Skip to main content

Advertisement

Log in

Nanoparticle-Mediated Brain-Specific Drug Delivery, Imaging, and Diagnosis

  • Expert Review
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Central nervous system (CNS) diseases represent the largest and fastest-growing area of unmet medical need. Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis. With the aid of nanoparticles of high specificity and multifunctionality, such as dendrimers and quantum dots, therapeutics, imaging agents, and diagnostic molecules can be delivered to the brain across the blood-brain barrier (BBB), enabling considerable progress in the understanding, diagnosis, and treatment of CNS diseases. Nanoparticles used in the CNS for drug delivery, imaging, and diagnosis are reviewed, as well as their administration routes, toxicity, and routes to cross the BBB. Future directions and major challenges are outlined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

REFERENCES

  1. Johnson N, Davis T, Bosanquet N. The epidemic of Alzheimer’s disease. How can we manage the costs? Pharmacoeconomics. 2000;18:215–23.

    Article  CAS  PubMed  Google Scholar 

  2. Pardridge WM. Blood-brain barrier biology and methodology. J Neurovirol. 1999;5:556–69.

    Article  CAS  PubMed  Google Scholar 

  3. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53.

    Article  CAS  PubMed  Google Scholar 

  4. Smith QR, Rapoport SI. Cerebrovascular permeability coefficients to sodium, potassium, and chloride. J Neurochem. 1986;46:1732–42.

    Article  CAS  Google Scholar 

  5. Pardridge WM, Buciak JL, Friden PM. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J Pharmacol Exp Ther. 1991;259:66–70.

    CAS  PubMed  Google Scholar 

  6. Goldstein GW, Betz AL. The blood-brain barrier. Sci Am. 1986;255:74–83.

    Article  CAS  PubMed  Google Scholar 

  7. Schlosshauer B. The blood-brain barrier: morphology, molecules, and neurothelin. Bioessays. 1993;15:341–6.

    Article  CAS  PubMed  Google Scholar 

  8. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2:3–14.

    Article  PubMed  Google Scholar 

  9. Levin VA. Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem. 1980;23:682–4.

    Article  CAS  PubMed  Google Scholar 

  10. Pardridge WM. Drug and gene delivery to the brain: the vascular route. Neuron. 2002;36:555–8.

    Article  CAS  PubMed  Google Scholar 

  11. Cornford EM, Young D, Paxton JW, Hyman S, Farrell CL, Elliott RB. Blood-brain glucose transfer in the mouse. Neurochem Res. 1993;18:591–7.

    Article  CAS  PubMed  Google Scholar 

  12. Mooradian AD, Morin AM. Brain uptake of glucose in diabetes mellitus: the role of glucose transporters. Am J Med Sci. 1991;301:173–7.

    Article  CAS  PubMed  Google Scholar 

  13. Kreuter J. Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev. 2001;47:65–81.

    Article  CAS  PubMed  Google Scholar 

  14. Gupta B, Levchenko TS, Torchilin VP. TAT peptide-modified liposomes provide enhanced gene delivery to intracranial human brain tumor xenografts in nude mice. Oncol Res. 2007;16:351–9.

    PubMed  Google Scholar 

  15. Herve F, Ghinea N, Scherrmann JM. CNS delivery via adsorptive transcytosis. AAPS J. 2008;10:455–72.

    Article  PubMed  Google Scholar 

  16. Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood-brain barrier. Endocrinology. 1994;135:1753–61.

    Article  CAS  PubMed  Google Scholar 

  17. Golden PL, Maccagnan TJ, Pardridge WM. Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest. 1997;99:14–8.

    Article  CAS  PubMed  Google Scholar 

  18. Fishman JB, Rubin JB, Handrahan JV, Connor JR, Fine RE. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res. 1987;18:299–304.

    Article  CAS  PubMed  Google Scholar 

  19. Ke W, Shao K, Huang R, Han L, Liu Y, Li J, Kuang Y, Ye L, Lou J, Jiang C. Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. Biomaterials. 2009;30:6976–85.

    Article  CAS  PubMed  Google Scholar 

  20. Shi N, Boado RJ, Pardridge WM. Receptor-mediated gene targeting to tissues in vivo following intravenous administration of pegylated immunoliposomes. Pharm Res. 2001;18:1091–5.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Y, Pardridge WM. Conjugation of brain-derived neurotrophic factor to a blood-brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin. Brain Research. 2001;889:49–56.

