Evolving drug delivery strategies to overcome the blood brain barrier

Current Pharmaceutical Design

Volumn 22, Issue 9, 2016, Pages 1177-1193

  Hersh, David S ^a   Wadajkar, Aniket S ^a   Roberts, Nathan B ^a   Perez, Jimena G ^a   Connolly, Nina P ^a   Frenkel, Victor ^a   Winkles, Jeffrey A ^a   Woodworth, Graeme F ^a   Kim, Anthony J ^a,b  

^a UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF MARYLAND SCHOOL OF PHARMACY   (United States)

Author keywords

Blood Brain Barrier (BBB); Central Nervous System (CNS); Immunotherapy; Nanotechnology; Ultrasound

Indexed keywords

CENTRAL NERVOUS SYSTEM AGENTS; INTERSTITIAL WAFERS; LIPOSOME; METAL NANOPARTICLE; NANOCARRIER; NANOPARTICLE; POLYMER; UNCLASSIFIED DRUG;

BLOOD BRAIN BARRIER; BRAIN TUMOR; CELL MEDIATED DRUG DELIVERY SYSTEM; CELL THERAPY; CELL TRANSPORT; CONVECTION ENHANCED DRUG DELIVERY SYSTEM; DRUG DELIVERY SYSTEM; FOCUSED ULTRASOUND; FOCUSED ULTRASOUND BASED DRUG DELIVERY SYSTEM; FOCUSED ULTRASOUND BASED GENE DELIVERY SYSTEM; GENE DELIVERY SYSTEM; HUMAN; IMMUNOCOMPETENT CELL; INTERSTITIAL DRUG DELIVERY SYSTEM; INTRANASAL DRUG DELIVERY SYSTEM; INTRATHECAL DRUG DELIVERY SYSTEM; INTRAVENTRICULAR DRUG DELIVERY SYTEM; MEMBRANE DAMAGE; MEMBRANE STRUCTURE; META ANALYSIS (TOPIC); NONHUMAN; OSMOSIS; PARACELLULAR TRANSPORT; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PULSED FOCUSED ULTRASOUND MEDIATED DRUG DELIVERY SYSTEM; PULSED FOCUSED ULTRASOUND MEDIATED GENE DELIVERY SYSTEM; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; STEM CELL; THERAPY EFFECT; TRANSCYTOSIS; ULTRASOUND THERAPY; ANIMAL; BRAIN DISEASES; DRUG EFFECTS;

ANIMALS; BLOOD-BRAIN BARRIER; BRAIN DISEASES; CENTRAL NERVOUS SYSTEM AGENTS; DRUG DELIVERY SYSTEMS; HUMANS;

EID: 84961742832     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612822666151221150733     Document Type: Review

References (256)

1. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005; 2: 3-14.
2. Yang Z, Liu ZW, Allaker RP, et al. A review of nanoparticle functionality and toxicity on the central nervous system. Interface Focus 2010; 7: S411-22.
3. van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat 2015; 19: 1-12.
4. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7: 41-53.
5. Alvarez JI, Dodelet-Devillers A, Kebir H, et al. The hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 2011; 334: 1727-31.
6. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013; 19: 1584-96.
7. Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 2012; 32: 1959-72.
8. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37: 13-25.
9. Demeule M, Regina A, Jodoin J, et al. Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood-brain barrier. Vascul Pharmacol 2002; 38: 339-48.
10. Rapoport SI, Hori M, Klatzo I. Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am J Physiol 1972; 223: 323-31.
11. Rapoport SI. Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol 2000; 20: 217-30.
12. Rapoport SI, Robinson PJ. Tight-junctional modification as the basis of osmotic opening of the blood-brain barrier. Ann N Y Acad Sci 1986; 481: 250-67.
13. Fredericks WR, Rapoport SI. Reversible osmotic opening of the blood-brain barrier in mice. Stroke 1988; 19: 266-8.
14. Rapoport SI, Thompson HK. Osmotic opening of the blood-brain barrier in the monkey without associated neurological deficits. Science 1973; 180: 971.
15. Neuwelt EA, Hill SA, Frenkel EP, et al. Osmotic blood-brain barrier disruption: pharmacodynamic studies in dogs and a clinical phase I trial in patients with malignant brain tumors. Cancer Treat Rep 1981; 65 Suppl 2: 39-43.
16. Neuwelt EA, Frenkel EP, Diehl JT, et al. Osmotic blood-brain barrier disruption: a new means of increasing chemotherapeutic agent delivery. Trans Am Neurol Assoc 1979; 104: 256-60.
17. Siegal T, Rubinstein R, Bokstein F, et al. In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans. J Neurosurg 2000; 92: 599-605.
18. Robinson PJ, Rapoport SI. Size selectivity of blood-brain barrier permeability at various times after osmotic opening. Am J Physiol 1987; 253: R459-66.
19. Ikeda M, Nagashima T, Bhattacharjee AK, Kondoh T, Kohmura E, Tamaki N. Quantitative analysis of hyperosmotic and hypothermic blood-brain barrier opening. Acta Neurochir Suppl 2003; 86: 559-63.
