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The Advances of Biomacromolecule-based Nanomedicine in Brain Disease

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Abstract

Brain diseases affect a sizable portion of people in the world. Various treatment modalities have been pursued to control, alleviate, or cure these disorders. Biomacromolecules, e.g., antibody, peptide, enzyme, cytokine, nucleic acid, etc., are one kind of important and promising therapeutic regimens that have forced researchers to make great efforts to realize their clinical applications. However, effective and safe systemic delivery of biomacromolecules into the brain faces diverse challenges such as insufficient drug administration, degradation in the blood, first pass clearance, physical brain barriers, off-target accumulation, immune response, and toxicity to normal tissues. Nanotechnology offers advanced strategies to address these problems through rational design and fabrication of biomacromolecule-loaded nanomedicine. In this chapter, we summarized the administration strategies to the brain and design concepts of various biomacromolecular nanomedicines, highlighted their recent advances in preclinical and clinical studies, and discussed the existing challenges and our perspectives on this field.

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References

  1. Lindsley CW, Lindsley CW, Lindsley CW. New 2016 data and statistics for global pharmaceutical products and projections through 2017. ACS Chem Neurosci. 2017;8(8):1635–6.

    Article  CAS  PubMed  Google Scholar 

  2. Alyautdin R, Khalin I, Nafeeza MI, Haron MH, Kuznetsov D. Nanoscale drug delivery systems and the blood-brain barrier. Int J Nanomedicine. 2014;9:795–811.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Azad TD, James P, Connolly ID, Austin R, Wilson CM, Grant GA. Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurg Focus. 2015;38(3):E9.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Saito R, Bringas JR, McKnight TR, Wendland MF, Mamot C, Drummond DC, Kirpotin DB, Park JW, Berger MS, Bankiewicz KS. Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res. 2004;64(7):2572–9.

    Article  CAS  PubMed  Google Scholar 

  5. Tian Y, Mi G, Chen Q, Chaurasiya B, Li Y, Shi D, Zhang Y, Webster TJ, Sun C, Shen Y. Acid-induced activated cell penetrating peptide modified cholesterol-conjugated polyoxyethylene sorbitol oleate mixed micelles for pH-triggered drug release and efficient brain tumor targeting based on a charge reversal mechanism. ACS Appl Mater Interfaces. 2018;10:43411.

    Article  CAS  PubMed  Google Scholar 

  6. Dwivedi N, Shah J, Mishra V, Mohd Amin MC, Iyer AK, Tekade RK, Kesharwani P. Dendrimer-mediated approaches for the treatment of brain tumor. J Biomater Sci Polym Ed. 2016;27(7):557–80.

    Article  CAS  PubMed  Google Scholar 

  7. Picone P, Sabatino MA, Ditta LA, Amato A, San Biagio PL, Mule F, Giacomazza D, Dispenza C, Di Carlo M. Nose-to-brain delivery of insulin enhanced by a nanogel carrier. J Control Release. 2018;270:23–36.

    Article  CAS  PubMed  Google Scholar 

  8. Elzoghby AO, Abd-Elwakil MM, Abd-Elsalam K, Elsayed MT, Hashem Y, Mohamed O. Natural polymeric nanoparticles for brain-targeting: implications on drug and gene delivery. Curr Pharm Des. 2016;22(22):3305–23.

    Article  CAS  PubMed  Google Scholar 

  9. Nigro A, Pellegrino M, Greco M, Comande A, Sisci D, Pasqua L, Leggio A, Morelli C. Dealing with skin and blood-brain barriers: the unconventional challenges of mesoporous silica nanoparticles. Pharmaceutics. 2018;10(4):E250.

    Article  PubMed  Google Scholar 

  10. Tomitaka A, Arami H, Huang Z, Raymond A, Rodriguez E, Cai Y, Febo M, Takemura Y, Nair M. Hybrid magneto-plasmonic liposomes for multimodal image-guided and brain-targeted HIV treatment. Nanoscale. 2017;10(1):184–94.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Banks WA. From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discov. 2016;15(4):275–92.

    Article  CAS  PubMed  Google Scholar 

  12. Keaney J, Campbell M. The dynamic blood-brain barrier. FEBS J. 2015;282(21):4067–79.

    Article  CAS  PubMed  Google Scholar 

  13. Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009;9(Suppl 1):S3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Hladky SB, Barrand MA. Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles. Fluids and barriers of the CNS. 2016;13(1):19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Segal MB. The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cell Mol Neurobiol. 2000;20(2):183–96.

    Article  CAS  PubMed  Google Scholar 

  16. Davson H, Hollingsworth G, Segal MB. The mechanism of drainage of the cerebrospinal fluid. Brain J Neurol. 1970;93(4):665–78.

    Article  CAS  Google Scholar 

  17. Saunders N, Habgood M. Understanding barrier mechanisms in the developing brain to aid therapy for the dysfunctional brain. Future Neurol. 2011;6(2):187–99.

    Article  Google Scholar 

  18. Spector R, Johanson CE. The mammalian choroid plexus. Sci Am. 1989;261(5):68–74.

    Article  CAS  PubMed  Google Scholar 

  19. Wang Z, Cai XJ, Qin J, Xie FJ, Han N, Lu HY. The role of histamine in opening blood-tumor barrier. Oncotarget. 2016;7(21):31299–310.