    Article  CAS  PubMed  Google Scholar 

  22. Shi N, Pardridge WM. Noninvasive gene targeting to the brain. Proc Natl Acad Sci U S A. 2000;97:7567–72.

    Article  CAS  PubMed  Google Scholar 

  23. Pardridge WM. Re-engineering biopharmaceuticals for delivery to brain with molecular Trojan horses. Bioconjug Chem. 2008;19:1327–38.

    Article  CAS  PubMed  Google Scholar 

  24. Aktas Y, Yemisci M, Andrieux K, Gursoy RN, Alonso MJ, Fernandez-Megia E et al. Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26. Bioconjug Chem. 2005;16:1503–11.

    Article  CAS  PubMed  Google Scholar 

  25. Lee HJ, Engelhardt B, Lesley J, Bickel U, Pardridge WM. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. J Pharmacol Exp Ther. 2000;292:1048–52.

    CAS  PubMed  Google Scholar 

  26. Ulbrich K, Hekmatara T, Herbert E, Kreuter J. Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB). Eur J Pharm Biopharm. 2009;71:251–6.

    Article  CAS  PubMed  Google Scholar 

  27. R-q Huang, W-l Ke, Y-h Qu, J-h Zhu, Y-y Pei, Jiang C. Characterization of lactoferrin receptor in brain endothelial capillary cells and mouse brain. J Biomed Sci (Dordrecht, Netherlands). 2007;14:121–8.

    Google Scholar 

  28. Boado RJ, Zhang Y, Zhang Y, Pardridge WM. Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier. Biotechnol Bioeng. 2006;96:381–91.

    Article  CAS  Google Scholar 

  29. Huwyler J, Wu D, Pardridge WM. Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci U S A. 1996;93:14164–9.

    Article  CAS  PubMed  Google Scholar 

  30. Pardridge WM, Boado RJ, Kang YS. Vector-mediated delivery of a polyamide (“peptide”) nucleic acid analogue through the blood-brain barrier in vivo. Proc Natl Acad Sci U S A. 1995;92:5592–6.

    Article  CAS  PubMed  Google Scholar 

  31. Pardridge WM. Vector-mediated drug delivery to the brain. Adv Drug Delivery Rev. 1999;36:299–321.

    Article  CAS  Google Scholar 

  32. Olivier JC, Huertas R, Lee HJ, Calon F, Pardridge WM. Synthesis of pegylated immunonanoparticles. Pharm Res. 2002;19:1137–43.

    Article  CAS  PubMed  Google Scholar 

  33. Feng B, Tomizawa K, Michiue H, Miyatake S, Han XJ, Fujimura A et al. Delivery of sodium borocaptate to glioma cells using immunoliposome conjugated with anti-EGFR antibodies by ZZ-His. Biomaterials. 2009;30:1746–55.

    Article  CAS  PubMed  Google Scholar 

  34. Kizelsztein P, Ovadia H, Garbuzenko O, Sigal A, Barenholz Y. Pegylated nanoliposomes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune encephalomyelitis. J Neuroimmunol. 2009;213:20–5.

    Article  CAS  PubMed  Google Scholar 

  35. Ko YT, Bhattacharya R, Bickel U. Liposome encapsulated polyethylenimine/ODN polyplexes for brain targeting. J Control Release. 2009;133:230–7.

    Article  CAS  PubMed  Google Scholar 

  36. Grahn AY, Bankiewicz KS, Dugich-Djordjevic M, Bringas JR, Hadaczek P, Johnson GA et al. Non-PEGylated liposomes for convection-enhanced delivery of topotecan and gadodiamide in malignant glioma: initial experience. J Neurooncol. 2009;95:185–97.

    Article  CAS  PubMed  Google Scholar 

  37. Afergan E, Epstein H, Dahan R, Koroukhov N, Rohekar K, Danenberg HD et al. Delivery of serotonin to the brain by monocytes following phagocytosis of liposomes. J Control Release. 2008;132:84–90.

    Article  CAS  PubMed  Google Scholar 

  38. Ishida T, Atobe K, Wang X, Kiwada H. Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J Control Release. 2006;115:251–8.

    Article  CAS  PubMed  Google Scholar 

  39. Szebeni J, Baranyi L, Savay S, Milosevits J, Bunger R, Laverman P et al. Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies. J Liposome Res. 2002;12:165–72.

