Advertisement

Nanoparticle and Iron Chelators as a Potential Novel Alzheimer Therapy

  • Gang Liu
  • Ping Men
  • George Perry
  • Mark A. Smith
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 610)

Abstract

Current therapies for Alzheimer disease (AD) such as the acetylcholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression or bring in meaningful remission. New approaches to the disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferrioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. Here, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show unique ability to cross the blood–brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may provide a safer and more effective means of reducing the metal load in neural tissue, thus attenuating the harmful effects of oxidative damage and its sequelae. Experimental procedures are presented in this chapter.

Key words

Alzheimer disease chelation therapy metal dysregulation nanoparticles 

Notes

Acknowledgments

The work in the authors’ laboratories is supported by the National Institutes of Health, the Alzheimer’s Association and Philip Morris USA Inc. and Philip Morris International.

References

  1. 1.
    Smith, M.A. (1998) Alzheimer disease. Int. Rev. Neurobiol. 42, 1–54.PubMedCrossRefGoogle Scholar
  2. 2.
    Gutteridge, J.M. (1994) Hydroxyl radicals, iron, oxidative stress, and neurodegeneration. Ann. NY Acad. Sci. 738, 201–213.PubMedCrossRefGoogle Scholar
  3. 3.
    Evans, P.H. (1993) Free radicals in brain metabolism and pathology. Br. Med. Bull. 49, 577–587.PubMedGoogle Scholar
  4. 4.
    Perry, G., Castellani, R.J., Hirai, K., and Smith, M.A. (1998) Reactive oxygen species mediate cellular damage in Alzheimer disease. J. Alzheimer’s Dis. 1, 45–55.Google Scholar
  5. 5.
    Smith, M.A., Sayre, L.M., Monnier, V.M., and Perry, G. (1995) Radical AGEing in Alzheimer’s disease. Trends Neurosci. 18, 172–176.PubMedCrossRefGoogle Scholar
  6. 6.
    Prasad, K.N., Hovland, A.R., Cole, W.C., Prasad, K.C., Nahreini, P., Edwards-Prasad, J., and Andreatta, C.P. (2000) Multiple antioxidants in the prevention and treatment of Alzheimer disease: Analysis of biologic rationale. Clin. Neuropharmacol. 23, 2–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Pitchumoni, S.S. and Doraiswamy, P.M. (1998) Current status of antioxidant therapy for Alzheimer’s disease. J. Am. Geriatr. Soc. 46, 1566–1572.PubMedGoogle Scholar
  8. 8.
    Christen, Y. (2000) Oxidative stress and Alzheimer disease. Am. J. Clin. Nutr. 71, 621S–629S.PubMedGoogle Scholar
  9. 9.
    Kennard, M.L., Feldman, H., Yamada, T., and Jefferies, W.A. (1996) Serum levels of the iron binding protein p97 are elevated in Alzheimer’s disease. Nat. Med. 2, 1230–1235.PubMedCrossRefGoogle Scholar
  10. 10.
    Jefferies, W.A., Food, M.R., Gabathuler, R., Rothenberger, S., Yamada, T., Yasuhara, O., and McGeer, P.L. (1996) Reactive microglia specifically associated with amyloid plaques in Alzheimer’s disease brain tissue express melanotransferrin. Brain Res. 712, 122–126.PubMedCrossRefGoogle Scholar
  11. 11.
    Harman, D. (1995) Free radical theory of aging: Alzheimer’s disease pathogensis. Age, 18, 97–119.CrossRefGoogle Scholar
  12. 12.
    Casadesus, G., Smith, M.A., Zhu, X., Aliev, G., Cash, A.D., Honda, K., Petersen, R.B., and Perry, G. (2004) Alzheimer disease: Evidence for a central pathogenic role of iron-mediated reactive oxygen species. J. Alzheimer’s Dis. 6, 165–169.Google Scholar
  13. 13.
