Brain-targeted nanoparticles to overcome the blood-brain barrier

Abstract

The blood-brain barrier is one of the most complicated barrier to pass for therapeutic drugs. Because of the structure of the blood-brain barrier, only a few small molecules with appropriate lipophilicity, molecular weight, and charge can penetrate through the blood-brain barrier and pass in the central nervous system. Because of this unique property, blood-brain barrier is still a major problem for the treatment of central nervous system diseases. In the last decades, many strategies to overcome this barrier have been investigated. Compared to other drug delivery strategies, due to the reduced side effects and no requirement for surgical operations, brain targeted nanoparticle is one the most promising and popular strategy used do deliver drugs to the brain. Many in vitro and in vivo preclinical studies have been conducted to determine optimum brain targeted nanoparticles. These studies were reported that characteristics of nanoparticles such as particle size, zeta potential, and targeting ligand are critical to achieving the goals. In this review, first of all, the structure of the blood-brain barrier and possible causes of blood-brain barrier disruption were summarized. Later, previous strategies of brain targeted drug delivery and characteristic prosperities for optimized brain-targeted nanoparticles were evaluated. Moreover, different strategies, such as focus ultrasound, which can increase the effectiveness of nanoparticular system applications, are mentioned.

Keywords

• Brain Targeting,Nanoparticles,Particle Size,The Blood-Brain Barrier,Zeta Potential

References

1. [1] Ribatti D, Nico B, Crivellato E, Artico M. Development of the blood- brain barrier: a historical point of view. Anat Rec (Part B: New Anat). (2006); 289(1): 3-8. https://doi.org/10.1002/ar.b.20087
2. [2] el-Bacha RS, Minn A. Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell Mol Biol (Noisy le grand). (1999); 45(1): 15-23.
3. [3] Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, Evans DA. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N Engl J Med. (1996); 334(2): 71-76. https://doi.org/10.1056/nejm199601113340202
4. [4] Ott A, Breteler MMB, van Harskamp F, Claus JJ, van der Cammen TJM, Grobbee DE, Hofman A. Prevalence of Alzheimer's disease and vascular dementia: association with education. The Rotterdam study. BMJ. (1995); 310(6985): 970-973. https://doi.org/10.1136/bmj.310.6985.970
5. [5] Hedden T, Gabrieli JD. Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci. (2004); 5(2): 87-96. https://doi.org/10.1038/nrn1323
6. [6] Pardridge WM. Alzheimer's disease drug development and the problem of the blood-brain barrier. Alzheimers Dement. (2009); 5(5): 427-432. https://doi.org/10.1016/j.jalz.2009.06.003
7. [7] Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. (2007); 13(6): 1663-1674. https://doi.org/10.1158/1078-0432.CCR-06-2854
8. [8] Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release. (2012); 161 (2): 264-273. https://doi.org/10.1016/j.jconrel.2011.08.017

9. [9] Vyas TK, Shahiwala A, Amiji MM. Improved oral bioavailability and brain transport of Saquinavir upon administration in novel nanoemulsion formulations. Int J Pharm. (2008); 347(1): 93-101. https://doi.org/10.1016/j.ijpharm.2007.06.016
10. [10] Pardridge WM. Molecular Trojan horses for blood-brain barrier drug delivery. Curr Opin Pharmacol. (2006); 6(5): 494-500. https://doi.org/10.1016/j.coph.2006.06.001
11. [11] Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. (2005); 57(2): 173-185. https://doi.org/10.1124/pr.57.2.4
12. [12] He Q, Liu J, Liang J, Liu X, Li W, Liu Z, Ding Z, Tuo D. Towards improvements for penetrating the blood-brain barrier-recent progress from a material and pharmaceutical perspective. Cells. (2018); 7(4). https://doi.org/10.3390/cells7040024
13. [13] Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. (2015); 7(1). https://doi.org/10.1101/cshperspect.a020412
14. [14] Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell. (2015); 163(5): 1064- 1078. https://doi.org/10.1016/j.cell.2015.10.067
15. [15] Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. (2018); 14(3): 133-150. https://doi.org/10.1038/nrneurol.2017.188
16. [16] Kolarova H, Ambruzova B, Svihalkova Sindlerova L, Klinke A, Kubala L. Modulation of endothelial glycocalyx structure under inflammatory conditions. Mediators Inflamm. (2014); 2014: 694312. https://doi.org/10.1155/2014/694312
17. [17] Kutuzov N, Flyvbjerg H, Lauritzen M. Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood -brain barrier. PNAS. (2018); 115(40): E9429-E9438. https://doi.org/10.1073/pnas.1802155115
18. [18] Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci. (2004); 5(5): 347-360. https://doi.org/10.1038/nrn1387
19. [19] Zhao H, Zheng T, Yang X, Fan M, Zhu L, Liu S, Wu L, Sun C. Cryptotanshinone attenuates oxygen-glucose deprivation / recovery- induced injury in an in vitro model of neurovascular unit. Front Neurolb. (2019); 10: 381-381. https://doi.org/10.3389/fneur.2019.00381
20. [20] Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonniere L, Bernard M, van Horssen J, de Vries HE, Charron F, Prat A. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science. (2011); 334(6063): 1727-1731. https://doi.org/10.1126/science.1206936