    PubMed  PubMed Central  Google Scholar 

  20. Zhou W, Chen C, Shi Y, Wu Q, Gimple RC, Fang X, Huang Z, Zhai K, Ke SQ, Ping YF, Feng H, Rich JN, Yu JS, Bao S, Bian XW. Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell Stem Cell. 2017;21(5):591–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wolak DJ, Thorne RG. Diffusion of macromolecules in the brain: implications for drug delivery. Mol Pharm. 2013;10(5):1492–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Saltzman WM, Radomsky ML. Drugs released from polymers: diffusion and elimination in brain tissue. Chem Eng Sci. 1991;46(10):2429–44.

    Article  CAS  Google Scholar 

  23. Nelson AL. Antibody fragments: hope and hype. MAbs. 2010;2(1):77–83.

    Article  PubMed  PubMed Central  Google Scholar 

  24. T. Yokota, ., D.E. Milenic, M. Whitlow, ., J. Schlom, . Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms, Cancer Res 52(12) (1992) 3402–3408.

    CAS  PubMed  Google Scholar 

  25. Jain RK. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 1990;50(3 Suppl):814s–9s.

    CAS  PubMed  Google Scholar 

  26. Lim ST, Airavaara M, Harvey BK. Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS. Pharm Res. 2010;61(1):14–26.

    Article  CAS  Google Scholar 

  27. Kamei N. Nose-to-brain delivery of peptide drugs enhanced by co-administration of cell-penetrating peptides: therapeutic potential for dementia. Yakugaku Zasshi : J Pharm Soc Jpn. 2017;137(10):1247–53.

    Article  CAS  Google Scholar 

  28. Joshi S, Cooke JRN, Ellis JA, Emala CW, Bruce JN. Targeting brain tumors by intra-arterial delivery of cell-penetrating peptides: a novel approach for primary and metastatic brain malignancy. J Neuro-Oncol. 2017;135(3):497–506.

    Article  CAS  Google Scholar 

  29. Mastakov MY, Baer K, Kotin RM, During MJ. Recombinant adeno-associated virus serotypes 2- and 5-mediated gene transfer in the mammalian brain: quantitative analysis of heparin co-infusion. Mol Ther. 2002;5(4):371–80.

    Article  CAS  PubMed  Google Scholar 

  30. Hamilton JF, Morrison PF, Chen MY, Harvey-White J, Pernaute RS, Phillips H, Oldfield E, Bankiewicz KS. Heparin coinfusion during convection-enhanced delivery (CED) increases the distribution of the glial-derived neurotrophic factor (GDNF) ligand family in rat striatum and enhances the pharmacological activity of neurturin. Exp Neurol. 2001;168(1):155–61.

    Article  CAS  PubMed  Google Scholar 

  31. Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, Atwal J, Elliott JM, Prabhu S, Watts RJ, Dennis MS. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011;3(84):84ra44.

    Article  PubMed  CAS  Google Scholar 

  32. Carcaboso AM, Elmeliegy MJ, Juel SJ, Zhang ZM, Calabrese C, Tracey L, Waters CM, Stewart CF. Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010;70(11):4499–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Doyle L, Ross DD, et al. Oncogene. 2003;22(47):7340.

    Article  PubMed  CAS  Google Scholar 

  34. Enokizono J, Kusuhara H, Ose A, Schinkel AH, Sugiyama Y. Quantitative investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) in limiting brain and testis penetration of xenobiotic compounds. Drug Metab Dispos. 2008;36(6):995.

    Article  CAS  PubMed  Google Scholar 

  35. Salama NN, Kelly EJ, Bui T, Ho RJ. The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice. J Pharm Sci. 2005;94(6):1216–25.

    Article  CAS  PubMed  Google Scholar 

  36. Wong HL, Bendayan R, Rauth AM, Wu XY. Simultaneous delivery of doxorubicin and GG918 (Elacridar) by new polymer-lipid hybrid nanoparticles (PLN) for enhanced treatment of multidrug-resistant breast cancer. J Control Release. 2006;116(3):275–84.

    Article  CAS  PubMed  Google Scholar 

  37. Glascock JJ, Osman EY, Coady TH, Rose FF, Shababi M, Lorson CL. Delivery of therapeutic agents through intracerebroventricular (ICV) and intravenous (IV) injection in mice. J Vis Exp Jove. 2010;56:e2968.

    Google Scholar 

  38. Tosi G, Musumeci T, Ruozi B, Carbone C, Belletti D, Pignatello R, Vandelli MA, Puglisi G. The “fate” of polymeric and lipid nanoparticles for brain delivery and targeting: strategies and mechanism of blood–brain barrier crossing and trafficking into the central nervous system. J Drug Delivery Sci Technol. 2016;32:66–76.

    Article  CAS  Google Scholar 

  39. Roland N, Fritz SR, Helmut E. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev. 2010;23(4):858–83.

    Article  CAS  Google Scholar 

  40. Duskey JT, Belletti D, Pederzoli F, Vandelli MA, Forni F, Ruozi B, Tosi G. Current strategies for the delivery of therapeutic proteins and enzymes to treat brain disorders. Int Rev Neurobiol. 2017;137:1–28.