    Article  CAS  PubMed  Google Scholar 

  40. McNeeley KM, Annapragada A, Bellamkonda RV. Decreased circulation time offsets increased efficacy of PEGylated nanocarriers targeting folate receptors of glioma. Nanotechnology. 2007;18:385101 (11pp).

    Article  CAS  Google Scholar 

  41. McNeeley KM, Karathanasis E, Annapragada AV, Bellamkonda RV. Masking and triggered unmasking of targeting ligands on nanocarriers to improve drug delivery to brain tumors. Biomaterials. 2009;30:3986–95.

    Article  CAS  PubMed  Google Scholar 

  42. Liu L, Guo K, Lu J, Venkatraman SS, Luo D, Ng KC et al. Biologically active core/shell nanoparticles self-assembled from cholesterol-terminated PEG-TAT for drug delivery across the blood-brain barrier. Biomaterials. 2008;29:1509–17.

    Article  CAS  PubMed  Google Scholar 

  43. Soni S, Babbar AK, Sharma RK, Maitra A. Delivery of hydrophobised 5-fluorouracil derivative to brain tissue through intravenous route using surface modified nanogels. J Drug Target. 2006;14:87–95.

    Article  CAS  PubMed  Google Scholar 

  44. Inoue T, Yamashita Y, Nishihara M, Sugiyama S, Sonoda Y, Kumabe T et al. Therapeutic efficacy of a polymeric micellar doxorubicin infused by convection-enhanced delivery against intracranial 9 L brain tumor models. Neuro Oncol. 2009;11:151–7.

    Article  CAS  PubMed  Google Scholar 

  45. Alakhov V, Moskaleva E, Batrakova EV, Kabanov AV. Hypersensitization of multidrug resistant human ovarian carcinoma cells by pluronic P85 block copolymer. Bioconjug Chem. 1996;7:209–16.

    Article  CAS  PubMed  Google Scholar 

  46. Miller DW, Batrakova EV, Waltner TO, Alakhov V, Kabanov AV. Interactions of pluronic block copolymers with brain microvessel endothelial cells: evidence of two potential pathways for drug absorption. Bioconjug Chem. 1997;8:649–57.

    Article  CAS  PubMed  Google Scholar 

  47. Batrakova EV, Vinogradov SV, Robinson SM, Niehoff ML, Banks WA, Kabanov AV. Polypeptide point modifications with fatty acid and amphiphilic block copolymers for enhanced brain delivery. Bioconjug Chem. 2005;16:793–802.

    Article  CAS  PubMed  Google Scholar 

  48. Tomalia DA, Baker H, Dewald J, Hall M, Kallos G, Martin S et al. A new class of polymers: starburst-dendritic macromolecules. Polym J (Tokyo). 1985;17:117–32.

    CAS  Google Scholar 

  49. Esfand R, Tomalia DA. Poly(amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications. Drug Discov Today. 2001;6:427–36.

    Article  CAS  PubMed  Google Scholar 

  50. Newkome GR, Yao Z, Baker GR, Gupta VK. Micelles. Part 1. Cascade molecules: a new approach to micelles. A [27]-arborol. J Org Chem. 1985;50:2003–4.

    Article  CAS  Google Scholar 

  51. Kailasan A, Yuan Q, Yang H. Synthesis and characterization of thermoresponsive polyamidoamine-polyethylene glycol-poly (D, L-lactide) (PAMAM-PEG-PDLLA) core-shell nanoparticles. Acta Biomaterialia. 2010;6:1131–9.

    Article  CAS  PubMed  Google Scholar 

  52. Sarkar K, Yang H. Encapsulation and extended release of anti-cancer anastrozole by stealth nanoparticles. Drug Deliv. 2008;15:343–6.

    Article  CAS  PubMed  Google Scholar 

  53. Yang H, Lopina ST. Stealth dendrimers for antiarrhythmic quinidine delivery. J Mater Sci Mater Med. 2007;18:2061–5.

    Article  CAS  PubMed  Google Scholar 

  54. Wiwattanapatapee R, Carreno-Gomez B, Malik N, Duncan R. Anionic PAMAM dendrimers rapidly cross adult rat intestine in vitro: a potential oral delivery system? Pharm Res. 2000;17:991–8.