21. [21] Fisher Mark J. Brain regulation of thrombosis and hemostasis. Stroke. (2013); 44(11): 3275-3285. https://doi.org/10.1161/STROKEAHA.113.000736
22. [22] Gaengel K, Genove G, Armulik A, Betsholtz C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol. (2009); 29(5): 630-638. https://doi.org/10.1161/atvbaha.107.161521
23. [23] Park DY, Lee J, Kim J, Kim K, Hong S, Han S, Kubota Y, Augustin HG, Ding L, Kim JW, Kim H, He Y, Adams RH, Koh GY. Plastic roles of pericytes in the blood-retinal barrier. Nat Commun. (2017); 8: 15296. https://doi.org/10.1038/ncomms15296
24. [24] Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-beta. J Neurosci. (2012); 32(46): 16458-16465. https://doi.org/10.1523/jneurosci.3987-12.2012
25. [25] Bickel U, Yoshikawa T, Pardridge WM. Delivery of peptides and proteins through the blood-brain barrier. Adv Drug Deliv Rev. (2001); 46(1): 247-279. https://doi.org/10.1016/S0169-409X(00)00139-3
26. [26] Andreone BJ, Chow BW, Tata A, Lacoste B, Ben-Zvi A, Bullock K, Deik AA, Ginty DD, Clish CB, Gu C. Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron. (2017); 94(3): 581-594. https://doi.org/10.1016/j.neuron.2017.03.043
27. [27] Salvador E, Burek M, Förster CY. Tight junctions and the tumor microenvironment. Curr Pathobiol Rep. (2016); 4: 135-145. https://doi.org/10.1007/s40139-016-0106-6
28. [28] Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh ELK, Silver DL. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. (2014); 509(7501): 503-506. https://doi.org/10.1038/nature13241
29. [29] Alakbarzade V, Hameed A, Quek DQY, Chioza BA, Baple EL, Cazenave-Gassiot A, Nguyen LN, Wenk MR, Ahmad AQ, Sreekantan-Nair A, Weedon MN, Rich P, Patton MA, Warner TT, Silver DL, Crosby AH. A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome. Nat Gen. (2015); 47(7): 814-817. https://doi.org/10.1038/ng.3313
30. [30] Guemez-Gamboa A, Nguyen LN, Yang H, Zaki MS, Kara M, Ben- Omran T, Akizu N, Rosti RO, Rosti B, Scott E, Schroth J, Copeland B, Vaux KK, Cazenave-Gassiot A, Quek DQY, Wong BH, Tan BC, Wenk MR, Gunel M, Gabriel S, Chi NC, Silver DL, Gleeson JG. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Gen. (2015); 47(7): 809-813. https://doi.org/10.1038/ng.3311
31. [31] Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. (2011); 29(4): 341-345. https://doi.org/10.1038/nbt.1807
32. [32] Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med. (2012); 2(3): a006312. https://doi.org/10.1101/cshperspect.a006312
33. [33] Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. (2013); 9(2): 106-118. https://doi.org/10.1038/nrneurol.2012.263
34. [34] Zhao N, Liu C-C, Qiao W, Bu G. Apolipoprotein E, Receptors, and modulation of Alzheimer's disease. Biol Psychiatry. (2018); 83(4): 347-357. https://doi.org/10.1016/j.biopsych.2017.03.003
35. [35] Zlokovic BV. Cerebrovascular Effects of Apolipoprotein E: Implications for Alzheimer disease. JAMA Neurol. (2013); 70(4): 440-444. https://doi.org/10.1001/jamaneurol.2013.2152
36. [36] Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG. Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging. (2007); 28(7): 977-986. https://doi.org/10.1016/j.neurobiolaging.2006.05.016
37. [37] Hultman K, Strickland S, Norris EH. The APOE varepsilon4/ varepsilon4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer's disease patients. J Cereb Blood Flow Metab. (2013); 33(8): 1251-1258. https://doi.org/10.1038/jcbfm.2013.76
38. [38] Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D'Angelo G, Liu C, Dixit S, Benzinger T, Fagan A, Goate A, Mintun MA. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. (2010); 30(50): 17035-17040. https://doi.org/10.1523/JNEUROSCI.3987-10.2010
39. [39] Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM. APOE ε4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol. (2010); 67(1): 93-98. https://doi.org/10.1001/archneurol.2009.913
40. [40] Ossenkoppele R, van der Flier WM, Zwan MD, Adriaanse SF, Boellaard R, Windhorst AD, Barkhof F, Lammertsma AA, Scheltens P, van Berckel BNM. Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia. Neurology. (2013); 80(4): 359-365. https://doi.org/10.1212/WNL.0b013e31827f0889
41. [41] Suri S, Mackay CE, Kelly ME, Germuska M, Tunbridge EM, Frisoni GB, Matthews PM, Ebmeier KP, Bulte DP, Filippini N. Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele. Alzheimers Dement. (2015); 11(6): 648-657. https://doi.org/10.1016/j.jalz.2014.05.1755
42. [42] Basun H, Bogdanovic N, Ingelsson M, Almkvist O, Näslund J, Axelman K, Bird TD, Nochlin D, Schellenberg GD, Wahlund LO, Lannfelt L. Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol. (2008); 65(4): 499-505. https://doi.org/10.1001/archneur.65.4.499
43. [43] Beckmann N, Gérard C, Abramowski D, Cannet C, Staufenbiel M. Noninvasive magnetic resonance imaging detection of cerebral amyloid angiopathy-related microvascular alterations using superparamagnetic iron oxide particles in APP transgenic mouse models of Alzheimer's disease: Application to Passive Aβ Immunotherapy. J Neurosci. (2011); 31(3): 1023-1031. https://doi.org/10.1523/JNEUROSCI.4936-10.2011