    Article  PubMed  Google Scholar 

  41. Garg T, Bhandari S, Rath G, Goyal AK. Current strategies for targeted delivery of bio-active drug molecules in the treatment of brain tumor. J Drug Target. 2015;23(10):865–87.

    Article  CAS  PubMed  Google Scholar 

  42. Parrish KE, Sarkaria JN, Elmquist WF. Improving drug delivery to primary and metastatic brain tumors: strategies to overcome the blood-brain barrier. Clin Pharmacol Ther. 2015;97(4):336–46.

    Article  CAS  PubMed  Google Scholar 

  43. R.H. Bobo, D.W. Laske, A. Akbasak, ., P.F. Morrison, R.L. Dedrick, E.H. Oldfield, Convection-enhanced delivery of macromolecules in the brain, Proc Natl Acad Sci U S A 91(6) (1994) 2076–2080.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Raghu R, Brady ML, Andreas H, Christoph P, Sampson JH. Convection-enhanced delivery of therapeutics for brain disease, and its optimization. Neurosurg Focus. 2006;20(4):E12.

    Article  Google Scholar 

  45. Barua NU, Gill SS, Seth L. Convection-enhanced drug delivery to the brain: therapeutic potential and neuropathological considerations. Brain Pathol. 2014;24(2):117–27.

    Article  CAS  PubMed  Google Scholar 

  46. Betbeder D, Spérandio S, Latapie JP, Nadaí JD, Etienne A, Zajac JM, Francés B. Biovector™ nanoparticles improve Antinociceptive efficacy of nasal morphine. Pharm Res. 2000;17(6):743–8.

    Article  CAS  PubMed  Google Scholar 

  47. Illum L. Is nose-to-brain transport of drugs in man a reality? J Pharm Pharmacol. 2010;56(1):3–17.

    Article  CAS  Google Scholar 

  48. Xiaoling G, Weixing T, Wei L, Qizhi Z, Yan Z, Xinguo J, Shoukuan F. Lectin-conjugated PEG-PLA nanoparticles: preparation and brain delivery after intranasal administration. Biomaterials. 2006;27(18):3482–90.

    Article  CAS  Google Scholar 

  49. Ruan Y, Yao L, Zhang B, Zhang S, Guo J. Nanoparticle-mediated delivery of neurotoxin-II to the brain with intranasal administration: an effective strategy to improve antinociceptive activity of neurotoxin. Drug Dev Ind Pharm. 2012;38(1):123–8.

    Article  CAS  PubMed  Google Scholar 

  50. Kumar M, Pandey RS, Patra KC, Jain SK, Soni ML, Dangi JS, Madan J. Evaluation of neuropeptide loaded trimethyl chitosan nanoparticles for nose to brain delivery. Int J Biol Macromol. 2013;61(10):189–95.

    Article  CAS  PubMed  Google Scholar 

  51. Alsarra IA, Hamed AY, Alanazi FK, Maghraby GME. Vesicular Systems for Intranasal Drug Delivery. NeuroMethods. 2010;45:175–203.

    Article  CAS  Google Scholar 

  52. Hongbing W, Kaili H, Xinguo J. From nose to brain: understanding transport capacity and transport rate of drugs. Expert Opin Drug Deliv. 2008;5(10):1159–68.

    Article  Google Scholar 

  53. Siew A, Le H, Thiovolet M, Gellert P, Schatzlein A, Uchegbu I. Enhanced oral absorption of hydrophobic and hydrophilic drugs using quaternary ammonium palmitoyl glycol chitosan nanoparticles. Mol Pharm. 2012;9(1):14–28.

    Article  CAS  PubMed  Google Scholar 

  54. Chooi KW, Carlos MIS, Soundararajan R, Gaisford S, Arifin N, Schätzlein AG, Uchegbu IF. Physical characterisation and Long-term stability studies on quaternary ammonium Palmitoyl glycol chitosan (GCPQ)—a new drug delivery polymer. J Pharm Sci. 2014;103(8):2296–306.

    Article  CAS  PubMed  Google Scholar 

  55. Lalatsa A, Garrett NL, Ferrarelli T, Moger J, Schatzlein AG, Uchegbu IF. Delivery of peptides to the blood and brain after oral uptake of quaternary ammonium palmitoyl glycol chitosan nanoparticles. Mol Pharm. 2012;9(6):1764–74.

    Article  CAS  PubMed  Google Scholar 

  56. S. Nakano, ., K. Matsukado, ., K.L. Black, Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide, Cancer Res 56(17) (1996) 4027–4031.

    CAS  PubMed  Google Scholar 

  57. E.A. Neuwelt, M. Glasberg, ., J. Diehl, ., E.P. Frenkel, P. Barnett, . Osmotic blood-brain barrier disruption in the posterior fossa of the dog, J Neurosurg 55(5) (1981) 742–748.

    Article  CAS  PubMed  Google Scholar 

  58. John BA, Apostolos TJ, Christoph HP, Ilhami K, Sherese F, Kartik K, Stephen SM, Susan PC, Theodore SH, Philip S. Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article. J Neurosurg. 2011;114(3):624.