20. Neuwelt EA, Frenkel EP, Rapoport S, Barnett P. Effect of osmotic blood-brain barrier disruption on methotrexate pharmacokinetics in the dog. Neurosurgery 1980; 7: 36-43.
21. Neuwelt EA, Glasberg M, Frenkel E, Barnett P. Neurotoxicity of chemotherapeutic agents after blood-brain barrier modification: neuropathological studies. Ann Neurol 1983; 14: 316-24.
22. Neuwelt EA, Barnett PA, Hellstrom I, et al. Delivery of melanomaassociated immunoglobulin monoclonal antibody and Fab fragments to normal brain utilizing osmotic blood-brain barrier disruption. Cancer Res 1988; 48: 4725-9.
23. Hicks JT, Albrecht P, Rapoport SI. Entry of neutralizing antibody to measles into brain and cerebrospinal fluid of immunized monkeys after osmotic opening of the blood-brain barrier. Exp Neurol 1976; 53: 768-79.
24. Muldoon LL, Nilaver G, Kroll RA, et al. Comparison of intracerebral inoculation and osmotic blood-brain barrier disruption for delivery of adenovirus, herpesvirus, and iron oxide particles to normal rat brain. Am J Pathol 1995; 147: 1840-51.
25. Jiao S, Miller PJ, Lapchak PA. Enhanced delivery of [125I]glial cell line-derived neurotrophic factor to the rat CNS following osmotic blood-brain barrier modification. Neurosci Lett 1996; 220: 187-90.
26. Gonzales-Portillo GS, Sanberg PR, Franzblau M, et al. Mannitolenhanced delivery of stem cells and their growth factors across the blood-brain barrier. Cell Transplant 2014; 23: 531-9.
27. Foley CP, Rubin DG, Santillan A, et al. Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption. J Control Release 2014; 196: 71-8.
28. Dahlborg SA, Henner WD, Crossen JR, et al. Non-AIDS primary CNS lymphoma: first example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J Sci Am 1996; 2: 166-74.
29. McAllister LD, Doolittle ND, Guastadisegni PE, et al. Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 2000; 46: 51-60; discussion -1.
30. Angelov L, Doolittle ND, Kraemer DF, et al. Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol 2009; 27: 3503-9.
31. Neuwelt EA, Wiliams PC, Mickey BE, Frenkel EP, Henner WD. Therapeutic dilemma of disseminated CNS germinoma and the potential of increased platinum-based chemotherapy delivery with osmotic blood-brain barrier disruption. Pediatr Neurosurg 1994; 21: 16-22.
32. Gumerlock MK, Belshe BD, Madsen R, Watts C. Osmotic bloodbrain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review. J Neurooncol 1992; 12: 33-46.
33. Neuwelt EA, Howieson J, Frenkel EP, et al. Therapeutic efficacy of multiagent chemotherapy with drug delivery enhancement by blood-brain barrier modification in glioblastoma. Neurosurgery 1986; 19: 573-82.
34. Doolittle ND, Miner ME, Hall WA, et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer 2000; 88: 637-47.
35. Rapoport SI, Fredericks WR, Ohno K, Pettigrew KD. Quantitative aspects of reversible osmotic opening of the blood-brain barrier. Am J Physiol 1980; 238: R421-31.
36. Nadal A, Fuentes E, Pastor J, McNaughton PA. Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Proc Natl Acad Sci USA 1995; 92: 1426-30.
37. Erdlenbruch B, Schinkhof C, Kugler W, et al. Intracarotid administration of short-chain alkylglycerols for increased delivery of methotrexate to the rat brain. Br J Pharmacol 2003; 139: 685-94.
38. Lee HJ, Zhang Y, Pardridge WM. Blood-brain barrier disruption following the internal carotid arterial perfusion of alkyl glycerols. J Drug Target 2002; 10: 463-7.
39. Gutman M, Laufer R, Eisenthal A, et al. Increased microvascular permeability induced by prolonged interleukin-2 administration is attenuated by the oxygen-free-radical scavenger dimethylthiourea. Cancer Immunol Immunother 1996; 43: 240-4.
40. Black KL, Chio CC. Increased opening of blood-tumour barrier by leukotriene C4 is dependent on size of molecules. Neurol Res 1992; 14: 402-4.
41. Cote J, Bovenzi V, Savard M, et al. Induction of selective bloodtumor barrier permeability and macromolecular transport by a biostable kinin B1 receptor agonist in a glioma rat model. PloS One 2012; 7: e37485.
42. Inamura T, Black KL. Bradykinin selectively opens blood-tumor barrier in experimental brain tumors. J Cereb Blood Flow Metab 1994; 14: 862-70.
43. Ford J, Osborn C, Barton T, Bleehen NM. A phase I study of intravenous RMP-7 with carboplatin in patients with progression of malignant glioma. Eur J Cancer 1998; 34: 1807-11.