44. [44] Klohs J, Politano IW, Deistung A, Grandjean J, Drewek A, Dominietto M, Keist R, Schweser F, Reichenbach JR, Nitsch RM, Knuesel I, Rudin M. Longitudinal assessment of amyloid pathology in transgenic ArcAbeta mice using multi-parametric magnetic resonance imaging. PLoS One. (2013); 8(6): e66097. https://doi.org/10.1371/journal.pone.0066097
45. [45] Zarranz JJ, Fernandez-Martinez M, Rodriguez O, Mateos B, Iglesias S, Baron JC. Iowa APP mutation-related hereditary cerebral amyloid angiopathy (CAA): A new family from Spain. J Neurol Sci. (2016); 363: 55-56. https://doi.org/10.1016/j.jns.2016.02.029
46. [46] Blair LJ, Frauen HD, Zhang B, Nordhues BA, Bijan S, Lin Y-C, Zamudio F, Hernandez LD, Sabbagh JJ, Selenica M-LB, Dickey CA. Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol Commun. (2015); 3(1): 8. https://doi.org/10.1186/s40478-015-0186-2
47. [47] Verstraeten A, Theuns J, Van Broeckhoven C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet. (2015); 31(3): 140-149. https://doi.org/10.1016/j.tig.2015.01.004
48. [48] Kortekaas R, Leenders KL, van Oostrom JCH, Vaalburg W, Bart J, Willemsen ATM, Hendrikse NH. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. (2005); 57(2): 176-179. https://doi.org/10.1002/ana.20369
49. [49] Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagacé M, Kuan W-L, Saint- Pierre M, Dury RJ, Alata W, St-Amour I, Mason SL, Calon F, Lacroix S, Gowland PA, Francis ST, Barker RA, Cicchetti F. Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology. Ann Neurol. (2015); 78(2): 160-177. https://doi.org/10.1002/ana.24406
50. [50] Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC. Amyotrophic lateral sclerosis. Lancet. (2011); 377(9769): 942-955. https://doi.org/10.1016/S0140-6736(10)61156-7
51. [51] Henkel JS, Beers DR, Wen S, Bowser R, Appel SH. Decreased mRna expression of tight junction proteins in lumbar spinal cords of patients with ALS. Neurology. (2009); 72(18): 1614-1616. https://doi.org/10.1212/WNL.0b013e3181a41228
52. [52] Keep RF, Xiang J, Ennis SR, Andjelkovic A, Hua Y, Xi G, Hoff JT. Blood-brain barrier function in intracerebral hemorrhage. In: Zhou L- F, Chen X-C, Huang F-P, Xi G, Keep RF, Hua Y, Muraszko K, Lu Y- C, editors. Cerebral Hemorrhage. Vienna: Springer; (2008). p. 73-77. ISBN:978-3-211-09469-3
53. [53] Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surg Neurol. (2006); 66(3): 232-245. https://doi.org/10.1016/j.surneu.2005.12.028
54. [54] Keaney J, Campbell M. The dynamic blood-brain barrier. FEBS J. (2015); 282(21): 4067-4079. https://doi.org/10.1111/febs.13412
55. [55] Rigau V, Morin M, Rousset M-C, de Bock F, Lebrun A, Coubes P, Picot M-C, Baldy-Moulinier M, Bockaert J, Crespel A, Lerner-Natoli M. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain. (2007); 130(7): 1942-1956. https://doi.org/10.1093/brain/awm118
56. [56] Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A. (1998); 95(8): 4607-4612. https://doi.org/10.1073/pnas.95.8.4607
57. [57] Monsky WL, Mouta Carreira C, Tsuzuki Y, Gohongi T, Fukumura D, Jain RK. Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. Clin Cancer Res. (2002); 8 (4): 1008-1013.
58. [58] Sarkaria JN, Hu LS, Parney IF, Pafundi DH, Brinkmann DH, Laack NN, Giannini C, Burns TC, Kizilbash SH, Laramy JK, Swanson KR, Kaufmann TJ, Brown PD, Agar NYR, Galanis E, Buckner JC, Elmquist WF. Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. (2018); 20(2): 184-191. https://doi.org/10.1093/neuonc/nox175
59. [59] Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, Lotvall J, Nakagama H, Ochiya T. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun. (2015); 6: 6716. https://doi.org/10.1038/ncomms7716
60. [60] Seano G, Nia HT, Emblem KE, Datta M, Ren J, Krishnan S, Kloepper J, Pinho MC, Ho WW, Ghosh M, Askoxylakis V, Ferraro GB, Riedemann L, Gerstner ER, Batchelor TT, Wen PY, Lin NU, Grodzinsky AJ, Fukumura D, Huang P, Baish JW, Padera TP, Munn LL, Jain RK. Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium. Nat Biomed Eng. (2019); 3(3): 230-245. https://doi.org/10.1038/s41551-018-0334-7
61. [61] Quail DF, Joyce JA. The Microenvironmental landscape of brain tumors. Cancer Cell. (2017); 31(3): 326-341. https://doi.org/10.1016/j.ccell.2017.02.009
62. [62] Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR. IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol. (2006); 177(8): 5574-5584. https://doi.org/10.4049/jimmunol.177.8.5574
63. [63] Engelhardt S, Patkar S, Ogunshola OO. Cell-specific blood-brain barrier regulation in health and disease: a focus on hypoxia. Br J Pharmacol. (2014); 171(5): 1210-1230. https://doi.org/10.1111/bph.12489
64. [64] Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu- Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A. (2013); 110 (47): 19059-19064. https://doi.org/10.1073/pnas.1318022110
65. [65] Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D, Borra RJH, Wen PY, Ivy P, Batchelor TT, Rosen BR, Jain RK, Sorensen AG. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med. (2013); 19(9): 1178- 1183. https://doi.org/10.1038/nm.3289
66. [66] Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, Mahase S, Dutta DJ, Seto J, Kramer EG, Ferrara N, Sofroniew MV, John GR. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Invest. (2012); 122 (7): 2454-2468. https://doi.org/10.1172/jci60842
67. [67] Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGF- mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci U S A. (2009); 106(6): 1977- 1982. https://doi.org/10.1073/pnas.0808698106