    Olanow, C.W. (1992) An introduction to the free radical hypothesis in Parkinson’s disease. Ann. Neurol. 32(Suppl), S2–S9.PubMedCrossRefGoogle Scholar
  14. 14.
    Halliwell, B. and Gutteridge, J.M.C. (Ed.) (1999) Free Radicals in Biology and Medicine, Oxford University, New York.Google Scholar
  15. 15.
    Markesbery, W.R. and Ehmann, W.D. (1999) Oxidative stress in Alzheimer disease. In: Alzheimer Disease (Terry, R.D., Katzman, R., Bick, K.L., and Sisodia, S.S., Eds.), Lippincott Williams & Wilkins, Philadelphia, pp. 401–414.Google Scholar
  16. 16.
    Ohtawa, M., Seko, M., and Takayama, F. (1983) Effect of aluminum ingestion on lipid peroxidation in rats. Chem. Pharm. Bull. (Tokyo), 31, 1415–1418.PubMedGoogle Scholar
  17. 17.
    Evans, P.H., Klinowski, J., Yano, E., and Urano, N. (1989) Alzheimer’s disease: A pathogenic role for aluminosilicate-induced phagocytic free radicals. Free Radic. Res. Commun. 6, 317–321.PubMedCrossRefGoogle Scholar
  18. 18.
    Garrel, C., Lafond, J.L., Guiraud, P., Faure, P., and Favier, A. (1994) Induction of production of nitric oxide in microglial cells by insoluble form of aluminium. Ann. NY Acad. Sci. 738, 455–461.PubMedCrossRefGoogle Scholar
  19. 19.
    Kong, S., Liochev, S., and Fridovich, I. (1992) Aluminum(III) facilitates the oxidation of NADH by the superoxide anion. Free Radic. Biol. Med. 13, 79–81.PubMedCrossRefGoogle Scholar
  20. 20.
    Bondy, S.C., Guo-Ross, S.X., and Truong, A.T. (1998) Promotion of transition metal-induced reactive oxygen species formation by beta-amyloid. Brain Res. 799, 91–96.PubMedCrossRefGoogle Scholar
  21. 21.
    Lovell, M.A., Robertson, J.D., Teesdale, W.J., Campbell, J.L., and Markesbery, W.R. (1998) Copper, iron and zinc in Alzheimer’s disease senile plaques. J. Neurol. Sci. 158, 47–52.PubMedCrossRefGoogle Scholar
  22. 22.
    Markesbery, W.R. and Carney, J.M. (1999) Oxidative alterations in Alzheimer’s disease. Brain Pathol. 9, 133–146.PubMedCrossRefGoogle Scholar
  23. 23.
    Multhaup, G., Schlicksupp, A., Hesse, L., Beher, D., Ruppert, T., Masters, C.L., and Beyreuther, K. (1996) The amyloid precursor protein of Alzheimer’s disease in the reduction of copper(II) to copper(I). Science, 271, 1406–1409.PubMedCrossRefGoogle Scholar
  24. 24.
    Sayre, L.M., Perry, G., and Smith, M.A. (1999) Redox metals and neurodegenerative disease. Curr. Opin. Chem. Biol. 3, 220–225.PubMedCrossRefGoogle Scholar
  25. 25.
    Linder, M.C. and Hazegh-Azam, M. (1996) Copper biochemistry and molecular biology. Am. J. Clin. Nutr. 63, 797S–811S.PubMedGoogle Scholar
  26. 26.
    Bush, A.I., Pettingell, W.H., Multhaup, G., d Paradis, M., Vonsattel, J.P., Gusella, J.F., Beyreuther, K., Masters, C.L., and Tanzi, R.E. (1994) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science, 265, 1464–1467.PubMedCrossRefGoogle Scholar
  27. 27.
    Hensley, K., Carney, J.M., Mattson, M.P., Aksenova, M., Harris, M., Wu, J.F., Floyd, R.A., and Butterfield, D.A. (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: Relevance to Alzheimer disease. Proc. Natl. Acad. Sci. USA, 91, 3270–3274.PubMedCrossRefGoogle Scholar
  28. 28.