    Article  CAS  Google Scholar 

  59. G. Nilaver, ., L.L. Muldoon, R.A. Kroll, M.A. Pagel, X.O. Breakefield, B.L. Davidson, E.A. Neuwelt, Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption, Proc Natl Acad Sci U S A 92(21) (1995) 9829–9833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. K. Matsukado, ., T. Inamura, ., S. Nakano, ., M. Fukui, ., R.T. Bartus, K.L. Black, Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7, Neurosurgery 39(1) (1996) 125–133.

    Article  CAS  PubMed  Google Scholar 

  61. Nickolai S, Nathan MD, Shipra S, Kullervo H. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008;34(7):1093–104.

    Article  Google Scholar 

  62. Park J, Aryal M, Vykhodtseva N, Zhang YZ, Mcdannold N. Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption. J Control Release. 2017;250:77–85.

    Article  CAS  PubMed  Google Scholar 

  63. Alison B, Kullervo H. Noninvasive and targeted drug delivery to the brain using focused ultrasound. ACS Chem Neurosci. 2013;4(4):519.

    Article  CAS  Google Scholar 

  64. Yao L, Song Q, Bai W, Zhang J, Miao D, Jiang M, Wang Y, Shen Z, Hu Q, Gu X. Facilitated brain delivery of poly (ethylene glycol)-poly (lactic acid) nanoparticles by microbubble-enhanced unfocused ultrasound. Biomaterials. 2014;35(10):3384–95.

    Article  CAS  PubMed  Google Scholar 

  65. Hao-Li L, Mu-Yi H, Hung-Wei Y, Chiung-Yin H, Po-Chun C, Jia-Shin W, I-Chou T, Jiun-Jie W, Tzu-Chen Y, Pin-Yuan C. Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci U S A. 2010;107(34):15205–10.

    Article  Google Scholar 

  66. Jeffrey LJ, Robert TG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–28.

    Article  CAS  Google Scholar 

  67. Lalatsa A, Schatzlein AG, Uchegbu IF. Strategies to deliver peptide drugs to the brain. Mol Pharm. 2014;11(4):1081–93.

    Article  CAS  PubMed  Google Scholar 

  68. Visser CC, Voorwinden LH, Crommelin DJ, Danhof M, de Boer AG. Characterization and modulation of the transferrin receptor on brain capillary endothelial cells. Pharm Res. 2004;21(5):761–9.

    Article  CAS  PubMed  Google Scholar 

  69. Pardridge WM, Boado RJ. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. 2012;503:269–92.

    Article  CAS  PubMed  Google Scholar 

  70. Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sun H, Su J, Meng Q, Yin Q, Chen L, Gu W, Zhang P, Zhang Z, Yu H, Wang S. Cancer-cell-biomimetic nanoparticles for targeted therapy of homotypic tumors. Adv Mater. 2016;28(43):9581–8.

    Article  CAS  PubMed  Google Scholar 

  72. Luk BT, Jiang Y, Copp JA, Hu CJ, Krishnan N, Gao W, Li S, Fang RH, Zhang L. Biomimetic targeting of nanoparticles to immune cell subsets via cognate antigen interactions. Mol Pharm. 2018;15:3723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Taurin S, Nehoff H, Aswegen TV, Greish K. Tumor vasculature, EPR effect, and anticancer nanomedicine: connecting the dots. In: Cancer targeted drug delivery: an elusive dream. New York: Springer; 2013.

    Google Scholar 

  74. Maedaa H, Daruwalla J. Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur J Pharm Biopharm. 2009;71(3):409–19.

    Article  CAS  Google Scholar 

  75. Yi X, Kabanov AV. Brain delivery of proteins via their fatty acid and block copolymer modifications. J Drug Target. 2013;21(10):940–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kinstler O, Molineux G, Treuheit M, Ladd D, Gegg C. Mono-N-terminal poly(ethylene glycol)–protein conjugates. Adv Drug Deliv Rev. 2002;54(4):477–85.

    Article  CAS  PubMed  Google Scholar 

  77. Lei T, Jingquan L, Davis TP. Branched polymer-protein conjugates made from mid-chain-functional P(HPMA). Biomacromolecules. 2009;10(10):2847–51.

    Article  CAS  Google Scholar 

  78. Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release. 2008;132(3):171–83.

    Article  CAS  PubMed  Google Scholar 

  79. Wilson B, Lavanya Y, Priyadarshini SR, Ramasamy M, Jenita JL. Albumin nanoparticles for the delivery of gabapentin: preparation, characterization and pharmacodynamic studies. Int J Pharm. 2014;473(1–2):73–9.

    Article  CAS  PubMed  Google Scholar 

  80. Tarun G, Animesh K, Goutam R, Goyal AK. Gastroretentive drug delivery systems for therapeutic management of peptic ulcer. Crit Rev Ther Drug Carrier Syst. 2014;31(6):531–57.

    Article  Google Scholar 

  81. Green MR, Manikhas GS, Afanasyev B, Makhson AM, Bhar P, Hawkins MJ. Abraxane, a novel Cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol. 2006;17(8):1263–8.

    Article  CAS  PubMed  Google Scholar 

  82. Lin T, Zhao P, Jiang Y, Tang Y, Jin H, Pan Z, He H, Yang VC, Huang Y. Blood–brain-barrier-penetrating albumin nanoparticles for biomimetic drug delivery via albumin-binding protein pathways for antiglioma therapy. ACS Nano. 2016;10(11):9999–10012.