    Article  CAS  PubMed  Google Scholar 

  55. Jevprasesphant R, Penny J, Attwood D, D’Emanuele A. Transport of dendrimer nanocarriers through epithelial cells via the transcellular route. J Control Release. 2004;97:259–67.

    Article  CAS  PubMed  Google Scholar 

  56. Kannan S, Kolhe P, Raykova V, Glibatec M, Kannan RM, Lieh-Lai M et al. Dynamics of cellular entry and drug delivery by dendritic polymers into human lung epithelial carcinoma cells. J Biomater Sci Polym Ed. 2004;15:311–30.

    Article  CAS  PubMed  Google Scholar 

  57. Xyloyannis M, Padilla De Jesus OL, Frechet JMJ, Duncan R. PEG-dendron architecture influences endocytic capture and intercellular trafficking. Proc Int Symp Control Release Bioact Mater. 2003;30:149.

    Google Scholar 

  58. Roberts JC, Bhalgat MK, Zera RT. Preliminary biological evaluation of polyamidoamine (PAMAM) starburst dendrimers. J Biomed Mater Res. 1996;30:53–65.

    Article  CAS  PubMed  Google Scholar 

  59. Yang H, Lopina ST, DiPersio LP, Schmidt SP. Stealth dendrimers for drug delivery: correlation between PEGylation, cytocompatibility, and drug payload. J Mater Sci Mater Med. 2008;19:1991–7.

    Article  CAS  PubMed  Google Scholar 

  60. Eichman JD, Bielinska AU, Kukowska-Latallo JF, Baker Jr JR. The use of PAMAM dendrimers in the efficient transfer of genetic material into cells. Pharm Sci Technol Today. 2000;3:232–45.

    Article  CAS  PubMed  Google Scholar 

  61. Liu M, Frechet JMJ. Designing dendrimers for drug delivery. Pharm Sci Technol Today. 1999;2:393–401.

    Article  CAS  PubMed  Google Scholar 

  62. Bielinska AU, Yen A, Wu HL, Zahos KM, Sun R, Weiner ND et al. Application of membrane-based dendrimer/DNA complexes for solid phase transfection in vitro and in vivo. Biomaterials. 2000;21:877–87.

    Article  CAS  PubMed  Google Scholar 

  63. Schatzlein AG, Zinselmeyer BH, Elouzi A, Dufes C, Chim YTA, Roberts CJ et al. Preferential liver gene expression with polypropylenimine dendrimers. J Control Release. 2005;101:247–58.

    Article  CAS  PubMed  Google Scholar 

  64. Haensler J, Szoka Jr FC. Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug Chem. 1993;4:372–9.

    Article  CAS  PubMed  Google Scholar 

  65. Bielinska AU, Kukowska-Latallo JF, Baker Jr JR. The interaction of plasmid DNA with polyamidoamine dendrimers: mechanism of complex formation and analysis of alterations induced in nuclease sensitivity and transcriptional activity of the complexed DNA. Biochim Biophys Acta. 1997;1353:180–90.

    CAS  PubMed  Google Scholar 

  66. Braun CS, Vetro JA, Tomalia DA, Koe GS, Koe JG, Middaugh CR. Structure/function relationships of polyamidoamine/DNA dendrimers as gene delivery vehicles. J Pharm Sci. 2005;94:423–36.

    Article  CAS  PubMed  Google Scholar 

  67. Yoo H, Juliano RL. Enhanced delivery of antisense oligonucleotides with fluorophore-conjugated PAMAM dendrimers. Nucleic Acids Res. 2000;28:4225–31.

    Article  CAS  PubMed  Google Scholar 

  68. Takahashi T, Harada A, Emi N, Kono K. Preparation of efficient gene carriers using a polyamidoamine dendron-bearing lipid: improvement of serum resistance. Bioconjug Chem. 2005;16:1160–5.

    Article  CAS  PubMed  Google Scholar 

  69. Sonawane ND, Szoka Jr FC, Verkman AS. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem. 2003;278:44826–31.

    Article  CAS  PubMed  Google Scholar 

  70. Zhang XQ, Intra J, Salem AK. Conjugation of polyamidoamine dendrimers on biodegradable microparticles for nonviral gene delivery. Bioconjug Chem. 2007;18:2068–76.

    Article  CAS  PubMed  Google Scholar 

  71. Agrawal A, Min DH, Singh N, Zhu H, Birjiniuk A, von Maltzahn G et al. Functional delivery of siRNA in mice using dendriworms. ACS Nano. 2009;3:2495–504.