44. Nomura T, Inamura T, Black KL. Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors. Brain Res 1994; 659: 62-6.
45. Nakano S, Matsukado K, Black KL. Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide. Cancer Res 1996; 56: 4027-31.
46. Matsukado K, Sugita M, Black KL. Intracarotid low dose bradykinin infusion selectively increases tumor permeability through activation of bradykinin B2 receptors in malignant gliomas. Brain Res 1998; 792: 10-5.
47. Bartus RT, Elliott P, Hayward N, Dean R, McEwen EL, Fisher SK. Permeability of the blood brain barrier by the bradykinin agonist, RMP-7: evidence for a sensitive, auto-regulated, receptor-mediated system. Immunopharmacology 1996; 33: 270-8.
48. Emerich DF, Dean RL, Osborn C, Bartus RT. The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation. Clin Pharmacokinet 2001; 40: 105-23.
49. Inamura T, Nomura T, Bartus RT, Black KL. Intracarotid infusion of RMP-7, a bradykinin analog: a method for selective drug delivery to brain tumors. J Neurosurg 1994; 81: 752-8.
50. Matsukado K, Inamura T, Nakano S, Fukui M, Bartus RT, Black KL. Enhanced tumor uptake of carboplatin and survival in gliomabearing rats by intracarotid infusion of bradykinin analog, RMP-7. Neurosurgery 1996; 39: 125-33 ; discussion 33-4.
51. Bartus RT, Snodgrass P, Marsh J, Agostino M, Perkins A, Emerich DF. Intravenous cereport (RMP-7) modifies topographic uptake profile of carboplatin within rat glioma and brain surrounding tumor, elevates platinum levels, and enhances survival. J Pharmacol Exp Ther 2000; 293: 903-11.
52. Elliott PJ, Hayward NJ, Dean RL, Blunt DG, Bartus RT. Intravenous RMP-7 selectively increases uptake of carboplatin into rat brain tumors. Cancer Res 1996; 56: 3998-4005.
53. Warren KE, Patel MC, Aikin AA, et al. Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors. Cancer Chemother Pharmacol 2001; 48: 275-82.
54. Gregor A, Lind M, Newman H, et al. Phase II studies of RMP-7 and carboplatin in the treatment of recurrent high grade glioma. RMP-7 European Study Group. J Neurooncol 1999; 44: 137-45.
55. Prados MD, Schold SJS, Fine HA, et al. A randomized, doubleblind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro Oncol 2003; 5: 96-103.
56. Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 2002; 1: 131-9.
57. Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 1987; 420: 32-8.
58. Fishman JB, Rubin JB, Handrahan JV, Connor JR, Fine RE. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res 1987; 18: 299-304.
59. Pardridge WM, Buciak JL, Friden PM. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J Pharmacol Exp Ther 1991; 259: 66-70.
60. Dehouck B, Fenart L, Dehouck MP, Pierce A, Torpier G, Cecchelli R. A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier. J Cell Biol 1997; 138: 877-89.
61. Shin SU, Friden P, Moran M, et al. Transferrin-antibody fusion proteins are effective in brain targeting. Proc Natl Acad Sci USA 1995; 92: 2820-4.
62. Zhang Y, Schlachetzki F, Zhang YF, Boado RJ, Pardridge WM. Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter. Hum Gene Ther 2004; 15: 339-50.
63. Yu YJ, Zhang Y, Kenrick M, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med 2011; 3: 84ra44.
64. Boado RJ, Hui EK, Lu JZ, Sumbria RK, Pardridge WM. Bloodbrain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey. Bioconjug Chem 2013; 24: 1741-9.
65. Drappatz J, Brenner A, Wong ET, et al. Phase I study of GRN1005 in recurrent malignant glioma. Clin Cancer Res 2013; 19: 1567-76.
66. Alam MI, Beg S, Samad A, et al. Strategy for effective brain drug delivery. Eur J Pharm Sci 2010; 40: 385-403.
67. De Jong WH, Borm PJA. Drug delivery and nanoparticles: Applications and hazards. Int J Nanomedicine 2008; 3: 133-49.
68. Cheng Y, Dai Q, Morshed RA, et al. Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging. Small 2014; 10: 5137-50.
69. Rungby J, Danscher G. Localization of exogenous silver in brain and spinal cord of silver exposed rats. Acta Neuropathologica 1983; 60: 92-8.
70. Kong SD, Lee J, Ramachandran S, et al. Magnetic targeting of nanoparticles across the intact blood-brain barrier. J Control Release 2012; 164: 49-57.
71. Wang JT, Al-Jamal KT. Functionalized carbon nanotubes: revolution in brain delivery. Nanomedicine 2015; 10: 2639-42.
72. Al-Jamal KT, Nerl H, Muller KH, et al. Cellular uptake mechanisms of functionalised multi-walled carbon nanotubes by 3D electron tomography imaging. Nanoscale 2011; 3: 2627-35.
73. Kafa H, Wang JT, Rubio N, et al. The interaction of carbon nanotubes with an in vitro blood-brain barrier model and mouse brain in vivo. Biomaterials 2015; 53: 437-52.