    Butterfield, D.A. (1997) beta-Amyloid-associated free radical oxidative stress and neurotoxicity: Implications for Alzheimer’s disease. Chem. Res. Toxicol. 10, 495–506.PubMedCrossRefGoogle Scholar
  29. 29.
    Pratico, D., Clark, C.M., Liun, F., Rokach, J., Lee, V.Y., and Trojanowski, J.Q. (2002) Increase of brain oxidative stress in mild cognitive impairment: A possible predictor of Alzheimer disease. Arch. Neurol. 59, 972–976.PubMedCrossRefGoogle Scholar
  30. 30.
    Atwood, C.S., Scarpa, R.C., Huang, X., Moir, R.D., Jones, W.D., Fairlie, D.P., Tanzi, R.E., and Bush, A.I. (2000) Characterization of copper interactions with alzheimer amyloid beta peptides: Identification of an attomolar-affinity copper binding site on amyloid beta1-42. J. Neurochem. 75, 1219–1233.PubMedCrossRefGoogle Scholar
  31. 31.
    Pratico, D., Uryu, K., Sung, S., Tang, S., Trojanowski, J.Q., and Lee, V.M. (2002) Aluminum modulates brain amyloidosis through oxidative stress in APP transgenic mice. FASEB J. 16, 1138–1140.PubMedGoogle Scholar
  32. 32.
    House, E., Collingwood, J., Khan, A., Korchazkina, O., Berthon, G., and Exley, C. (2004) Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer’s disease. J. Alzheimer’s Dis. 6, 291–301.Google Scholar
  33. 33.
    McLachlan, D.R., Kruck, T.P., Lukiw, W.J., and Krishnan, S.S. (1991) Would decreased aluminum ingestion reduce the incidence of Alzheimer’s disease? CMAJ, 145, 793–804.PubMedGoogle Scholar
  34. 34.
    Cuajungco, M.P., Faget, K.Y., Huang, X., Tanzi, R.E., and Bush, A.I. (2000) Metal chelation as a potential therapy for Alzheimer’s disease. Ann. NY Acad. Sci. 920, 292–304.PubMedCrossRefGoogle Scholar
  35. 35.
    Richardson, D.R. and Ponka, P. (1998) Development of iron chelators to treat iron overload disease and their use as experimental tools to probe intracellular iron metabolism. Am. J. Hematol. 58, 299–305.PubMedCrossRefGoogle Scholar
  36. 36.
    Keberle, H. (1964) The biochemistry of desferrioxamine and its relation to iron metabolism. Ann. NY Acad. Sci. 119, 758–768.PubMedCrossRefGoogle Scholar
  37. 37.
    Hider, R.C. and Hall, A.D. (1991) Clinically useful chelators of tripositive elements. Prog. Med. Chem. 28, 41–173.PubMedCrossRefGoogle Scholar
  38. 38.
    Finefrock, A.E., Bush, A.I., and Doraiswamy, P.M. (2003) Current status of metals as therapeutic targets in Alzheimer’s disease. J. Am. Geriatr. Soc. 51, 1143–1148.PubMedCrossRefGoogle Scholar
  39. 39.
    Ben-Shachar, D., Riederer, P., and Youdim, M.B. (1991) Iron-melanin interaction and lipid peroxidation: Implications for Parkinson’s disease. J. Neurochem. 57, 1609–1614.PubMedCrossRefGoogle Scholar
  40. 40.
    Floor, E. (2000) Iron as a vulnerability factor in nigrostriatal degeneration in aging and Parkinson’s disease. Cell Mol. Biol. (Noisy-le-grand), 46, 709–720.PubMedGoogle Scholar
  41. 41.
    Blake, D.R., Winyard, P., Lunec, J., Williams, A., Good, P.A., Crewes, S.J., Gutteridge, J.M., Rowley, D., Halliwell, B., Cornish, A. et al. (1985) Cerebral and ocular toxicity induced by desferrioxamine. Q. J. Med. 56, 345–355.PubMedGoogle Scholar
  42. 42.