68. [68] Phoenix TN, Patmore DM, Boop S, Boulos N, Jacus MO, Patel YT, Roussel MF, Finkelstein D, Goumnerova L, Perreault S, Wadhwa E, Cho YJ, Stewart CF, Gilbertson RJ. Medulloblastoma genotype dictates blood brain barrier phenotype. Cancer Cell. (2016); 29(4): 508-522. https://doi.org/10.1016/j.ccell.2016.03.002
69. [69] Lin F, de Gooijer MC, Roig EM, Buil LC, Christner SM, Beumer JH, Wurdinger T, Beijnen JH, van Tellingen O. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res. (2014); 20(10): 2703-2713. https://doi.org/10.1158/1078-0432.Ccr-14-0084
70. [70] Wijaya J, Fukuda Y, Schuetz JD. Obstacles to brain tumor therapy: key ABC transporters. Int J Mol Sci. (2017); 18(12). https://doi.org/10.3390/ijms18122544
71. [71] Dubois LG, Campanati L, Righy C, D'Andrea-Meira I, Spohr TC, Porto-Carreiro I, Pereira CM, Balca-Silva J, Kahn SA, DosSantos MF, Oliveira Mde A, Ximenes-da-Silva A, Lopes MC, Faveret E, Gasparetto EL, Moura-Neto V. Gliomas and the vascular fragility of the blood brain barrier. Front Cell Neurosci. (2014); 8: 418. https://doi.org/10.3389/fncel.2014.00418
72. [72] Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, Bao S. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. (2013); 153(1): 139-152. https://doi.org/10.1016/j.cell.2013.02.021
73. [73] Boucher Y, Salehi H, Witwer B, Harsh GRt, Jain RK. Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br J Cancer. (1997); 75(6): 829-836. https://doi.org/10.1038/bjc.1997.148
74. [74] Zhou W, Chen C, Shi Y, Wu Q, Gimple RC, Fang X, Huang Z, Zhai K, Ke SQ, Ping Y-F, Feng H, Rich JN, Yu JS, Bao S, Bian X-W. Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell stem cell. (2017); 21(5): 591-603.e594. https://doi.org/10.1016/j.stem.2017.10.002
75. [75] Avraham HK, Jiang S, Fu Y, Nakshatri H, Ovadia H, Avraham S. Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain. J Pathol. (2014); 232(3): 369-381. https://doi.org/10.1002/path.4304
76. [76] Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases. Neurobiol Dis. (2010); 37 (1): 48-57. https://doi.org/10.1016/j.nbd.2009.07.028
77. [77] Chauhan NB. Trafficking of intracerebroventricularly injected antisense oligonucleotides in the mouse brain. Antisense Nucleic Acid Drug Dev. (2002); 12(5): 353-357. https://doi.org/10.1089/108729002761381320
78. [78] Saucier-Sawyer JK, Seo Y-E, Gaudin A, Quijano E, Song E, Sawyer AJ, Deng Y, Huttner A, Saltzman WM. Distribution of polymer nanoparticles by convection-enhanced delivery to brain tumors. J Control Release. (2016); 232: 103-112. https://doi.org/10.1016/j.jconrel.2016.04.006
79. [79] Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. (2005); 2(1): 3-14. https://doi.org/10.1602/neurorx.2.1.3
80. [80] Vandergrift WA, Patel SJ, Nicholas JS, Varma AK. Convection- enhanced delivery of immunotoxins and radioisotopes for treatment of malignant gliomas. Neurosurg Focus. (2006); 20(4): E13. https://doi.org/10.3171/foc.2006.20.4.8
81. [81] Fortin D, Gendron C, Boudrias M, Garant MP. Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in the treatment of cerebral metastasis. Cancer. (2007); 109(4): 751-760. https://doi.org/10.1002/cncr.22450
82. [82] Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem Biophys Res Commun. (2006); 340(4): 1085-1090. https://doi.org/10.1016/j.bbrc.2005.12.112
83. [83] Borlongan CV, Emerich DF. Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport. Brain Res Bull. (2003); 60(3): 297-306. https://doi.org/10.1016/s0361-9230(03)00043-1
84. [84] Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. (2001); 46(1-3): 3-26. https://doi.org/10.1016/S0169-409X(96)00423-1
85. [85] Witt KA, Gillespie TJ, Huber JD, Egleton RD, Davis TP. Peptide drug modifications to enhance bioavailability and blood-brain barrier permeability. Peptides. (2001); 22(12): 2329-2343. https://doi.org/10.1016/S0196-9781(01)00537-X
86. [86] Witt KA, Slate CA, Egleton RD, Huber JD, Yamamura HI, Hruby VJ, Davis TP. Assessment of stereoselectivity of trimethylphenylalanine analogues of delta-opioid [D-Pen(2),D-Pen(5)]-enkephalin. J Neurochem. (2000); 75(1): 424-435. https://doi.org/10.1046/j.1471-4159.2000.0750424.x
87. [87] Pardridge WM. Blood-brain barrier delivery. Drug Discov Today. (2007); 12(1-2): 54-61. https://doi.org/10.1016/j.drudis.2006.10.013
88. [88] Karatas H, Aktas Y, Gursoy-Ozdemir Y, Bodur E, Yemisci M, Caban S, Vural A, Pinarbasli O, Capan Y, Fernandez-Megia E, Novoa- Carballal R, Riguera R, Andrieux K, Couvreur P, Dalkara T. A nanomedicine transports a peptide caspase-3 inhibitor across the blood-brain barrier and provides neuroprotection. J Neurosci. (2009); 29(44): 13761-13769. https://doi.org/10.1523/jneurosci.4246-09.2009
89. [89] Montes-Burgos I, Walczyk D, Hole P, Smith J, Lynch I, Dawson K. Characterisation of nanoparticle size and state prior to nanotoxicological studies. J Nanoparticle Res. (2010); 12(1): 47-53. https://doi.org/10.1007/s11051-009-9774-z
90. [90] He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. (2010); 31(13): 3657-3666. https://doi.org/10.1016/j.biomaterials.2010.01.065
91. [91] He Q, Zhang Z, Gao F, Li Y, Shi J. In vivo Biodistribution and urinary excretion of mesoporous silica nanoparticles: effects of particle size and PEGylation. Small. (2011); 7(2): 271-280. https://doi.org/10.1002/smll.201001459