    Article  CAS  PubMed  Google Scholar 

  83. Blaire OL, Henrik OS, Bernardetta N, James MH, Joe ZXH, Andrew G, Gordon M, Liubov ZS, Cynthia S. Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther. 2002;303(2):540–8.

    Article  CAS  Google Scholar 

  84. Balan V, Sulkowski M, Nelson D, Everson G, Bambury T, Recta J, Zhong J, Mesghali H, Murray J, Osborn B. 313 A 1/2phase study to evaluate the pharmacokinetics, safety, tolerability, immunogenicity, and pharmacodynamics of Albuferon™ in the treatment experienced subjects with chronic hepatitis C. Hepatology. 2003;38(5):307.

    Article  Google Scholar 

  85. Yun X, Maximov VD, Yu J, Zhu G, Vertegel AA, Kindy MS. Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury. J Cereb Blood Flow Metab. 2013;33(4):583–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhao YZ, Lin M, Lin Q, Yang W, Yu XC, Tian FR, Mao KL, Yang JJ, Lu CT, Wong HL. Intranasal delivery of bFGF with nanoliposomes enhances in vivo neuroprotection and neural injury recovery in a rodent stroke model. J Control Release. 2016;224:165–75.

    Article  CAS  PubMed  Google Scholar 

  87. Wang X, Bodman A, Shi C, Guo D, Wang L, Luo J, Hall WA. Tunable Lipidoid-Telodendrimer hybrid nanoparticles for intracellular protein delivery in brain tumor treatment. Small. 2016;12(31):4185–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. K. Michaelis, ., M.M. Hoffmann, S. Dreis, ., E. Herbert, ., R.N. Alyautdin, M. Michaelis, ., J. Kreuter, ., K. Langer, . Covalent linkage of apolipoprotein e to albumin nanoparticles strongly enhances drug transport into the brain, J Pharmacol Exp Ther 317(3) (2006) 1246.

    Article  CAS  PubMed  Google Scholar 

  89. Abakumov MA, Nukolova NV, Sokolsky-Papkov M, Shein SA, Sandalova TO, Vishwasrao HM, Grinenko NF, Gubsky IL, Abakumov AM, Kabanov AV, Chekhonin VP. VEGF-targeted magnetic nanoparticles for MRI visualization of brain tumor. Nanomedicine. 2015;11(4):825–33.

    Article  CAS  PubMed  Google Scholar 

  90. Spencer B, Emadi S, Desplats P, Eleuteri S, Michael S, Kosberg K, Shen J, Rockenstein E, Patrick C, Adame A, Gonzalez T, Sierks M, Masliah E. ESCRT-mediated uptake and degradation of brain-targeted alpha-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol Ther. 2014;22(10):1753–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chaturvedi M, Molino Y, Sreedhar B, Khrestchatisky M, Kaczmarek L. Tissue inhibitor of matrix metalloproteinases-1 loaded poly(lactic-co-glycolic acid) nanoparticles for delivery across the blood-brain barrier. Int J Nanomedicine. 2014;9:575–88.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Liu Z, Jiang M, Kang T, Miao D, Gu G, Song Q, Yao L, Hu Q, Tu Y, Pang Z, Chen H, Jiang X, Gao X, Chen J. Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration. Biomaterials. 2013;34(15):3870–81.

    Article  CAS  PubMed  Google Scholar 

  93. Chertok B, David AE, Yang VC. Delivery of functional proteins to brain tumor using MRI-monitored, magnetically-targeted nanoparticles. J Control Release. 2008;132(3):e61–2.

    Article  CAS  Google Scholar 

  94. Lindqvist A, Rip J, Gaillard PJ, Bjorkman S, Hammarlund-Udenaes M. Enhanced brain delivery of the opioid peptide DAMGO in glutathione pegylated liposomes: a microdialysis study. Mol Pharm. 2013;10(5):1533–41.

    Article  CAS  PubMed  Google Scholar 

  95. Zhao Y, Haney MJ, Mahajan V, Reiner BC, Dunaevsky A, Mosley RL, Kabanov AV, Gendelman HE, Batrakova EV. Active targeted macrophage-mediated delivery of catalase to affected brain regions in models of Parkinson’s disease. J Nanosci Nanotechnol. 2011;01:S4.

    Google Scholar 

  96. Morris MC, Deshayes S, Heitz F, Divita G. Cell-penetrating peptides: from molecular mechanisms to therapeutics. Biol Cell. 2008;100(4):201–17.

    Article  CAS  PubMed  Google Scholar 

  97. Eiriksdottir E, Konate K, Langel U, Divita G, Deshayes S. Secondary structure of cell-penetrating peptides controls membrane interaction and insertion. Biochim Biophys Acta. 2010;1798(6):1119–28.

    Article  CAS  PubMed  Google Scholar 

  98. Herve F, Ghinea N, Scherrmann JM. CNS delivery via adsorptive transcytosis. AAPS J. 2008;10(3):455–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, Lee SK, Shankar P, Manjunath N. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448(7149):39–43.