74. Schroeder U, Sommerfeld P, Ulrich S, Sabel BA. Nanoparticle technology for delivery of drugs across the blood–brain barrier. J Pharm Sci 1998; 87: 1305-7.
75. Barbu E, Molnar E, Tsibouklis J, Gorecki DC. The potential for nanoparticle-based drug delivery to the brain: overcoming the blood-brain barrier. Expert Opin Drug Deliv 2009; 6: 553-65.
76. Zensi A, Begley D, Pontikis C, et al. Albumin nanoparticles targeted with Apo E enter the CNS by transcytosis and are delivered to neurones. J Control Release 2009; 137: 78-86.
77. Kreuter Jr, Shamenkov D, Petrov V, et al. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target 2002; 10: 317-25.
78. Ren T, Xu N, Cao C, et al. Preparation and therapeutic efficacy of polysorbate-80-coated amphotericin B/PLA-b-PEG nanoparticles. J Biomater Sci Polym Ed 2009; 20: 1369-80.
79. Vergoni AV, Tosi G, Tacchi R, Vandelli MA, Bertolini A, Costantino L. Nanoparticles as drug delivery agents specific for CNS: in vivo biodistribution. Nanomedicine 2009; 5: 369-77.
80. Serramia MJ, Alvarez S, Fuentes-Paniagua E, et al. In vivo delivery of siRNA to the brain by carbosilane dendrimer. J Control Release 2015; 200: 60-70.
81. Samad A, Sultana Y, Aqil M. Liposomal drug delivery systems: an update review. Curr Drug Deliv 2007; 4: 297-305.
82. Micheli MR, Bova R, Magini A, Polidoro M, Emiliani C. Lipidbased nanocarriers for CNS-targeted drug delivery. Recent Pat CNS Drug Discov 2012; 7: 71-86.
83. Schnyder A, Huwyler Jr. Drug transport to brain with targeted liposomes. NeuroRx 2005; 2: 99-107.
84. Gabizon A, Goren D, Horowitz AT, Tzemach D, Lossos A, Siegal T. Long-circulating liposomes for drug delivery in cancer therapy: a review of biodistribution studies in tumor-bearing animals. Adv Drug Deliv Rev 1997; 24: 337-44.
85. Qin Y, Fan W, Chen H, et al. In vitro and in vivo investigation of glucose-mediated brain-targeting liposomes. J Drug Target 2010; 18: 536-49.
86. Jones AR, Shusta EV. Blood-brain barrier transport of therapeutics via receptor-mediation. Pharm Res 2007; 24: 1759-71.
87. Lai F, Fadda AM, Sinico C. Liposomes for brain delivery. Expert Opin Drug Deliv 2013; 10: 1003-22.
88. Ying X, Wen H, Lu WL, et al. Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals. J Control Release 2010; 141: 183-92.
89. Rose J, Neal J, Kopacz D. Extended-duration analgesia: update on microspheres and liposomes. Reg Anesth Pain Med 2005; 30: 275-85.
90. Du D, Chang N, Sun S, et al. The role of glucose transporters in the distribution of p-aminophenyl-a-d-mannopyranoside modified liposomes within mice brain. J Control Release 2014; 182: 99-110.
91. Qin J, Zhang RX, Li JL, et al. cRGD mediated liposomes enhanced antidepressant-like effects of edaravone in rats. Eur J Pharm Sci 2014; 58: 63-71.
92. Tosi G, Bondioli L, Ruozi B, et al. NIR-labeled nanoparticles engineered for brain targeting: in vivo optical imaging application and fluorescent microscopy evidences. J Neural Transm 2011; 118: 145-53.
93. Lajoie JM, Shusta EV. Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. Annu Rev Pharmacol Toxicol 2015; 55: 613-31.
94. Fornaguera C, Dols-Perez A, Calderó G, García-Celma MJ, Camarasa J, Solans C. PLGA nanoparticles prepared by nano-emulsion templating using low-energy methods as efficient nanocarriers for drug delivery across the blood–brain barrier. J Control Release 2015; 211: 134-43.
95. Clark AJ, Davis ME. Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core. Proc Natl Acad Sci USA 2015; 112: 12486-91.
96. Zhang F, Xu C-L, Liu C-M. Drug delivery strategies to enhance the permeability of the blood–brain barrier for treatment of glioma. Drug Des Dev Ther 2015; 9: 2089-100.
97. Sowers J, Johnson K, Conrad C, Patterson J, Sowers L. The role of inflammation in brain cancer. In: Aggarwal BB, Sung B, Gupta SC, Eds. Inflammation and Cancer. Basel: Springer 2014; pp. 75-105.
98. Behnan J, Isakson P, Joel M, et al. Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells 2014; 32: 1110-23.
99. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol 2014; 32: 659-702.
100. Bovenberg MSS, Degeling MH, Tannous BA. Advances in stem cell therapy against gliomas. Trends Mol Med 2013; 19: 281-91.