92. [92] Min KH, Park K, Kim Y-S, Bae SM, Lee S, Jo HG, Park R-W, Kim I -S, Jeong SY, Kim K, Kwon IC. Hydrophobically modified glycol chitosan nanoparticles-encapsulated camptothecin enhance the drug stability and tumor targeting in cancer therapy. J Control Release. (2008); 127(3): 208-218. https://doi.org/10.1016/j.jconrel.2008.01.013
93. [93] Beck-Broichsitter M, Rytting E, Lebhardt T, Wang X, Kissel T. Preparation of nanoparticles by solvent displacement for drug delivery: A shift in the "ouzo region" upon drug loading. Eur J Pharm Sci. (2010); 41(2): 244-253. https://doi.org/10.1016/j.ejps.2010.06.007
94. [94] Sahin A, Esendagli G, Yerlikaya F, Caban-Toktas S, Yoyen-Ermis D, Horzum U, Aktas Y, Khan M, Couvreur P, Capan Y. A small variation in average particle size of PLGA nanoparticles prepared by nanoprecipitation leads to considerable change in nanoparticles' characteristics and efficacy of intracellular delivery. Artif Cells Nanomed Biotechnol. (2017); 45(8): 1657-1664. https://doi.org/10.1080/21691401.2016.1276924
95. [95] Desai MP, Labhasetwar V, Walter E, Levy RJ, Amidon GL. The mechanism of uptake of biodegradable microparticles in Caco-2 cells is size dependent. Pharm Res. (1997); 14(11): 1568-1573. https://doi.org/10.1023/a:1012126301290
96. [96] Yadav KS, Sawant KK. Modified nanoprecipitation method for preparation of cytarabine-loaded PLGA nanoparticles. AAPS PharmSciTech. (2010); 11(3): 1456-1465. https://doi.org/10.1208/s12249-010-9519-4
97. [97] Dunne M, Corrigan O, Ramtoola Z. Influence of particle size and dissolution conditions on the degradation properties of polylactide-co- glycolide particles. Biomaterials. (2000); 21(16): 1659-1668. https://doi.org/10.1016/S0142-9612(00)00040-5
98. [98] Hanada S, Fujioka K, Inoue Y, Kanaya F, Manome Y, Yamamoto K. Cell-based in vitro blood-brain barrier model can rapidly evaluate nanoparticles' brain permeability in association with particle size and surface modification. Int J Mol Sci. (2014); 15(2): 1812-1825. https://doi.org/10.3390/ijms15021812
99. [99] Shilo M, Sharon A, Baranes K, Motiei M, Lellouche J-PM, Popovtzer R. The effect of nanoparticle size on the probability to cross the blood -brain barrier: an in-vitro endothelial cell model. J Nanobiotechnology. (2015); 13(1): 19. https://doi.org/10.1186/s12951-015-0075-7
100. [100] Nance E, Timbie K, Miller GW, Song J, Louttit C, Klibanov AL, Shih TY, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ. Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound. J Control Release. (2014); 189: 123-132. https://doi.org/10.1016/j.jconrel.2014.06.031
101. [101] Schroeder A, Heller DA, Winslow MM, Dahlman JE, Pratt GW, Langer R, Jacks T, Anderson DG. Treating metastatic cancer with nanotechnology. Nat Rev Cancer. (2011); 12: 39. https://doi.org/10.1038/nrc3180
102. [102] Karmali PP, Simberg D. Interactions of nanoparticles with plasma proteins: implication on clearance and toxicity of drug delivery systems. Expert Opin Drug Deliv. (2011); 8(3): 343-357. https://doi.org/10.1517/17425247.2011.554818
103. [103] Muller RH, Maassen S, Weyhers H, Mehnert W. Phagocytic uptake and cytotoxicity of solid lipid nanoparticles (SLN) sterically stabilized with poloxamine 908 and poloxamer 407. J Drug Target. (1996); 4(3): 161-170. https://doi.org/10.3109/10611869609015973
104. [104] Gessner A, Waicz R, Lieske A, Paulke BR, Mäder K, Müller RH. Nanoparticles with decreasing surface hydrophobicities: influence on plasma protein adsorption. Int J Pharm. (2000); 196(2): 245-249. https://doi.org/10.1016/S0378-5173(99)00432-9
105. [105] Shima F, Akagi T, Uto T, Akashi M. Manipulating the antigen- specific immune response by the hydrophobicity of amphiphilic poly (γ-glutamic acid) nanoparticles. Biomaterials. (2013); 34(37): 9709- 9716. https://doi.org/10.1016/j.biomaterials.2013.08.064
106. [106] Zhu ZJ, Posati T, Moyano DF, Tang R, Yan B, Vachet RW, Rotello VM. The interplay of monolayer structure and serum protein interactions on the cellular uptake of gold nanoparticles. Small. (2012); 8(17): 2659-2663. https://doi.org/10.1002/smll.201200794
107. [107] Saha K, Moyano DF, Rotello VM. Protein coronas suppress the hemolytic activity of hydrophilic and hydrophobic nanoparticles. Mater Horiz. (2014); 1(1): 102-105. https://doi.org/10.1039/C3MH00075C
108. [108] Sperling RA, Parak WJ. Surface modification, functionalization and bioconjugation of colloidal inorganic nanoparticles. Philos Trans R Soc A. (2010); 368(1915): 1333-1383. https://doi.org/10.1098/rsta.2009.0273
109. [109] Shao S, Zheng K, Zidek K, Chabera P, Pullerits T, Zhang F. Optimizing ZnO nanoparticle surface for bulk heterojunction hybrid solar cells. Sol Energy Mater Sol. (2013); 118: 43-47. https://doi.org/10.1016/j.solmat.2013.07.046
110. [110] Shubhra QTH, Tóth J, Gyenis J, Feczkó T. Surface modification of HSA containing magnetic PLGA nanoparticles by poloxamer to decrease plasma protein adsorption. Colloids Surf B. (2014); 122: 529-536. https://doi.org/10.1016/j.colsurfb.2014.07.025
111. [111] Olivier JC. Drug transport to brain with targeted nanoparticles. NeuroRx. (2005); 2(1): 108-119. https://doi.org/10.1602/neurorx.2.1.108