    Article  CAS  PubMed  Google Scholar 

  100. Park TE, Singh B, Li H, Lee JY, Kang SK, Choi YJ, Cho CS. Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer’s disease. Biomaterials. 2015;38:61–71.

    Article  CAS  PubMed  Google Scholar 

  101. Haroon MM, Dar GH, Jeyalakshmi D, Venkatraman U, Saba K, Rangaraj N, Patel AB, Gopal V. A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain. J Control Release. 2016;228:120–31.

    Article  CAS  PubMed  Google Scholar 

  102. Kim JY, Choi WI, Kim YH, Tae G. Brain-targeted delivery of protein using chitosan- and RVG peptide-conjugated, pluronic-based nano-carrier. Biomaterials. 2013;34(4):1170–8.

    Article  CAS  PubMed  Google Scholar 

  103. Demeule M, Currie JC, Bertrand Y, Che C, Nguyen T, Regina A, Gabathuler R, Castaigne JP, Beliveau R. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem. 2008;106(4):1534–44.

    Article  CAS  PubMed  Google Scholar 

  104. Bertrand Y, Currie JC, Demeule M, Regina A, Che C, Abulrob A, Fatehi D, Sartelet H, Gabathuler R, Castaigne JP, Stanimirovic D, Beliveau R. Transport characteristics of a novel peptide platform for CNS therapeutics. J Cell Mol Med. 2010;14(12):2827–39.

    Article  CAS  PubMed  Google Scholar 

  105. Thomas FC, Kunal T, Vinay R, Satyanarayana G, Thorsheim HR, Gaasch JA, Mittapalli RK, Diane P, Steeg PS, Lockman PR. Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res. 2009;26(11):2486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Regina A, Demeule M, Che C, Lavallee I, Poirier J, Gabathuler R, Beliveau R, Castaigne JP. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol. 2008;155(2):185–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Hao Y, Zhang B, Zheng C, Ji R, Ren X, Guo F, Sun S, Shi J, Zhang H, Zhang Z, Wang L, Zhang Y. The tumor-targeting core-shell structured DTX-loaded PLGA@Au nanoparticles for chemo-photothermal therapy and X-ray imaging. J Control Release. 2015;220(Pt A):545–55.

    Article  CAS  PubMed  Google Scholar 

  108. Huang R, Ma H, Guo Y, Liu S, Kuang Y, Shao K, Li J, Liu Y, Han L, Huang S, An S, Ye L, Lou J, Jiang C. Angiopep-conjugated nanoparticles for targeted long-term gene therapy of Parkinson’s disease. Pharm Res. 2013;30(10):2549–59.

    Article  CAS  PubMed  Google Scholar 

  109. Yan H, Wang L, Wang J, Weng X, Lei H, Wang X, Jiang L, Zhu J, Lu W, Wei X, Li C. Two-order targeted brain tumor imaging by using an optical/paramagnetic nanoprobe across the blood brain barrier. ACS Nano. 2012;6(1):410–20.

    Article  CAS  PubMed  Google Scholar 

  110. S. Zhang, ., T. Holmes, ., C. Lockshin, ., A. Rich, . Spontaneous assembly of a self-complementary oligopeptide to form a stable macroscopic membrane, Proc Natl Acad Sci U S A 90(8) (1993) 3334–3338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ulijn RV, Smith AM. Designing peptide based nanomaterials. Chem Soc Rev. 2008;37(4):664–75.

    Article  CAS  PubMed  Google Scholar 

  112. Zhang S, Marini DM, Hwang W, Santoso S. Design of nanostructured biological materials through self-assembly of peptides and proteins. Curr Opin Chem Biol. 2002;6(6):865–71.

    Article  PubMed  Google Scholar 

  113. Mazza M, Notman R, Anwar J, Rodger A, Hicks M, Parkinson G, McCarthy D, Daviter T, Moger J, Garrett N, Mead T, Briggs M, Schatzlein AG, Uchegbu IF. Nanofiber-based delivery of therapeutic peptides to the brain. ACS Nano. 2013;7(2):1016–26.

    Article  CAS  PubMed  Google Scholar 

  114. Pang Z, Lu W, Gao H, Hu K, Chen J, Zhang C, Gao X, Jiang X, Zhu C. Preparation and brain delivery property of biodegradable polymersomes conjugated with OX26. J Control Release. 2008;128(2):120–7.

    Article  CAS  PubMed  Google Scholar 

  115. Aktas Y, Yemisci M, Andrieux K, Gursoy RN, Alonso MJ, Fernandez-Megia E, Novoa-Carballal R, Quinoa E, Riguera R, Sargon MF, Celik HH, Demir AS, Hincal AA, Dalkara T, Capan Y, Couvreur P. Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26. Bioconjug Chem. 2005;16(6):1503–11.

    Article  CAS  PubMed  Google Scholar 

  116. Yue PJ, He L, Qiu SW, Li Y, Liao YJ, Li XP, Xie D, Peng Y. OX26/CTX-conjugated PEGylated liposome as a dual-targeting gene delivery system for brain glioma. Mol Cancer. 2014;13(1):191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Shi N, Zhang Y, Zhu C, Boado RJ, Pardridge WM. Brain-specific expression of an exogenous gene after i.v. administration. Proc Natl Acad Sci U S A. 2001;98(22):12754–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Battaglia L, Gallarate M, Peira E, Chirio D, Solazzi I, Giordano SM, Gigliotti CL, Riganti C, Dianzani C. Bevacizumab loaded solid lipid nanoparticles prepared by the coacervation technique: preliminary in vitro studies. Nanotechnology. 2015;26(25):255102.