    Kruck, T.P., Fisher, E.A., and McLachlan, D.R. (1993) A predictor for side effects in patients with Alzheimer’s disease treated with deferoxamine mesylate. Clin. Pharmacol. Ther. 53, 30–37.PubMedCrossRefGoogle Scholar
  43. 43.
    Struck, M., Waldmeier, P., and Berdoukas, V. (1993) The treatment of iron overload-psychiatric implication. In: Iron in Central Nervous System Disorders (Riederer, P. and Youdim, M.B.H., Eds.) Springer Verlag, Wien, pp. 189–196.Google Scholar
  44. 44.
    Klaasen, C.D. (1996) Heavy metals and heavy-metalantagonists. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics (Hardman, J.G., Limbird, L.E., Molinoff, P.B., Ruddon, R.W., and Gilman, A.G., Eds.), McGraw Hill, New York, pp. 1649–1671.Google Scholar
  45. 45.
    Jenner, P. and Olanow, C.W. (1998) Understanding cell death in Parkinson’s disease. Ann. Neurol. 44, S72–S84.PubMedGoogle Scholar
  46. 46.
    May, P.M. and Bulman, R.A. (1983) The present status of chelating agents in medicine. Prog. Med. Chem. 20, 225–336.PubMedCrossRefGoogle Scholar
  47. 47.
    Olivieri, N.F. and Brittenham, G.M. (1997) Iron-chelating therapy and the treatment of thalassemia. Blood, 89, 739–761.PubMedGoogle Scholar
  48. 48.
    Lynch, S.G., Fonseca, T., and Levine, S.M. (2000) A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol. Biol. (Noisy-le-grand), 46, 865–869.PubMedGoogle Scholar
  49. 49.
    Crowe, A. and Morgan, E.H. (1994) Effects of chelators on iron uptake and release by the brain in the rat. Neurochem. Res. 19, 71–76.PubMedCrossRefGoogle Scholar
  50. 50.
    Kontoghiorghes, G.J. (1995) New concepts of iron and aluminium chelation therapy with oral L1 (deferiprone) and other chelators. A review. Analyst, 120, 845–851.PubMedCrossRefGoogle Scholar
  51. 51.
    Ward, R.J., Dexter, D., Florence, A., Aouad, F., Hider, R., Jenner, P., and Crichton, R.R. (1995) Brain iron in the ferrocene-loaded rat: Its chelation and influence on dopamine metabolism. Biochem. Pharmacol. 49, 1821–1826.PubMedCrossRefGoogle Scholar
  52. 52.
    Richardson, D.R. (1999) The therapeutic potential of iron chelators. Expert Opin. Investig. Drugs, 8, 2141–2158.PubMedCrossRefGoogle Scholar
  53. 53.
    Medical News Today (2005) FDA grants priority review for Exjade(R) for the treatment of chronic iron overload due to blood transfusions, http://www.medicalnewstoday.com/medicalnews.php?newsid=26610.
  54. 54.
    Neufeld, E.J. (2006) Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: New data, new questions. Blood, 107, 3436–3441.PubMedCrossRefGoogle Scholar
  55. 55.
    Piga, A., Galanello, R., Forni, G.L., Cappellini, M.D., Origa, R., Zappu, A., Donato, G., Bordone, E., Lavagetto, A., Zanaboni, L., Sechaud, R., Hewson, N., Ford, J.M., Opitz, H., and Alberti, D. (2006) Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica, 91, 873–880.PubMedGoogle Scholar
  56. 56.
    Hider, R.C., Porter, J.B., and Singh, S. (1994) The design of therapeutically useful iron chelators. In: The Development of Iron Chelators for Clinical Use (Bergeron, R.J. and Brittenham, G.M., Eds.), CRC, Boca Raton, pp. 353–371.Google Scholar
  57. 57.
    Gassen, M. and Youdim, M.B. (1997) The potential role of iron chelators in the treatment of Parkinson’s disease and related neurological disorders. Pharmacol. Toxicol. 80, 159–166.PubMedCrossRefGoogle Scholar
  58. 58.