112. [112] Couvreur P, Barratt G, Fattal E, Vauthier C. Nanocapsule technology: a review. Crit Rev Ther Drug. (2002); 19(2): 36. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v19.i2.10
113. [113] Kango S, Kalia S, Celli A, Njuguna J, Habibi Y, Kumar R. Surface modification of inorganic nanoparticles for development of organic- inorganic nanocomposites—A review. Prog Polym Sci. (2013); 38(8): 1232-1261. https://doi.org/10.1016/j.progpolymsci.2013.02.003
114. [114] Lee J-H, Hwang KS, Jang SP, Lee BH, Kim JH, Choi SUS, Choi CJ. Effective viscosities and thermal conductivities of aqueous nanofluids containing low volume concentrations of Al2O3 nanoparticles. Int J Heat Mass Transf. (2008); 51(11-12): 2651-2656. https://doi.org/10.1016/j.ijheatmasstransfer.2007.10.026
115. [115] Papadia K, Markoutsa E, Antimisiaris SG. How do the physicochemical properties of nanoliposomes affect their interactions with the hCMEC/D3 cellular model of the BBB? Int J Pharm. (2016); 509(1): 431-438. https://doi.org/10.1016/j.ijpharm.2016.06.019
116. [116] Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. (2016); 99, Part A: 28-51. https://doi.org/10.1016/j.addr.2015.09.012
117. [117] Walkey CD, Olsen JB, Guo H, Emili A, Chan WCW. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc. (2012); 134(4): 2139-2147. https://doi.org/10.1021/ja2084338
118. [118] Bazile D, Prud'homme C, Bassoullet MT, Marlard M, Spenlehauer G, Veillard M. Stealth Me. PEG‐PLA nanoparticles avoid uptake by the mononuclear phagocytes system. J Pharm Sci. (1995); 84(4): 493- 498. https://doi.org/10.1002/jps.2600840420
119. [119] Sheng Y, Yuan Y, Liu C, Tao X, Shan X, Xu F. In vitro macrophage uptake and in vivo biodistribution of PLA-PEG nanoparticles loaded with hemoglobin as blood substitutes: effect of PEG content. J Mater Sci Mater Med. (2009); 20(9): 1881-1891. https://doi.org/10.1007/s10856-009-3746-9
120. [120] Hak S, Helgesen E, Hektoen HH, Huuse EM, Jarzyna PA, Mulder WJ, Haraldseth O, Davies Cde L. The effect of nanoparticle polyethylene glycol surface density on ligand-directed tumor targeting studied in vivo by dual modality imaging. ACS Nano. (2012); 6(6): 5648-5658. https://doi.org/10.1021/nn301630n
121. [121] Moghimi SM, Hunter AC, Andresen TL. Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu Rev of Pharmacol. (2012); 52(1): 481-503. https://doi.org/10.1146/annurev-pharmtox-010611-134623
122. [122] Schluep T, Hwang J, Hildebrandt IJ, Czernin J, Choi CHJ, Alabi CA, Mack BC, Davis ME. Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements. PNAS. (2009); 106(27): 11394-11399. https://doi.org/10.1073/pnas.0905487106
123. [123] Liu J, Yu M, Ning X, Zhou C, Yang S, Zheng J. PEGylation and Zwitterionization: pros and cons in the renal clearance and tumor targeting of near-IR-emitting gold nanoparticles. Angew Chem Int Ed. (2013); 52(48): 12572-12576. https://doi.org/10.1002/anie.201304465
124. [124] Liu J, Yu M, Zhou C, Zheng J. Renal clearable inorganic nanoparticles: a new frontier of bionanotechnology. Mater Today. (2013); 16(12): 477-486. https://doi.org/10.1016/j.mattod.2013.11.003
125. [125] Lacerda L, Herrero MA, Venner K, Bianco A, Prato M, Kostarelos K. Carbon-nanotube shape and individualization critical for renal excretion. Small. (2008); 4(8): 1130-1132. https://doi.org/10.1002/smll.200800323
126. [126] Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano -sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (Lond). (2008); 3(5): 703-717. https://doi.org/10.2217/17435889.3.5.703
127. [127] Tsoi KM, MacParland SA, Ma XZ, Spetzler VN, Echeverri J, Ouyang B, Fadel SM, Sykes EA, Goldaracena N, Kaths JM, Conneely JB, Alman BA, Selzner M, Ostrowski MA, Adeyi OA, Zilman A, McGilvray ID, Chan WC. Mechanism of hard-nanomaterial clearance by the liver. Nat Mater. (2016); 15(11): 1212-1221. https://doi.org/10.1038/nmat4718
128. [128] Zhang YN, Poon W, Tavares AJ, McGilvray ID, Chan WCW. Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination. J Control Release. (2016); 240: 332-348. https://doi.org/10.1016/j.jconrel.2016.01.020
129. [129] Cho WS, Cho M, Jeong J, Choi M, Cho HY, Han BS, Kim SH, Kim HO, Lim YT, Chung BH, Jeong J. Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles. Toxicol Appl Pharmacol. (2009); 236(1): 16-24. https://doi.org/10.1016/j.taap.2008.12.023
130. [130] Sadauskas E, Wallin H, Stoltenberg M, Vogel U, Doering P, Larsen A, Danscher G. Kupffer cells are central in the removal of nanoparticles from the organism. Part Fibre Toxicol. (2007); 4: 10. https://doi.org/10.1186/1743-8977-4-10
131. [131] Wisse E, Jacobs F, Topal B, Frederik P, De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther. (2008); 15(17): 1193- 1199. https://doi.org/10.1038/gt.2008.60
132. [132] Arvizo RR, Miranda OR, Moyano DF, Walden CA, Giri K, Bhattacharya R, Robertson JD, Rotello VM, Reid JM, Mukherjee P. Modulating pharmacokinetics, tumor uptake and biodistribution by engineered nanoparticles. PLoS One. (2011); 6(9): e24374. https://doi.org/10.1371/journal.pone.0024374
133. [133] Hirn S, Semmler-Behnke M, Schleh C, Wenk A, Lipka J, Schaffler M, Takenaka S, Moller W, Schmid G, Simon U, Kreyling WG. Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration. Eur J Pharm Biopharm. (2011); 77(3): 407-416. https://doi.org/10.1016/j.ejpb.2010.12.029