101. Miao H, Choi BD, Suryadevara CM, et al. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma. PLoS One 2014; 9: e94281.
102. Pawlowski NA, Kaplan G, Abraham E, Cohn ZA. The selective binding and transmigration of monocytes through the junctional complexes of human endothelium. J Exp Med 1988; 168: 1865-82.
103. Lyck R, Engelhardt B. Going against the tide – how encephalitogenic T cells breach the blood-brain barrier. J Vasc Res 2012; 49: 497-509.
104. Liu L, Eckert MA, Riazifar H, Kang D-K, Agalliu D, Zhao W. From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells Int 2013; 2013: 7.
105. Rüster B, Göttig S, Ludwig RJ, et al. Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. Blood 2006; 108: 3938-44.
106. Schackert G, Simmons RD, Buzbee TM, Hume DA, Fidler IJ. Macrophage infiltration into experimental brain metastases: occurrence through an intact blood-brain barrier. J Natl Cancer Inst 1988; 80: 1027-34.
107. Bagci-Onder T, Du W, Figueiredo J-L, Martinez-Quintanilla J, Shah K. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells. Brain 2015; 138: 1710-21.
108. Aboody KS, Brown A, Rainov NG, et al. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc Natl Acad Sci USA 2000; 97: 12846-51.
109. Ryu CH, Park S-H, Park SA, et al. Gene therapy of intracranial glioma using interleukin 12–secreting human umbilical cord blood–derived mesenchymal stem cells. Hum Gene Ther 2011; 22: 733-43.
110. Li Q, Wijesekera O, Salas SJ, et al. Mesenchymal stem cells from human fat engineered to secrete BMP4 are nononcogenic, suppress brain cancer, and prolong survival. Clin Cancer Res 2014; 20: 2375-87.
111. Steinfeld U, Pauli C, Kaltz N, Bergemann C, Lee H-H. T lymphocytes as potential therapeutic drug carrier for cancer treatment. Int J Pharm 2006; 311: 229-36.
112. Batrakova EV, Gendelman HE, Kabanov AV. Cell-mediated drugs delivery. Expert Opin Drug Deliv 2011; 8: 415-33.
113. Rogers WJ, Basu P. Factors regulating macrophage endocytosis of nanoparticles: implications for targeted magnetic resonance plaque imaging. Atherosclerosis 2005; 178: 67-73.
114. J. Panyam VL. Dynamics of endocytosis and exocytosis of poly(D,L-lactide-co-glycolide) nanoparticles in vascular smooth muscle cells. Pharm Res 2003; 20: 212-20.
115. Nowacek AS, Miller RL, McMillan J, et al. NanoART synthesis, characterization, uptake, release and toxicology for human monocyte— macrophage drug delivery. Nanomedicine (Lond) 2009; 4: 903-17.
116. Champion JA, Katare YK, Mitragotri S. Particle shape: a new design parameter for micro-and nanoscale drug delivery carriers. J Control Release 2007; 121: 3-9.
117. Thiele L, Diederichs JE, Reszka R, Merkle HP, Walter E. Competitive adsorption of serum proteins at microparticles affects phagocytosis by dendritic cells. Biomaterials 2003; 24: 1409-18.
118. Durymanov MO, Rosenkranz AA, Sobolev AS. Current approaches for improving intratumoral accumulation and distribution of nanomedicines. Theranostics 2015; 5: 1007-20.
119. Li L, Guan Y, Liu H, et al. Silica nanorattle–doxorubicin-anchored mesenchymal stem cells for tumor-tropic therapy. ACS Nano 2011; 5: 7462-70.
120. Jain S, Mishra V, Singh P, Dubey PK, Saraf DK, Vyas SP. RGDanchored magnetic liposomes for monocytes/neutrophils-mediated brain targeting. Int J Pharm 2003; 261: 43-55.
121. Wu J, Yang S, Luo H, Zeng L, Ye L, Lu Y. Quantitative evaluation of monocyte transmigration into the brain following chemical opening of the blood–brain barrier in mice. Brain Res 2006; 1098: 79-85.
122. Ballantine HT, Jr., Bell E, Manlapaz J. Progress and problems in the neurological applications of focused ultrasound. J Neurosurg 1960; 17: 858-76.
123. Hynynen K, Jolesz FA. Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med Biol 1998; 24: 275-83.
124. Cline HE, Hynynen K, Hardy CJ, Watkins RD, Schenck JF, Jolesz FA. MR temperature mapping of focused ultrasound surgery. Magn Reson Med 1994; 31: 628-36.
125. Clement GT. Perspectives in clinical uses of high-intensity focused ultrasound. Ultrasonics 2004; 42: 1087-93.
126. Krasovitski B, Frenkel V, Shoham S, Kimmel E. Intramembrane cavitation as a unifying mechanism for ultrasound-induced bioeffects. Proc Natl Acad Sci USA 2011; 108: 3258-63.
127. Park J, Zhang Y, Vykhodtseva N, Jolesz FA, McDannold NJ. The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. J Control Release 2012; 162: 134-42.