    Article  CAS  PubMed  Google Scholar 

  72. Huang R, Ke W, Han L, Liu Y, Shao K, Ye L et al. Brain-targeting mechanisms of lactoferrin-modified DNA-loaded nanoparticles. J Cereb Blood Flow Metab. 2009;29(12):1914–23.

    Article  CAS  PubMed  Google Scholar 

  73. Yang W, Barth RF, Wu G, Huo T, Tjarks W, Ciesielski M et al. Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors. J Neurooncol. 2009;95:355–65.

    Article  CAS  PubMed  Google Scholar 

  74. Kaneshiro TL, Lu ZR. Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier. Biomaterials. 2009;30:5660–6.

    Article  CAS  PubMed  Google Scholar 

  75. Wu G, Barth RF, Yang W, Kawabata S, Zhang L, Green-Church K. Targeted delivery of methotrexate to epidermal growth factor receptor-positive brain tumors by means of cetuximab (IMC-C225) dendrimer bioconjugates. Mol Cancer Ther. 2006;5:52–9.

    Article  CAS  PubMed  Google Scholar 

  76. Dhanikula RS, Hildgen P. Synthesis and evaluation of novel dendrimers with a hydrophilic interior as nanocarriers for drug delivery. Bioconjug Chem. 2006;17:29–41.

    Article  CAS  PubMed  Google Scholar 

  77. Sarin H, Kanevsky AS, Wu H, Brimacombe KR, Fung SH, Sousa AA et al. Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells. J Transl Med. 2008;6:80.

    Article  PubMed  CAS  Google Scholar 

  78. Gelperina S, Maksimenko O, Khalansky A, Vanchugova L, Shipulo E, Abbasova K et al. Drug delivery to the brain using surfactant-coated poly(lactide-co-glycolide) nanoparticles: influence of the formulation parameters. Eur J Pharm Biopharm. 2009;74(2):157–63.

    Article  PubMed  CAS  Google Scholar 

  79. Alyautdin RN, Petrov VE, Langer K, Berthold A, Kharkevich DA, Kreuter J. Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm Res. 1997;14:325–8.

    Article  CAS  PubMed  Google Scholar 

  80. Wilson B, Samanta MK, Santhi K, Kumar KP, Paramakrishnan N, Suresh B. Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles. Eur J Pharm Biopharm. 2008;70:75–84.

    Article  CAS  PubMed  Google Scholar 

  81. Olivier JC, Fenart L, Chauvet R, Pariat C, Cecchelli R, Couet W. Indirect evidence that drug brain targeting using polysorbate 80-coated polybutylcyanoacrylate nanoparticles is related to toxicity. Pharm Res. 1999;16:1836–1842.

    Article  CAS  PubMed  Google Scholar 

  82. Kurakhmaeva KB, Djindjikhashvili IA, Petrov VE, Balabanyan VU, Voronina TA, Trofimov SS et al. Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles. J Drug Target. 2009;17:564–74.

    Article  CAS  PubMed  Google Scholar 

  83. Ren T, Xu N, Cao C, Yuan W, Yu X, Chen J et al. Preparation and therapeutic efficacy of polysorbate-80-coated amphotericin B/PLA-b-PEG nanoparticles. J Biomater Sci Polym Ed. 2009;20:1369–80.

    Article  CAS  PubMed  Google Scholar 

  84. Zensi A, Begley D, Pontikis C, Legros C, Mihoreanu L, Wagner S et al. Albumin nanoparticles targeted with Apo E enter the CNS by transcytosis and are delivered to neurones. J Control Release. 2009;137:78–86.

    Article  CAS  PubMed  Google Scholar 

  85. Xu F, Lu W, Wu H, Fan L, Gao X, Jiang X. Brain delivery and systemic effect of cationic albumin conjugated PLGA nanoparticles. J Drug Target. 2009;17:423–34.

    Article  CAS  PubMed  Google Scholar 

  86. Kremer S, Pinel S, Vedrine PO, Bressenot A, Robert P, Bracard S et al. Ferumoxtran-10 enhancement in orthotopic xenograft models of human brain tumors: an indirect marker of tumor proliferation? J Neurooncol. 2007;83:111–9.