134. [134] Decuzzi P, Pasqualini R, Arap W, Ferrari M. Intravascular delivery of particulate systems: does geometry really matter? Pharm Res. (2009); 26(1): 235-243. https://doi.org/10.1007/s11095-008-9697-x
135. [135] Dou Y , Y ang X. Novel high-sensitive fluorescent detection of deoxyribonuclease I based on DNA-templated gold/silver nanoclusters. Anal Chim Acta. (2013); 784: 53-58. https://doi.org/10.1016/j.aca.2013.04.038
136. [136] Weadick DS, Liu J. Phosphorothioate DNA stabilized fluorescent gold and silver nanoclusters. Nanomaterials (Basel). (2015); 5(2): 804 -813. https://doi.org/10.3390/nano5020804
137. [137] Lacerda L, Herrero MA, Venner K, Bianco A, Prato M, Kostarelos K. Carbon-nanotube shape and individualization critical for renal excretion. Small. (2008); 4(8): 1130-1132. https://doi.org/10.1002/smll.200800323
138. [138] Truong NP, Whittaker MR, Mak CW, Davis TP. The importance of nanoparticle shape in cancer drug delivery. Expert Opin Drug Deliv. (2015); 12(1): 129-142. https://doi.org/10.1517/17425247.2014.950564
139. [139] Vyas SP, Sihorkar V. Endogenous carriers and ligands in non- immunogenic site-specific drug delivery. Adv Drug Deliv Rev. (2000); 43(2-3): 101-164. https://doi.org/10.1016/S0169-409X(00)00067-3
140. [140] Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov. (2002); 1(2): 131-139. https://doi.org/10.1038/nrd725
141. [141] Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood- brain barrier. Endocrinology. (1994); 135(5): 1753-1761. https://doi.org/10.1210/endo.135.5.7525251
142. [142] Descamps L, Dehouck MP, Torpier G, Cecchelli R. Receptor- mediated transcytosis of transferrin through blood-brain barrier endothelial cells. Am J Physiol. (1996); 270(4 Pt 2): H1149-1158. https://doi.org/10.1152/ajpheart.1996.270.4.H1149
143. [143] Zhao R, Seither R, Brigle KE, Sharina IG, Wang PJ, Goldman ID. Impact of overexpression of the reduced folate carrier (RFC1), an anion exchanger, on concentrative transport in murine L1210 leukemia cells. J Biol Chem. (1997); 272(34): 21207-21212. https://doi.org/10.1074/jbc.272.34.21207
144. [144] Li S, Amat D, Peng Z, Vanni S, Raskin S, De Angulo G, Othman AM, Graham RM, Leblanc RM. Transferrin conjugated nontoxic carbon dots for doxorubicin delivery to target pediatric brain tumor cells. Nanoscale. (2016); 8(37): 16662-16669. https://doi.org/10.1039/C6NR05055G
145. [145] Clark AJ, Davis ME. Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core. PNAS. (2015); 112(40): 12486-12491. https://doi.org/10.1073/pnas.1517048112
146. [146] Wei L, Guo X-Y, Yang T, Yu M-Z, Chen D-W, Wang J-C. Brain tumor-targeted therapy by systemic delivery of siRNA with Transferrin receptor-mediated core-shell nanoparticles. Int J Pharm. (2016); 510 (1): 394-405. https://doi.org/10.1016/j.ijpharm.2016.06.127
147. [147] Agrawal P, Singh RP, Sonali, Kumari L, Sharma G, Koch B, Rajesh CV, Mehata AK, Singh S, Pandey BL, Muthu MS. TPGS-chitosan cross-linked targeted nanoparticles for effective brain cancer therapy. Mater Sci Eng C. (2017); 74: 167-176. https://doi.org/10.1016/j.msec.2017.02.008
148. [148] Lopes AM, Chen KY, Kamei DT. A transferrin variant as the targeting ligand for polymeric nanoparticles incorporated in 3-D PLGA porous scaffolds. Mater Sci Eng C. (2017); 73: 373-380. https://doi.org/10.1016/j.msec.2016.12.091
149. [149] Kuo Y-C, Chen Y-C. Targeting delivery of etoposide to inhibit the growth of human glioblastoma multiforme using lactoferrin- and folic acid-grafted poly(lactide-co-glycolide) nanoparticles. Int J Pharm. (2015); 479(1): 138-149. https://doi.org/10.1016/j.ijpharm.2014.12.070
150. [150] Chen Y-C, Chiang C-F, Chen L-F, Liang P-C, Hsieh W-Y, Lin W-L. Polymersomes conjugated with des-octanoyl ghrelin and folate as a BBB-penetrating cancer cell-targeting delivery system. Biomaterials. (2014); 35(13): 4066-4081. https://doi.org/10.1016/j.biomaterials.2014.01.042
151. [151] Wang X, Tu M, Tian B, Yi Y, Wei Z, Wei F. Synthesis of tumor- targeted folate conjugated fluorescent magnetic albumin nanoparticles for enhanced intracellular dual-modal imaging into human brain tumor cells. Anal Biochem. (2016); 512: 8-17. https://doi.org/10.1016/j.ab.2016.08.010
152. [152] Fan C-H, Chang E-L, Ting C-Y, Lin Y-C, Liao E-C, Huang C-Y, Chang Y-C, Chan H-L, Wei K-C, Yeh C-K. Folate-conjugated gene- carrying microbubbles with focused ultrasound for concurrent blood- brain barrier opening and local gene delivery. Biomaterials. (2016); 106: 46-57. https://doi.org/10.1016/j.biomaterials.2016.08.017
153. [153] Neves AR, Queiroz JF, Lima SAC, Reis S. Apo E-functionalization of solid lipid nanoparticles enhances brain drug delivery: uptake mechanism and transport pathways. Bioconjugate Chem. (2017). https://doi.org/10.1021/acs.bioconjchem.6b00705
154. [154] Girotra P, Singh SK. A Comparative study of orally delivered PBCA and ApoE coupled BSA nanoparticles for brain targeting of sumatriptan succinate in therapeutic management of migraine. Pharm Res. (2016); 33(7): 1682-1695. https://doi.org/10.1007/s11095-016-1910-8
155. [155] Bana L, Minniti S, Salvati E, Sesana S, Zambelli V, Cagnotto A, Orlando A, Cazzaniga E, Zwart R, Scheper W, Masserini M, Re F. Liposomes bi-functionalized with phosphatidic acid and an ApoE- derived peptide affect Aβ aggregation features and cross the blood- brain-barrier: Implications for therapy of Alzheimer disease. Nanomed-Nanatechnol. (2014); 10(7): 1583-1590. https://doi.org/10.1016/j.nano.2013.12.001