128. Vykhodtseva NI, Hynynen K, Damianou C. Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo. Ultrasound Med Biol 1995; 21: 969-79.
129. Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 2001; 220: 640-6.
130. Sheikov N, McDannold N, Sharma S, Hynynen K. 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: 1093-104.
131. Sheikov N, McDannold N, Jolesz F, Zhang YZ, Tam K, Hynynen K. Brain arterioles show more active vesicular transport of bloodborne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier. Ultrasound Med Biol 2006; 32: 1399-409.
132. Sheikov N, McDannold N, Vykhodtseva N, Jolesz F, Hynynen K. Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles. Ultrasound Med Biol 2004; 30: 979-89.
133. Meijering BD, Juffermans LJ, van Wamel A, et al. Ultrasound and microbubble-targeted delivery of macromolecules is regulated by induction of endocytosis and pore formation. Circ Res 2009; 104: 679-87.
134. Deng J, Huang Q, Wang F, et al. The role of caveolin-1 in bloodbrain barrier disruption induced by focused ultrasound combined with microbubbles. J Mol Neurosci 2012; 46: 677-87.
135. Xia CY, Zhang Z, Xue YX, Wang P, Liu YH. Mechanisms of the increase in the permeability of the blood-tumor barrier obtained by combining low-frequency ultrasound irradiation with small-dose bradykinin. J Neurooncol 2009; 94: 41-50.
136. Nhan T, Burgess A, Cho EE, Stefanovic B, Lilge L, Hynynen K. Drug delivery to the brain by focused ultrasound induced bloodbrain barrier disruption: quantitative evaluation of enhanced permeability of cerebral vasculature using two-photon microscopy. J Control Release 2013; 172: 274-80.
137. Raymond SB, Skoch J, Hynynen K, Bacskai BJ. Multiphoton imaging of ultrasound/Optison mediated cerebrovascular effects in vivo. J Cereb Blood Flow Metab 2007; 27: 393-403.
138. Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vykhodtseva N. Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. NeuroImage 2005; 24: 12-20.
139. Hynynen K, McDannold N, Vykhodtseva N, et al. Focal disruption of the blood-brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J Neurosurg 2006; 105: 445-54.
140. McDannold N, Vykhodtseva N, Hynynen K. Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index. Ultrasound Med Biol 2008; 34: 834-40.
141. McDannold N, Vykhodtseva N, Hynynen K. Effects of acoustic parameters and ultrasound contrast agent dose on focusedultrasound induced blood-brain barrier disruption. Ultrasound Med Biol 2008; 34: 930-7.
142. McDannold N, Arvanitis CD, Vykhodtseva N, Livingstone MS. Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. Cancer Res 2012; 72: 3652-63.
143. Downs ME, Buch A, Sierra C, et al. Long-term safety of repeated blood-brain barrier opening via focused ultrasound with microbubbles in non-human primates performing a cognitive task. PloS One 2015; 10: e0125911.
144. Treat LH, McDannold N, Vykhodtseva N, Zhang Y, Tam K, Hynynen K. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer 2007; 121: 901-7.
145. Treat LH, McDannold N, Zhang Y, Vykhodtseva N, Hynynen K. Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma. Ultrasound Med Biol 2012; 38: 1716-25.
146. Aryal M, Vykhodtseva N, Zhang YZ, Park J, McDannold N. Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improve outcomes in a rat glioma model. J Control Release 2013; 169: 103-11.
147. Kovacs Z, Werner B, Rassi A, Sass JO, Martin-Fiori E, Bernasconi M. Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models. J Control Release 2014; 187: 74-82.
148. Mei J, Cheng Y, Song Y, et al. Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound. J Ultrasound Med 2009; 28: 871-80.
149. Liu HL, Hua MY, Yang HW, et al. Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci USA 2010; 107: 15205-10.
150. Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 2004; 10: 3728-36.
151. Liu HL, Huang CY, Chen JY, Wang HY, Chen PY, Wei KC. Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood-brain barrier opening for enhanced temozolomide delivery in glioma treatment. PloS One 2014; 9: e114311.
152. Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Targeted delivery of antibodies through the blood-brain barrier by MRIguided focused ultrasound. Biochem Biophys Res Commun 2006; 340: 1085-90.
153. Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci USA 2006; 103: 11719-23.
154. Park EJ, Zhang YZ, Vykhodtseva N, McDannold N. Ultrasoundmediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model. J Control Release 2012; 163: 277-84.
155. Janus C, Pearson J, McLaurin J, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 2000; 408: 979-82.
156. Jordao JF, Thevenot E, Markham-Coultes K, et al. Amyloid-beta plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol 2013; 248: 16-29.
157. Jordao JF, Ayala-Grosso CA, Markham K, et al. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer's disease. PloS One 2010; 5: e10549.
158. Raymond SB, Treat LH, Dewey JD, McDannold NJ, Hynynen K, Bacskai BJ. Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models. PloS One 2008; 3: e2175.
