. Pharm Res 29:1808–1820PubMedCrossRefGoogle Scholar
  42. Jiang W, Lionberger R, Yu LX (2011) In vitro and in vivo characterizations of PEGylated liposomal doxorubicin. Bioanalysis 3(3):333–344PubMedCrossRefGoogle Scholar
  43. Jiskoot W, van Schie RM, Carstens MG, Schellekens H (2009) Immunological risk of injectable drug delivery systems. Pharm Res 26(6):1303–1314PubMedCrossRefGoogle Scholar
  44. Jones AR, Shusta EV (2007) Blood-brain barrier transport of therapeutics via receptor-mediation. Pharm Res 24(9):1759–1771PubMedCentralPubMedCrossRefGoogle Scholar
  45. Kaur IP, Bhandari R, Bhandari S, Kakkar V (2008) Potential of solid lipid nanoparticles in brain targeting. J Control Release 127(2):97–109PubMedCrossRefGoogle Scholar
  46. Kean T, Thanou M (2010) Biodegradation, biodistribution and toxicity of chitosan. Adv Drug Deliv Rev 62(1):3–11PubMedCrossRefGoogle Scholar
  47. Kim BY, Rutka JT, Chan WC (2010) Nanomedicine. N Engl J Med 363(25):2434–2443PubMedCrossRefGoogle Scholar
  48. Konofagou EE (2014) Emerging engineering technologies for opening the BBB. In: Hammarlund-Udenaes M, de Lange E, Thorne R (eds) Drug delivery to the brain—physiological concepts, methodologies and approaches. Springer, New York, Chapter 22 of this bookGoogle Scholar
  49. Kratz F (2008) Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release 132(3):171–183PubMedCrossRefGoogle Scholar
  50. Lin JH (2008) CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr Drug Metab 9(1):46–59PubMedCrossRefGoogle Scholar
  51. 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 10:1533–1541PubMedCrossRefGoogle Scholar
  52. Luppi B, Bigucci F, Cerchiara T, Zecchi V (2010) Chitosan-based hydrogels for nasal drug delivery: from inserts to nanoparticles. Expert Opin Drug Deliv 7(7):811–828PubMedCrossRefGoogle Scholar
  53. Lutz J, Augustin AJ, Jager LJ, Bachmann D, Brandl M (1995) Acute toxicity and depression of phagocytosis in vivo by liposomes: influence of lysophosphatidylcholine. Life Sci 56(2):99–106PubMedCrossRefGoogle Scholar
  54. Mishra V, Mahor S, Rawat A, Gupta PN, Dubey P, Khatri K, Vyas SP (2006) Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles. J Drug Target 14(1):45–53PubMedCrossRefGoogle Scholar
  55. Morigi V, Tocchio A, Pellegrini CB, Sakamoto JH, Arnone M, Tasciotti E (2012) Nanotechnology in medicine: from inception to market domain. J Drug Deliv Article ID 389485, 7 pages. doi:10.1155/2012/389485Google Scholar
  56. Mufamadi MS, Pillay V, Choonara YE, Du Toit LC, Modi G, Naidoo D, Ndesendo VM (2011) A review on composite liposomal technologies for specialized drug delivery. J Drug Deliv Article ID 939851, 19 pages. doi:10.1155/2011/939851 Google Scholar
  57. Muller RH, Keck CM (2012) Twenty years of drug nanocrystals: where are we, and where do we go? Eur J Pharm Biopharm 80(1):1–3PubMedCrossRefGoogle Scholar
  58. Nagpal K, Singh SK, Mishra DN (2010) Chitosan nanoparticles: a promising system in novel drug delivery. Chem Pharm Bull (Tokyo) 58(11):1423–1430CrossRefGoogle Scholar
  59. Nystrom AM, Fadeel B (2012) Safety assessment of nanomaterials: implications for nanomedicine. J Control Release 161(2):403–408PubMedCrossRefGoogle Scholar
  60. Palmieri D, Chambers AF, Felding-Habermann B, Huang S, Steeg PS (2007) The biology of metastasis to a sanctuary site. Clin Cancer Res 13(6):1656–1662PubMedCrossRefGoogle Scholar
  61. Pardridge WM (2010) Preparation of Trojan horse liposomes (THLs) for gene transfer across the blood-brain barrier. Cold Spring Harb Protoc (4): pdb prot5407Google Scholar
  62. Parnham MJ, Wetzig H (1993) Toxicity screening of liposomes. Chem Phys Lipids 64(1–3):263–274PubMedCrossRefGoogle Scholar
  63. Patel T, Zhou J, Piepmeier JM, Saltzman WM (2011) Polymeric nanoparticles for drug delivery to the central nervous system. Adv Drug Deliv Rev 64(7):701–705PubMedCentralPubMedCrossRefGoogle Scholar
  64. Reddy MK, Wu L, Kou W, Ghorpade A, Labhasetwar V (2008) Superoxide dismutase-loaded PLGA nanoparticles protect cultured human neurons under oxidative stress. Appl Biochem Biotechnol 151(2–3):565–577PubMedCentralPubMedCrossRefGoogle Scholar
  65. Rempe R, Cramer S, Huwel S, Galla HJ (2011) Transport of Poly(n-butylcyano-acrylate) nanoparticles across the blood-brain barrier in vitro and their influence on barrier integrity. Biochem Biophys Res Commun 406(1):64–69PubMedCrossRefGoogle Scholar
  66. Rip J, Appeldoorn CC, Manca FM, Dorland R, Van Kregten JM and Gaillard PJ (2010) Receptor-mediated delivery of drugs across the blood-brain barrier. Front. Pharmacol. Conference Abstract: Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU. doi:10.3389/conf.fphar.2010.02.00025Google Scholar