156. [156] Rotman M, Welling MM, Bunschoten A, de Backer ME, Rip J, Nabuurs RJA, Gaillard PJ, van Buchem MA, van der Maarel SM, van der Weerd L. Enhanced glutathione PEGylated liposomal brain delivery of an anti-amyloid single domain antibody fragment in a mouse model for Alzheimer's disease. J Control Release. (2015); 203: 40-50. https://doi.org/10.1016/j.jconrel.2015.02.012
157. [157] Englert C, Trützschler A-K, Raasch M, Bus T, Borchers P, Mosig AS, Traeger A, Schubert US. Crossing the blood-brain barrier: Glutathione-conjugated poly(ethylene imine) for gene delivery. J Control Release. (2016); 241: 1-14. https://doi.org/10.1016/j.jconrel.2016.08.039
158. [158] Grover A, Hirani A, Pathak Y, Sutariya V. Brain-targeted delivery of docetaxel by glutathione-coated nanoparticles for brain cancer. AAPS PharmSciTech. (2014); 15(6): 1562-1568. https://doi.org/10.1208/s12249-014-0165-0
159. [159] Loureiro JA, Gomes B, Fricker G, Coelho MAN, Rocha S, Pereira MC. Cellular uptake of PLGA nanoparticles targeted with anti- amyloid and anti-transferrin receptor antibodies for Alzheimer's disease treatment. Colloid Surface B. (2016); 145: 8-13. https://doi.org/10.1016/j.colsurfb.2016.04.041
160. [160] Yue P-j, He L, Qiu S-w, Li Y, Liao Y-j, Li X-p, Xie D, Peng Y. OX26/CTX-conjugated PEGylated liposome as a dual-targeting gene delivery system for brain glioma. Mol Cancer. (2014); 13: 191. https://doi.org/10.1186/1476-4598-13-191
161. [161] Paris-Robidas S, Brouard D, Emond V, Parent M, Calon F. Internalization of targeted quantum dots by brain capillary endothelial cells in vivo. J Cerebr Blood F Met. (2016); 36(4): 731-742. https://doi.org/10.1177/0271678X15608201
162. [162] Ljubimova JY, Patil R, Gangalum P, Wagner S, Inoue S, Ding H, Portilla J, Rekechenetskiy K, Bindu K, Markman J, Chesnokova A, Black KL, Holler E. Abstract A50: Nanobiocojugates of differential imaging and treatment of brain metastatic tumors. Cancer Res. (2013); 73(3 Supplement): A50-A50. https://doi.org/10.1158/1538-7445.tim2013-a50
163. [163] Papadia K, Giannou AD, Markoutsa E, Bigot C, Vanhoute G, Mourtas S, Van der Linded A, Stathopoulos GT, Antimisiaris SG. Multifunctional LUV liposomes decorated for BBB and amyloid targeting - B. In vivo brain targeting potential in wild-type and APP/ PS1 mice. Eur J Pharm Sci. (2017); 102: 180-187. https://doi.org/10.1016/j.ejps.2017.03.010
164. [164] Papadia K, Markoutsa E, Mourtas S, Giannou AD, La Ferla B, Nicotra F, Salmona M, Klepetsanis P, Stathopoulos GT, Antimisiaris SG. Multifunctional LUV liposomes decorated for BBB and amyloid targeting. A. In vitro proof-of-concept. Eur J Pharm Sci. (2017); 101: 140-148. https://doi.org/10.1016/j.ejps.2017.02.019
165. [165] Boado RJ, Ka-Wai Hui E, Zhiqiang Lu J, Pardridge WM. Insulin receptor antibody-iduronate 2-sulfatase fusion protein: Pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys. Biotechnol Bioeng. (2014); 111(11): 2317-2325. https://doi.org/10.1002/bit.25289
166. [166] Boado RJ, Hui EK-W, Lu JZ, Pardridge WM. Very high plasma concentrations of a monoclonal antibody against the human insulin receptor are produced by subcutaneous injection in the Rhesus monkey. Mol Pharm. (2016); 13(9): 3241-3246. https://doi.org/10.1021/acs.molpharmaceut.6b00456
167. [167] Kuo Y-C, Ko H-F. Targeting delivery of saquinavir to the brain using 83-14 monoclonal antibody-grafted solid lipid nanoparticles. Biomaterials. (2013); 34(20): 4818-4830. https://doi.org/10.1016/j.biomaterials.2013.03.013
168. [168] Dieu L-H, Wu D, Palivan CG, Balasubramanian V, Huwyler J. Polymersomes conjugated to 83-14 monoclonal antibodies: In vitro targeting of brain capillary endothelial cells. Eur J Pharm Biopharm. (2014); 88(2): 316-324. https://doi.org/10.1016/j.ejpb.2014.05.021
169. [169] Johnsen KB, Moos T. Revisiting nanoparticle technology for blood- brain barrier transport: Unfolding at the endothelial gate improves the fate of transferrin receptor-targeted liposomes. J Control Release. (2016); 222: 32-46. https://doi.org/10.1016/j.jconrel.2015.11.032
170. [170] St-Amour I, Paré I, Alata W, Coulombe K, Ringuette-Goulet C, Drouin-Ouellet J, Vandal M, Soulet D, Bazin R, Calon F. Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier. J Cereb Blood Flow Metab. (2013); 33(12): 1983-1992. https://doi.org/doi:10.1038/jcbfm.2013.160
171. [171] Pardridge WM. Blood-brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody. Expert Opin Drug Deliv. (2015); 12(2): 207-222. https://doi.org/10.1517/17425247.2014.952627
172. [172] 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(3): 1048-1052.
173. [173] Aryal M, Vykhodtseva N, Zhang Y-Z, McDannold N. Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: A safety study. J Control Release. (2015); 204(Supplement C): 60-69. https://doi.org/10.1016/j.jconrel.2015.02.033
174. [174] Horodyckid C, Canney M, Vignot A, Boisgard R, Drier A, Huberfeld G, Francois C, Prigent A, Santin MD, Adam C, Willer JC, Lafon C, Chapelon JY, Carpentier A. Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: a multiparametric study in a primate model. J Neurosurg. (2017); 126 (4): 1351-1361. https://doi.org/10.3171/2016.3.Jns151635