    Article  CAS  PubMed  Google Scholar 

  87. Manninger SP, Muldoon LL, Nesbit G, Murillo T, Jacobs PM, Neuwelt EA. An exploratory study of ferumoxtran-10 nanoparticles as a blood-brain barrier imaging agent targeting phagocytic cells in CNS inflammatory lesions. AJNR Am J Neuroradiol. 2005;26:2290–300.

    PubMed  Google Scholar 

  88. Neuwelt EA, Varallyay CG, Manninger S, Solymosi D, Haluska M, Hunt MA et al. The potential of ferumoxytol nanoparticle magnetic resonance imaging, perfusion, and angiography in central nervous system malignancy: a pilot study. Neurosurgery. 2007;60:601–11. discussion 611-2.

    Article  PubMed  Google Scholar 

  89. Bourrinet P, Bengele HH, Bonnemain B, Dencausse A, Idee JM, Jacobs PM et al. Preclinical safety and pharmacokinetic profile of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent. Invest Radiol. 2006;41:313–24.

    Article  CAS  PubMed  Google Scholar 

  90. Fatouros PP, Corwin FD, Chen ZJ, Broaddus WC, Tatum JL, Kettenmann B et al. In vitro and in vivo imaging studies of a new endohedral metallofullerene nanoparticle. Radiology. 2006;240:756–64.

    Article  PubMed  Google Scholar 

  91. Arndt-Jovin DJ, Kantelhardt SR, Caarls W, de Vries AH, Giese A, Jovin Ast TM. Tumor-targeted quantum dots can help surgeons find tumor boundaries. IEEE Trans Nanobioscience. 2009;8:65–71.

    Article  PubMed  Google Scholar 

  92. Wang J, Yong WH, Sun Y, Vernier PT, Koeffler HP, Gundersen MA et al. Receptor-targeted quantum dots: fluorescent probes for brain tumor diagnosis. J Biomed Opt. 2007;12:044021.

    Article  PubMed  CAS  Google Scholar 

  93. Bonoiu A, Mahajan SD, Ye L, Kumar R, Ding H, Yong KT et al. MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier. Brain Res. 2009;1282:142–55.

    Article  CAS  PubMed  Google Scholar 

  94. Santra S, Yang H, Stanley JT, Holloway PH, Moudgil BM, Walter G et al. Rapid and effective labeling of brain tissue using TAT-conjugated CdS:Mn/ZnS quantum dots. Chem Commun. 2005;25:3144–46.

    Google Scholar 

  95. Xu G, Yong KT, Roy I, Mahajan SD, Ding H, Schwartz SA et al. Bioconjugated quantum rods as targeted probes for efficient transmigration across an in vitro blood-brain barrier. Bioconjug Chem. 2008;19:1179–85.

    Article  CAS  PubMed  Google Scholar 

  96. Gao X, Chen J, Wu B, Chen H, Jiang X. Quantum dots bearing lectin-functionalized nanoparticles as a platform for in vivo brain imaging. Bioconjug Chem. 2008;19:2189–95.

    Article  CAS  Google Scholar 

  97. Bertin A, Steibel J, Michou-Gallani AI, Gallani JL, Felder-Flesch D. Development of a dendritic manganese-enhanced magnetic resonance imaging (MEMRI) contrast agent: synthesis, toxicity (in vitro) and relaxivity (in vitro, in vivo) studies. Bioconjug Chem. 2009;20:760–7.

    Article  CAS  PubMed  Google Scholar 

  98. Skaat H, Margel S. Synthesis of fluorescent-maghemite nanoparticles as multimodal imaging agents for amyloid-beta fibrils detection and removal by a magnetic field. Biochem Biophys Res Commun. 2009;386:645–9.

    Article  CAS  PubMed  Google Scholar 

  99. Tysiak E, Asbach P, Aktas O, Waiczies H, Smyth M, Schnorr J et al. Beyond blood brain barrier breakdown—in vivo detection of occult neuroinflammatory foci by magnetic nanoparticles in high field MRI. J Neuroinflammation. 2009;6:20.

    Article  PubMed  Google Scholar 

  100. Veiseh O, Sun C, Fang C, Bhattarai N, Gunn J, Kievit F et al. Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier. Cancer Res. 2009;69:6200–7.

    Article  CAS  PubMed  Google Scholar 

  101. Veiseh M, Gabikian P, Bahrami SB, Veiseh O, Zhang M, Hackman RC et al. Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res. 2007;67:6882–8.