    Lee, J.Y., Friedman, J.E., Angel, I., Kozak, A., and Koh, J.Y. (2004) The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human beta-amyloid precursor protein transgenic mice. Neurobiol. Aging, 25, 1315–1321.PubMedCrossRefGoogle Scholar
  59. 59.
    Porter, J.B., Morgan, J., Hoyes, K.P., Burke, L.C., Huehns, E.R., and Hider, R.C. (1990) Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice. Blood, 76, 2389–2396.PubMedGoogle Scholar
  60. 60.
    Kreuter, J. (2001) Nanoparticulate systems for brain delivery of drugs. Adv. Drug Deliv. Rev. 47, 65–81.PubMedCrossRefGoogle Scholar
  61. 61.
    Raymond, K.N. and Xu, J. (1994) Siderophore-based hydroxypyridonate sequestering agents. In: The Development of Iron Chelators for Clinical Use (Bergeron, R.J. and Brittenham, G.M., Eds.), CRC Press, Boca Raton, pp. 354–371.Google Scholar
  62. 62.
    Hider, R.C., Choudhury, R., Rai, B.L., Dehkordi, L.S., and Singh, S. (1996) Design of orally active iron chelators. Acta Haematol. 95, 6–12.PubMedCrossRefGoogle Scholar
  63. 63.
    Martell, A.E., Motekaitis, R.J., Sun, Y., Ma, R., Welch, M.J., and Pajeau, T. (1999) New chelating-agents suitable for the treatment of iron overload. Inorg. Chim. Acta, 291, 238–246.CrossRefGoogle Scholar
  64. 64.
    Caravan, P. and Orvig, C. (1997) Tripodal aminophenolate ligand complexes of aluminum(III), gallium(III), and indium(III) in water. Inorg. Chem. 36, 237–248.Google Scholar
  65. 65.
    Faller, B., Spanka, C., Sergejew, T., and Tschinke, V. (2000) Improving the oral bioavailability of the iron chelator HBED by breaking the symmetry of the intramolecular H-bond network. J. Med. Chem. 43, 1467–1475.PubMedCrossRefGoogle Scholar
  66. 66.
    Bergeron, R.J. and McManis, J.S. (1994) Synthesis and biological activity of hydroxamate-based iron chelators. In: The Development of Iron Chelators for Clinical Use (Bergeron, R.J. and Brittenham, G.M., Eds.), CRC, Boca Raton, pp. 237–273.Google Scholar
  67. 67.
    Richardson, D.R. and Ponka, P. (1998) Pyridoxal isonicotinoyl hydrazone and its analogs: Potential orally effective iron-chelating agents for the treatment of iron overload disease. J. Lab. Clin. Med. 131, 306–315.PubMedCrossRefGoogle Scholar
  68. 68.
    Cherny, R.A., Atwood, C.S., Xilinas, M.E., Gray, D.N., Jones, W.D., McLean, C.A., Barnham, K.J., Volitakis, I., Fraser, F.W., Kim, Y., Huang, X., Goldstein, L.E., Moir, R.D., Lim, J.T., Beyreuther, K., Zheng, H., Tanzi, R.E., Masters, C.L., and Bush, A.I. (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron, 30, 665–676.PubMedCrossRefGoogle Scholar
  69. 69.
    Cherny, R.A., Legg, J.T., McLean, C.A., Fairlie, D.P., Huang, X., Atwood, C.S., Beyreuther, K., Tanzi, R.E., Masters, C.L., and Bush, A.I. (1999) Aqueous dissolution of Alzheimer’s disease Abeta amyloid deposits by biometal depletion. J. Biol. Chem. 274, 23223–23228.PubMedCrossRefGoogle Scholar
  70. 70.
    Loske, C., Gerdemann, A., Schepl, W., Wycislo, M., Schinzel, R., Palm, D., Riederer, P., and Munch, G. (2000) Transition metal-mediated glycoxidation accelerates cross-linking of beta-amyloid peptide. Eur. J. Biochem. 267, 4171–4178.PubMedCrossRefGoogle Scholar
  71. 71.