159. Chen PY, Hsieh HY, Huang CY, Lin CY, Wei KC, Liu HL. Focused ultrasound-induced blood-brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J Transl Med 2015; 13: 93.
160. Burgess A, Ayala-Grosso CA, Ganguly M, Jordao JF, Aubert I, Hynynen K. Targeted delivery of neural stem cells to the brain us ing MRI-guided focused ultrasound to disrupt the blood-brain barrier. PloS One 2011; 6: e27877.
161. Alkins R, Burgess A, Ganguly M, et al. Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res 2013; 73: 1892-9.
162. Huang Q, Deng J, Xie Z, et al. Effective gene transfer into central nervous system following ultrasound-microbubbles-induced opening of the blood-brain barrier. Ultrasound Med Biol 2012; 38: 1234-43.
163. Huang Q, Deng J, Wang F, et al. Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced bloodbrain barrier disruption. Exp Neurol 2012; 233: 350-6.
164. Thevenot E, Jordao JF, O'Reilly MA, et al. Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound. Hum Gene Ther 2012; 23: 1144-55.
165. Wang S, Olumolade OO, Sun T, Samiotaki G, Konofagou EE. Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther 2015; 22: 104-10.
166. Hsu PH, Wei KC, Huang CY, et al. Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound. PloS One 2013; 8: e57682.
167. Ting CY, Fan CH, Liu HL, et al. Concurrent blood-brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials 2012; 33: 704-12.
168. Fan CH, Ting CY, Liu HL, et al. Antiangiogenic-targeting drugloaded microbubbles combined with focused ultrasound for glioma treatment. Biomaterials 2013; 34: 2142-55.
169. Dakhil S, Ensminger W, Kindt G, et al. Implanted system for intraventricular drug infusion in central nervous system tumors. Cancer Treat Rep 1981; 65: 401-11.
170. Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 1975; 195: 73-83.
171. Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 2005; 44: 1-31.
172. Beauchesne P. Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours. Lancet Oncol 2010; 11: 871-9.
173. Platini C, Long J, Walter S. Meningeal carcinomatosis from breast cancer treated with intrathecal trastuzumab. Lancet Oncol 2006; 7: 778-80.
174. Gururangan S, Petros WP, Poussaint TY, et al. Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004). Clin Cancer Res 2006; 12: 1540-6.
175. Cheung CW, Burton C, Smith P, Linch DC, Hoskin PJ, Ardeshna KM. Central nervous system chemoprophylaxis in non-Hodgkin lymphoma: current practice in the UK. Br J Haematol 2005; 131: 193-200.
176. Ochiai H, Campbell SA, Archer GE, et al. Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus. Clin Cancer Res 2006; 12: 1349-54.
177. Witham TF, Fukui MB, Meltzer CC, Burns R, Kondziolka D, Bozik ME. Survival of patients with high grade glioma treated with intrathecal thiotriethylenephosphoramide for ependymal or leptomeningeal gliomatosis. Cancer 1999; 86: 1347-53.
178. Grabb PA, Guin-Renfroe S, Meythaler JM. Midthoracic catheter tip placement for intrathecal baclofen administration in children with quadriparetic spasticity. Neurosurgery 1999; 45: 833-6; discussion 6-7.
179. Murphy NA, Irwin MC, Hoff C. Intrathecal baclofen therapy in children with cerebral palsy: efficacy and complications. Arch Phys Med Rehabil 2002; 83: 1721-5.
180. Bennett G, Burchiel K, Buchser E, et al. Clinical guidelines for intraspinal infusion: report of an expert panel. PolyAnalgesic Consensus Conference 2000. J Pain Symptom Manage 2000; 20: S37-43.
181. Deer TR, Smith HS, Cousins M, et al. Consensus guidelines for the selection and implantation of patients with noncancer pain for intrathecal drug delivery. Pain Phys 2010; 13: E175-213.
182. Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm 2007; 337: 1-24.
183. Pardridge WM. Blood-brain barrier delivery. Drug Discov Today 2007; 12: 54-61.
184. Graff CL, Pollack GM. Nasal drug administration: potential for targeted central nervous system delivery. J Pharm Sci 2005; 94: 1187-95.
185. Allhenn D, Shetab Boushehri MA, Lamprecht A. Drug delivery strategies for the treatment of malignant gliomas. Int J Pharm 2012; 436: 299-310.
186. Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012; 64: 614-28.
187. Wu H, Hu K, Jiang X. From nose to brain: understanding transport capacity and transport rate of drugs. Expert Opin Drug Deliv 2008; 5: 1159-68.
188. Ying W, Wei G, Wang D, et al. Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia. Front Biosci 2007; 12: 2728-34.
189. Wei G, Wang D, Lu H, et al. Intranasal administration of a PARG inhibitor profoundly decreases ischemic brain injury. Front Biosci 2007; 12: 4986-96.
190. Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm 2009; 379: 146-57.
191. Wang X, Chi N, Tang X. Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting. Eur J Pharm Biopharm 2008; 70: 735-40.
192. Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm 2008; 358: 285-91.