  67. Sanhai WR, Sakamoto JH, Canady R, Ferrari M (2008) Seven challenges for nanomedicine. Nat Nanotechnol 3(5):242–244PubMedCrossRefGoogle Scholar
  68. Shih AY, Mateo C, Drew PJ, Tsai PS, Kleinfeld D (2012) A polished and reinforced thinned-skull window for long-term imaging of the mouse brain. J Vis Exp pii(61):3742Google Scholar
  69. Smith QR, Allen DD (2003) In situ brain perfusion technique. Methods Mol Med 89:209–218PubMedGoogle Scholar
  70. Szebeni J, Alving CR, Baranyi L, Bunger R (2010) Interaction of liposomes with complement leading to adverse reactions. In: Gregoriadis G (ed) Liposome technology—volume III interactions of liposomes with the biological milieu, 3rd edn. Informa Healthcare USA, Inc, ZugGoogle Scholar
  71. Szebeni J, Muggia F, Gabizon A, Barenholz Y (2011) Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: prediction and prevention. Adv Drug Deliv Rev 63(12):1020–1030PubMedCrossRefGoogle Scholar
  72. Szebeni J, Bedocs P, Rozsnyay Z et al (2012) Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome. Nanomedicine 8(2):176–184PubMedCrossRefGoogle Scholar
  73. Tazina EV, Kostin KV, Oborotova NA (2011) Specific features of drug encapsulation in liposomes (a review). Pharm Chem J 45(8):481–490CrossRefGoogle Scholar
  74. Thorne R (2014) Intranasal drug delivery to the brain. In: Hammarlund-Udenaes M, de Lange E, Thorne R (eds) Drug delivery to the brain—physiological concepts, methodologies and approaches. Springer, New York, Chapter 16 of this bookGoogle Scholar
  75. Tsai CS, Park JW, Chen LT (2011) Nanovector-based therapeis in advanced pancreatic cancer. J Gastrointest Oncol 2:185–194PubMedCentralPubMedGoogle Scholar
  76. Ulbrich K, Hekmatara T, Herbert E, Kreuter J (2009) Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB). Eur J Pharm Biopharm 71(2):251–256PubMedCrossRefGoogle Scholar
  77. Ulbrich K, Knobloch T, Kreuter J (2011) Targeting the insulin receptor: nanoparticles for drug delivery across the blood-brain barrier (BBB). J Drug Target 19(2):125–132PubMedCrossRefGoogle Scholar
  78. van Rooy I, Cakir-Tascioglu S, Couraud PO et al (2010) Identification of peptide ligands for targeting to the blood-brain barrier. Pharm Res 27(4):673–682PubMedCentralPubMedCrossRefGoogle Scholar
  79. van Rooy I, Hennink WE, Storm G, Schiffelers RM, Mastrobattista E (2012) Attaching the phage display-selected GLA peptide to liposomes: factors influencing target binding. Eur J Pharm Sci 45(3):330–335PubMedCrossRefGoogle Scholar
  80. Wagner S, Kufleitner J, Zensi A et al (2010) Nanoparticulate transport of oximes over an in vitro blood-brain barrier model. PLoS One 5(12):e14213PubMedCentralPubMedCrossRefGoogle Scholar
  81. Wang JJ, Zeng ZW, Xiao RZ, Xie T, Zhou GL, Zhan XR, Wang SL (2011) Recent advances of chitosan nanoparticles as drug carriers. Int J Nanomedicine 6:765–774PubMedCentralPubMedGoogle Scholar
  82. Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood-brain barrier. Acta Neurobiol Exp (Wars) 71(1):113–128Google Scholar
  83. Wilson B (2009) Brain targeting PBCA nanoparticles and the blood-brain barrier. Nanomedicine (Lond) 4(5):499–502CrossRefGoogle Scholar
  84. WMA (2008) World Medical Association Declaration of Helsinki. http://www.wma.net/en/30publications/10policies/b3/17c.pdf
  85. Wohlfart S, Gelperina S, Kreuter J (2011) Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release 161(2):264–273PubMedCrossRefGoogle Scholar
  86. Wolf SM, Jones CM (2011) Designing oversight for nanomedicine research in human subjects: systematic analysis of exceptional oversight for emerging technologies. J Nanopart Res 13:1449–1465PubMedCentralPubMedCrossRefGoogle Scholar
  87. Wong HL, Wu XY, Bendayan R (2011) Nanotechnological advances for the delivery of CNS therapeutics. Adv Drug Deliv Rev 64(7):686–700PubMedCrossRefGoogle Scholar
  88. Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC (2008) Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther 83(5):761–769PubMedCrossRefGoogle Scholar
  89. Zucker D, Marcus D, Barenholz Y, Goldblum A (2009) Liposome drugs’ loading efficiency: a working model based on loading conditions and drug's physicochemical properties. J Control Release 139(1):73–80PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Pieter J. Gaillard
    • 1
  • Corine C. Visser
    • 1
  • Marco de Boer
    • 1
  • Chantal C. M. Appeldoorn
    • 1
  • Jaap Rip
    • 1
  1. 1.to-BBB technologies BVLeidenThe Netherlands

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