    Ritchie, C.W., Bush, A.I., Mackinnon, A., Macfarlane, S., Mastwyk, M., MacGregor, L., Kiers, L., Cherny, R., Li, Q.X., Tammer, A., Carrington, D., Mavros, C., Volitakis, I., Xilinas, M., Ames, D., Davis, S., Beyreuther, K., Tanzi, R.E., and Masters, C.L. (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: A pilot phase 2 clinical trial. Arch. Neurol. 60, 1685–1691.PubMedCrossRefGoogle Scholar
  72. 72.
    Doraiswamy, P.M. and Xiong, G.L. (2006) Pharmacological strategies for the prevention of Alzheimer’s disease. Expert Opin. Pharmacother. 7, 1–10.PubMedCrossRefGoogle Scholar
  73. 73.
    Brem, H., Walter, K.A., Tamargo, R.J., Olivi, A., and Langer, R. (1994) Drug delivery to the brain. In: Polymeric Site-Specific Pharmacotherapy (Domb, A.J., Ed.), John Wiley & Sons, New York, pp. 117–139.Google Scholar
  74. 74.
    Kreuter, J., Shamenkov, D., Petrov, V., Ramge, P., Cychutek, K., Koch-Brandt, C., and Alyautdin, R. (2002) Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J. Drug Target. 10, 317–325.PubMedCrossRefGoogle Scholar
  75. 75.
    Schroeder, U., Sommerfeld, P., Ulrich, S., and Sabel, B.A. (1998) Nanoparticle technology for delivery of drugs across the blood-brain barrier. J. Pharm. Sci. 87, 1305–1307.PubMedCrossRefGoogle Scholar
  76. 76.
    Alyautdin, R.N., Tezikov, E.B., Ramge, P., Kharkevich, D.A., Begley, D.J., and Kreuter, J. (1998) Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: An in situ brain perfusion study. J. Microencapsul. 15, 67–74.PubMedCrossRefGoogle Scholar
  77. 77.
    Siegemund, T., Paulke, B.R., Schmiedel, H., Bordag, N., Hoffmann, A., Harkany, T., Tanila, H., Kacza, J., and Hartig, W. (2006) Thioflavins released from nanoparticles target fibrillar amyloid beta in the hippocampus of APP/PS1 transgenic mice. Int. J. Dev. Neurosci. 24, 195–201.PubMedCrossRefGoogle Scholar
  78. 78.
    Cui, Z., Lockman, P.R., Atwood, C.S., Hsu, C.H., Gupte, A., Allen, D.D., and Mumper, R.J. (2005) Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer’s and other CNS diseases. Eur. J. Pharm. Biopharm. 59, 263–272.PubMedCrossRefGoogle Scholar
  79. 79.
    Shea, T.B., Ortiz, D., Nicolosi, R.J., Kumar, R., and Watterson, A.C. (2005) Nanosphere-mediated delivery of vitamin E increases its efficacy against oxidative stress resulting from exposure to amyloid beta. J. Alzheimer’s Dis. 7, 297–301.Google Scholar
  80. 80.
    Liu, G., Men, P., Harris, P.L., Rolston, R.K., Perry, G., and Smith, M.A. (2006) Nanoparticle iron chelators: A new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance. Neurosci. Lett. 406, 189–193.PubMedCrossRefGoogle Scholar
  81. 81.
    Ravi Kumar, M.N. (2000) Nano and microparticles as controlled drug delivery devices. J. Pharm. Sci. 3, 234–258.Google Scholar
  82. 82.
    Dehouck, B., Fenart, L., Dehouck, M.P., Pierce, A., Torpier, G., and Cecchelli, R. (1997) A new function for the LDL receptor: Transcytosis of LDL across the blood-brain barrier. J. Cell Biol. 138, 877–889.PubMedCrossRefGoogle Scholar
  83. 83.