    Article  CAS  PubMed  Google Scholar 

  102. Rapoport SI. Microinfarction: osmotic BBB opening or microcrystals in infusate? J Neurosurg. 1991;74:685.

    CAS  PubMed  Google Scholar 

  103. Broaddus WC, Liu Y, Steele LL, Gillies GT, Lin PS, Loudon WG et al. Enhanced radiosensitivity of malignant glioma cells after adenoviral p53 transduction. J Neurosurg. 1999;91:997–1004.

    Article  CAS  PubMed  Google Scholar 

  104. Song BW, Vinters HV, Wu D, Pardridge WM. Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. J Pharmacol Exp Ther. 2002;301:605–10.

    Article  CAS  PubMed  Google Scholar 

  105. Lerner EN, van Zanten EH, Stewart GR. Enhanced delivery of octreotide to the brain via transnasal iontophoretic administration. J Drug Target. 2004;12:273–80.

    Article  CAS  PubMed  Google Scholar 

  106. Krauze MT, Vandenberg SR, Yamashita Y, Saito R, Forsayeth J, Noble C et al. Safety of real-time convection-enhanced delivery of liposomes to primate brain: a long-term retrospective. Exp Neurol. 2008;210:638–44.

    Article  CAS  PubMed  Google Scholar 

  107. Saito R, Krauze MT, Bringas JR, Noble C, McKnight TR, Jackson P et al. Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain. Exp Neurol. 2005;196:381–9.

    Article  CAS  PubMed  Google Scholar 

  108. Huynh GH, Ozawa T, Deen DF, Tihan T, Szoka Jr FC. Retro-convection enhanced delivery to increase blood to brain transfer of macromolecules. Brain Res. 2007;1128:181–90.

    Article  CAS  PubMed  Google Scholar 

  109. Sarin H. Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors. J Transl Med. 2009;7:77.

    Article  PubMed  CAS  Google Scholar 

  110. Arumugam K, Subramanian GS, Mallayasamy SR, Averineni RK, Reddy MS, Udupa N. A study of rivastigmine liposomes for delivery into the brain through intranasal route. Acta Pharm. 2008;58:287–97.

    Article  CAS  PubMed  Google Scholar 

  111. Migliore MM, Vyas TK, Campbell RB, Amiji MM, Waszczak BL. Brain delivery of proteins by the intranasal route of administration: a comparison of cationic liposomes versus aqueous solution formulations. J Pharm Sci. 2009;99(4):1745–61.

    Google Scholar 

  112. Zhao Y, Meng H, Chen Z, Zhao F, Chai Z. Biological activities of nanomaterials/nanoparticles. In: Zhao YZ, Nalwa HS, editors. Nanotoxicology. California, USA: American Scientific Publishers. 2007;1–27.

  113. Powers KW, Palazuelos M, Moudgil BM, Roberts SM. Characterization of the size, shape, and state of dispersion of nanoparticles for toxicological studies. Nanotoxicology. 2007;1:42–51.

    Article  CAS  Google Scholar 

  114. Bauer M, Kristensen BW, Meyer M, Gasser T, Widmer HR, Zimmer J et al. Toxic effects of lipid-mediated gene transfer in ventral mesencephalic explant cultures. Basic Clin Pharmacol Toxicol. 2006;98:395–400.

    Article  CAS  PubMed  Google Scholar 

  115. Hardman R. A toxicologic review of quantum dots: toxicity depends on physicochemical and environmental factors. Environ Health Perspect. 2006;114:165–72.

    Article  PubMed  Google Scholar 

  116. Muldoon LL, Sandor M, Pinkston KE, Neuwelt EA. Imaging, distribution, and toxicity of superparamagnetic iron oxide magnetic resonance nanoparticles in the rat brain and intracerebral tumor. Neurosurgery. 2005;57:785–96.

    Article  PubMed  Google Scholar 

  117. Stanness KA, Guatteo E, Janigro D. A dynamic model of the blood-brain barrier “in vitro”. Neurotoxicology. 1996;17:481–96.

    CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGEMENTS

This work was supported by National Institutes of Health (R21NS063200).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hu Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, H. Nanoparticle-Mediated Brain-Specific Drug Delivery, Imaging, and Diagnosis. Pharm Res 27, 1759–1771 (2010). https://doi.org/10.1007/s11095-010-0141-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0141-7

KEY WORDS

Navigation