    Article  PubMed  CAS  Google Scholar 

  119. Carradori D, Balducci C, Re F, Brambilla D, Le Droumaguet B, Flores O, Gaudin A, Mura S, Forloni G, Ordonez-Gutierrez L, Wandosell F, Masserini M, Couvreur P, Nicolas J, Andrieux K. Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer’s disease-like transgenic mouse model. Nanomedicine. 2018;14(2):609–18.

    Article  CAS  PubMed  Google Scholar 

  120. Giovanni T, Luca B, Barbara R, Anna Valeria V, Lucia B, Anna F, Francesco R, Flavio F, Maria Angela V. Can leptin-derived sequence-modified nanoparticles be suitable tools for brain delivery? Nanomedicine. 2012;7(3):365–82.

    Article  CAS  Google Scholar 

  121. Ruan S, Yuan M, Zhang L, Hu G, Chen J, Cun X, Zhang Q, Yang Y, He Q, Gao H. Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles. Biomaterials. 2015;37:425–35.

    Article  CAS  PubMed  Google Scholar 

  122. Ruan S, Qian J, Shen S, Chen J, Zhu J, Jiang X, He Q, Yang W, Gao H. Fluorescent carbonaceous nanodots for noninvasive glioma imaging after angiopep-2 decoration. Bioconjug Chem. 2014;25(12):2252–9.

    Article  CAS  PubMed  Google Scholar 

  123. Tang SC, Bates S, Kesari S, Brenner AJ, Anders CK, Garcia A, Ibrahim NK, Tkaczuk K, Kumthekar P. Abstract P6-17-04: A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases. Cancer Res. 2016;76(4 Supplement):P6-17-04.

    Google Scholar 

  124. Yong L, Pan Y, Shi Y, Huang X, Jia N, Jiang J. Delivery of large molecules via poly(butyl cyanoacrylate) nanoparticles into the injured rat brain. Nanotechnology. 2012;23(23):165101.

    Google Scholar 

  125. Vinzant N, Scholl JL, Wu CM, Kindle T, Koodali R, Forster GL. Iron oxide nanoparticle delivery of peptides to the brain: reversal of anxiety during drug withdrawal. Front Neurosci. 2017;11:608.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Mamot C, Drummond DC, Noble CO, Kallab V, Guo Z, Hong K, Kirpotin DB, Park JW. Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo. Cancer Res. 2005;65(24):11631–8.

    Article  CAS  PubMed  Google Scholar 

  127. Muthusamy J, Ansell SM, Mui BL, Tam KY, Jianxin C, Xinyao D, David B, Laxman E, Shigeo M, Narayanannair JK. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem. 2012;51(34):8529–33.

    Article  CAS  Google Scholar 

  128. Wei L, Guo XY, Yang T, Yu MZ, Chen DW, Wang JC. Brain tumor-targeted therapy by systemic delivery of siRNA with transferrin receptor-mediated core-shell nanoparticles. Int J Pharm. 2016;510(1):394–405.

    Article  CAS  PubMed  Google Scholar 

  129. Rungta RL, Choi HB, Lin PJ, Ko RW, Ashby D, Nair J, Manoharan M, Cullis PR, Macvicar BA. Lipid nanoparticle delivery of siRNA to silence neuronal gene expression in the brain. Mol Ther–Nucleic Acids. 2013;2(12):e136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Dwarki VJ, Malone RW, Verma IM, Wu R. Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci U S A. 1989;86(16):6077–81.

    Article  Google Scholar 

  131. Kwok A. The challenges and current advances in delivering RNAi as therapeutics. Berlin/Heidelberg: Springer; 2013.

    Book  Google Scholar 

  132. Jiehua Z, Shum KT, Burnett JC, Rossi JJ. Nanoparticle-based delivery of RNAi therapeutics: Progress and challenges. Pharmaceuticals. 2013;6(1):85–107.

    Article  CAS  Google Scholar 

  133. Zheng M, Tao W, Zou Y, Farokhzad OC, Shi B. Nanotechnology-based strategies for siRNA brain delivery for disease therapy. Trends Biotechnol. 2018;36(5):562–75.

    Article  CAS  PubMed  Google Scholar 

  134. Dalby B, Cates S, Harris A, Ohki EC, Tilkins ML, Price PJ, Ciccarone VC. Advanced transfection with Lipofectamine 2000 reagent: primary neurons, siRNA, and high-throughput applications. Methods. 2004;33(2):95–103.

    Article  CAS  PubMed  Google Scholar 

  135. Julia B, Meng D, Sebastian T, Kamilla P, Elke K, Godehard F, Ulrich S, Claus-Michael L, Ulrich K, Mürdter TE. Efficient telomerase inhibition in human non-small cell lung cancer cells by liposomal delivery of 2′-O-methyl-RNA. J Pharm Sci. 2010;98(5):1765–74.