    Muller, R.H., Jacobs, C., and Kayser, O. (2001) Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. Adv. Drug Deliv. Rev. 47, 3–19.PubMedCrossRefGoogle Scholar
  84. 84.
    Ramge, P. (Ed.) (1998) Untersuchungen zur Ueberwindung der Blut-Hirn-Schranke mit Hilfe von Nanopartileln, Shaker Verlag, Aachen.Google Scholar
  85. 85.
    Fenart, L., Casanova, A., Dehouck, B., Duhem, C., Slupek, S., Cecchelli, R., and Betbeder, D. (1999) Evaluation of effect of charge and lipid coating on ability of 60-nm nanoparticles to cross an in vitro model of the blood-brain barrier. J. Pharmacol. Exp. Ther. 291, 1017–1022.PubMedGoogle Scholar
  86. 86.
    Davson, H. and Segal, M.B. (Ed.) (1996) Physiology of the CSF and Blood-Brain Barriers, CRC Press, Boca Raton, FL.Google Scholar
  87. 87.
    Porter, J.B., Gyparaki, M., Burke, L.C., Huehns, E.R., Sarpong, P., Saez, V., and Hider, R.C. (1988) Iron mobilization from hepatocyte monolayer cultures by chelators: The importance of membrane permeability and the iron-binding constant. Blood, 72, 1497–1503.PubMedGoogle Scholar
  88. 88.
    Liu, G., Garrett, M.R., Men, P., Zhu, X., Perry, G., and Smith, M.A. (2005) Nanoparticle and other metal chelation therapeutics in Alzheimer disease. Biochim. Biophys. Acta, 1741, 246–252.PubMedGoogle Scholar
  89. 89.
    Liu, G., Bruenger, F.W., Miller, S.C., and Arif, A.M. (1998) Molecular structure and biological and pharmacological properties of 3-hydroxy-2-methyl-1-(beta-D-ribofuranosyl or pyranosyl)-4-pyridinone: Potential iron overload drugs for oral administration. Bioorg. Med. Chem. Lett. 8, 3077–3080.PubMedCrossRefGoogle Scholar
  90. 90.
    Liu, G., Men, P., Kenner, G.H., Miller, S.C., and Bruenger, F.W. (2004) Acyclonucleoside iron chelators of 1-(2-hydroxyethoxy)methyl-2-alkyl-3-hydroxy-4-pyridinones: Potential oral iron chelation therapeutics. Nucleosides Nucleotides Nucleic Acids, 23, 599–611.PubMedCrossRefGoogle Scholar
  91. 91.
    Liu, G., Miller, S.C., and Bruenger, F.W. (1995) Synthesis of lipophilic 3-hydroxy-2-methyl-4-pyridinone derivatives. Syn. Commun. 25, 3247–3253.CrossRefGoogle Scholar
  92. 92.
    Blunk, T., Hochstrasser, D.F., Sanchez, J.C., Muller, B.W., and Muller, R.H. (1993) Colloidal carriers for intravenous drug targeting: Plasma protein adsorption patterns on surface-modified latex particles evaluated by two-dimensional polyacrylamide gel electrophoresis. Electrophoresis, 14, 1382–1387.PubMedCrossRefGoogle Scholar
  93. 93.
    Smith, M.A., Harris, P.L., Sayre, L.M., and Perry, G. (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl. Acad. Sci. USA, 94, 9866–9868.PubMedCrossRefGoogle Scholar
  94. 94.
    Bangs Laboratories, Inc. (1999) TechNote 201, Working with microspheres.Google Scholar
  95. 95.
    Dobbin, P.S., Hider, R.C., Hall, A.D., Taylor, P.D., Sarpong, P., Porter, J.B., Xiao, G., and van der Helm, D. (1993) Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: Orally active iron chelators with clinical potential. J. Med. Chem. 36, 2448–2458.PubMedCrossRefGoogle Scholar
  96. 96.
    Liu, G., Miller, S.C., and Bruenger, F.W. (1996) Efficient synthesis of N-[2-hydroxyethoxy)methyl]-2-alkyl-3-hydroxy-4-pyridinone by a modified Hilbert-Johnson reaction. Syn. Commun. 26, 2681–2686.CrossRefGoogle Scholar
  97. 97.