    Google Scholar 

  136. Xingfang S, Jennifer F, Kavanagh DG, Irvine DJ. In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles. Mol Pharm. 2011;8(3):774–87.

    Article  CAS  Google Scholar 

  137. Kormann MSD, Günther H, Aneja MK, Gabriela N, Flemmer AW, Susanne HJ, Marceline H, Mays LE, Marta I, Andrea S. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol. 2011;29(2):154–7.

    Article  CAS  PubMed  Google Scholar 

  138. Thess A, Grund S, Mui BL, Hope MJ, Baumhof P, Fotin-Mleczek M, Schlake T. Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol Ther. 2015;23(9):1456–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Gomesdasilva LC, Fonseca NA, Moura V, Mc PDL, Simões S, Moreira JN. Lipid-based nanoparticles for siRNA delivery in cancer therapy: paradigms and challenges. Acc Chem Res. 2012;45(7):1163.

    Article  CAS  Google Scholar 

  140. Joppi R, Bertele V, Garattini S. Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU. Eur J Clin Pharmacol. 2013;69(4):1009–24.

    Article  PubMed  Google Scholar 

  141. Yang ZZ, Li JQ, Wang ZZ, Dong DW, Qi XR. Tumor-targeting dual peptides-modified cationic liposomes for delivery of siRNA and docetaxel to gliomas. Biomaterials. 2014;35(19):5226–39.

    Article  CAS  PubMed  Google Scholar 

  142. Keam SJ. Inotersen: first global approval. Drugs. 2018;78:1–6.

    Article  CAS  Google Scholar 

  143. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22–31.

    Article  CAS  PubMed  Google Scholar 

  144. Yurek DM, Flectcher AM, Kowalczyk TH, Padegimas L, Cooper MJ. Compacted DNA nanoparticle gene transfer of GDNF to the rat striatum enhances the survival of grafted fetal dopamine neurons. Cell Transplant. 2009;18(10):1183–96.

    Article  PubMed  Google Scholar 

  145. Yurek DM, Hasselrot U, Cass WA, Sesenoglu-Laird O, Padegimas L, Cooper MJ. Age and lesion-induced increases of GDNF transgene expression in brain following intracerebral injections of DNA nanoparticles. Neuroscience. 2015;284:500–12.

    Article  CAS  PubMed  Google Scholar 

  146. Ugur S, Katalin K, Türeci Ö. mRNA-based therapeutics--developing a new class of drugs. Nat Rev Drug Discov. 2014;13(10):759–80.

    Article  CAS  Google Scholar 

  147. Kreiter S, Diken M, Selmi A, Türeci Ö, Sahin U. Tumor vaccination using messenger RNA: prospects of a future therapy. Curr Opin Immunol. 2011;23(3):399–406.

    Article  CAS  PubMed  Google Scholar 

  148. Axel H, Doris C, Jens D, Donna Y, Maurice MA, Lallas CD, Philipp D, Donna N, Eli G, Johannes V. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Investig. 2002;109(3):409–17.

    Article  Google Scholar 

  149. Geall AJ, Mandl CW, Ulmer JB. RNA: the new revolution in nucleic acid vaccines. Semin Immunol. 2013;25(2):152–9.

    Article  CAS  PubMed  Google Scholar 

  150. Wong HL, Wu XY, Bendayan R. Nanotechnological advances for the delivery of CNS therapeutics. Adv Drug Deliv Rev. 2012;64(7):686–700.

    Article  CAS  PubMed  Google Scholar 

  151. Hussain SM, Javorina AM, Schrand AK, Duhart HM, Ali SF, Schlager JJ. The interaction of manganese nanoparticles with PC-12 cells induces dopamine depletion. Toxicol Sci. 2006;92(2):456–63.

    Article  CAS  PubMed  Google Scholar 

  152. Wang J, Rahman MF, Duhart HM, Newport GD, Patterson TA, Murdock RC, Hussain SM, Schlager JJ, Ali SF. Expression changes of dopaminergic system-related genes in PC12 cells induced by manganese, silver, or copper nanoparticles. Neurotoxicology. 2009;30(6):926–33.

    Article  PubMed  CAS  Google Scholar 

  153. Hu YL, Gao JQ. Potential neurotoxicity of nanoparticles. Int J Pharm. 2010;394(1):115–21.

    Article  CAS  PubMed  Google Scholar 

  154. Wu J, Wang C, Sun J, Xue Y. Neurotoxicity of silica nanoparticles: brain localization and dopaminergic neurons damage pathways. ACS Nano. 2011;5(6):4476–89.

    Article  CAS  PubMed  Google Scholar 

  155. Xiaoyong D, Qixia L, Wenting C, Yanli W, Minghong W, Haijiao Z, Zheng J. Nanosized zinc oxide particles induce neural stem cell apoptosis. Nanotechnology. 2009;20(11):115101.

    Article  CAS  Google Scholar 

  156. Long TC, Saleh N, Tilton RD, Lowry GV, Veronesi B. Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. Environ Sci Technol. 2006;40(14):4346–52.

    Article  CAS  PubMed  Google Scholar 

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Weng, Y., Huang, Y. (2019). The Advances of Biomacromolecule-based Nanomedicine in Brain Disease. In: Xue, X. (eds) Nanomedicine in Brain Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-13-8731-9_7

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