    Robins, M.J. and Hatfield, P.W. (1982) Nucleic acid related compounds. 37. Convenient and high-yield synthesis of N-[(2-hydroxyethoxy)methyl] heterocycles as “acyclic nucleoside” analogues. Can. J. Chem. 60, 547–553.CrossRefGoogle Scholar
  98. 98.
    Schaeffer, H.J., Gurwara, S., Vince, R., and Bittner, S. (1971) Novel substrate of adenosine deaminase. J. Med. Chem. 14, 367–369.PubMedCrossRefGoogle Scholar
  99. 99.
    Streater, M., Taylor, P.D., Hider, R.C., and Porter, J. (1990) Novel 3-hydroxy-2(1H)-pyridinones. Synthesis, iron(III)-chelating properties, and biological activity. J. Med. Chem. 33, 1749–1755.PubMedCrossRefGoogle Scholar
  100. 100.
    Nelson, W.O., Timothy, B., Karpishin, T.B., Retting, S.J., and Orvig, C. (1988) Aluminum and gallium compounds of 3-hydroxy-4-pyridinones: Synthesis, characterization, and crystallography of biologically active complexes with unusual hydrogen bonding. Inorg. Chem. 27, 1045–1051.CrossRefGoogle Scholar
  101. 101.
    Harris, R.L.N. (1976) Potential wool growth inhibitors. Improved synthesis of mimosine and related 4(1H)-pyridones. Australian J. Chem. 29, 1329–1334.CrossRefGoogle Scholar
  102. 102.
    Sayre, L.M., Perry, G., Harris, P.L., Liu, Y., Schubert, K.A., and Smith, M.A. (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: A central role for bound transition metals. J. Neurochem. 74, 270–279.PubMedCrossRefGoogle Scholar
  103. 103.
    Liu, G., Men, P., Perry, G., and Smith, M.A. (2007) Nanoparticles for the treatment of Alzheimer’s disease: Theoretical rationale, present status and future perspectives. In: Nanomaterials for Medical Diagnosis and Therapy (Kumar, C.S.S.R., Ed.), Wiley-VCH Verlag GmbH & Co. KGaA. (Nanotechnologies for the Life Sciences) Weinheim, pp. 644–706.Google Scholar
  104. 104.
    Wong, S.S. (Ed.) (1991) Chemistry of Protein Conjugation and Cross-Linking, CRC Press, Boca Raton, Fl.Google Scholar
  105. 105.
    Arano, Y., Matsushima, H., Tagawa, M., Koizumi, M., Endo, K., Konishi, J., and Yokoyama, A. (1991) A novel bifunctional metabolizable linker for the conjugation of antibodies with radionuclides. Bioconjug. Chem. 2, 71–76.PubMedCrossRefGoogle Scholar
  106. 106.
    Anjaneyulu, P.S. and Staros, J.V. (1987) Reactions of N-hydroxysulfosuccinimide active esters. Int. J. Pept. Protein Res. 30, 117–124.PubMedCrossRefGoogle Scholar
  107. 107.
    Staros, J.V., Wright, R.W., and Swingle, D.M. (1986) Enhancement by N-hydroxysulfosuccinimide of water-soluble carbodiimide-mediated coupling reactions. Anal. Biochem. 156, 220–222.PubMedCrossRefGoogle Scholar
  108. 108.
    Kreuter, J. (2004) Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain. J. Nanosci. Nanotechnol. 4, 484–488.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Gang Liu
    • 1
  • Ping Men
    • 1
  • George Perry
    • 2
    • 3
  • Mark A. Smith
    • 2
  1. 1.Department of RadiologyUniversity of UtahSalt Lake CityUSA
  2. 2.Department of PathologyCase Western Reserve UniversityClevelandUSA
  3. 3.College of SciencesUniversity of Texas at San AntonioSan AntonioUSA

Personalised recommendations