193. Kumar M, Misra A, Mishra AK, Mishra P, Pathak K. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Target 2008; 16: 806-14.
194. da Fonseca CO, Schwartsmann G, Fischer J, et al. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol 2008; 70: 259-66.
195. Fonseca C, Linden R, Futuro Db, Gattass C, Quirico-Santos T. Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcohol. Arch Immunol Ther Exp 2008; 56: 267-76.
196. Yang J, Lu L, Wang H-C, et al. Effect of intranasal arginine vasopressin on human headache. Peptides 2012; 38: 100-4.
197. Langer R, Folkman J. Polymers for the sustained release of proteins and other macromolecules. Nature 1976; 263: 797-800.
198. Leach KJ, Mathiowitz E. Degradation of double-walled polymer microspheres of PLLA and P(CPP: SA)20: 80: in vitro degradation. Biomaterials 1998; 19: 1973-80.
199. Shieh L, Tamada J, Chen I, Pang J, Domb A, Langer R. Erosion of a new family of biodegradable polyanhydrides. J Biomed Mater Res 1994; 28: 1465-75.
200. Lavik EB, Hrkach JS, Lotan N, Nazarov R, Langer R. A simple synthetic route to the formation of a block copolymer of poly(lactic-co-glycolic acid) and polylysine for the fabrication of functionalized, degradable structures for biomedical applications. J Biomed Mater Res 2001; 58: 291-4.
201. Lesniak MS, Langer R, Brem H. Drug delivery to tumors of the central nervous system. Curr Neurol Neurosci Rep 2001; 1: 210-6.
202. Bouhadir KH, Alsberg E, Mooney DJ. Hydrogels for combination delivery of antineoplastic agents. Biomaterials 2001; 22: 2625-33.
203. Olivi A, Ewend MG, Utsuki T, et al. Interstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat. Cancer Chemother Pharmacol 1996; 39: 90-6.
204. Sun ZJ, Chen C, Sun MZ, et al. The application of poly (glycerolsebacate) as biodegradable drug carrier. Biomaterials 2009; 30: 5209-14.
205. Brem H, Mahaley MS, Jr., Vick NA, et al. Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 1991; 74: 441-6.
206. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 1995; 345: 1008-12.
207. Brem H, Ewend MG, Piantadosi S, Greenhoot J, Burger PC, Sisti M. The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. J Neurooncol 1995; 26: 111-23.
208. Valtonen S, Timonen U, Toivanen P, et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 1997; 41: 44-8; discussion 8-9.
209. Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 2003; 5: 79-88.
210. Santini JT Jr, Cima MJ, Langer R. A controlled-release microchip. Nature 1999; 397: 335-8.
211. Richards Grayson AC, Choi IS, Tyler BM, et al. Multi-pulse drug delivery from a resorbable polymeric microchip device. Nat Mater 2003; 2: 767-72.
212. Li Y, Ho Duc HL, Tyler B, et al. In vivo delivery of BCNU from a MEMS device to a tumor model. J Control Release 2005; 106: 138-45.
213. Kim GY, Tyler BM, Tupper MM, et al. Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model. J Control Release 2007; 123: 172-8.
214. Bregy A, Shah AH, Diaz MV, et al. The role of Gliadel wafers in the treatment of high-grade gliomas. Expert Rev Anticancer Ther 2013; 13: 1453-61.
215. Fung LK, Shin M, Tyler B, Brem H, Saltzman WM. Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm Res 1996; 13: 671-82.
216. Kroin JS, Penn RD. Intracerebral chemotherapy: chronic microinfusion of cisplatin. Neurosurgery 1982; 10: 349-54.
217. Sendelbeck SL, Urquhart J. Spatial distribution of dopamine, methotrexate and antipyrine during continuous intracerebral microperfusion. Brain Res 1985; 328: 251-8.
218. Lieberman DM, Laske DW, Morrison PF, Bankiewicz KS, Oldfield EH. Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 1995; 82: 1021-9.
219. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 1994; 91: 2076-80.
220. Lonser RR, Sarntinoranont M, Morrison PF, Oldfield EH. Convection-enhanced delivery to the central nervous system. J Neurosurg 2015; 122: 697-706.
221. Strasser JF, Fung LK, Eller S, Grossman SA, Saltzman WM. Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea and tracers in the rabbit brain after interstitial delivery by biodegradable polymer implants. J Pharmacol Exp Ther 1995; 275: 1647-55.
222. Shi M, Fortin D, Sanche L, Paquette B. Convection-enhancement delivery of platinum-based drugs and Lipoplatin(TM) to optimize the concomitant effect with radiotherapy in F98 glioma rat model. Invest New Drugs 2015; 33: 555-63.
223. Sewing AC, Caretti V, Lagerweij T, et al. Convection enhanced delivery of carmustine to the murine brainstem: a feasibility study. J Neurosci Methods 2014; 238: 88-94.
224. Anderson RC, Kennedy B, Yanes CL, et al. Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children. J Neurosurg Pediatr 2013; 11: 289-95.
225. Hardy PA, Keeley D, Schorn G, et al. Convection enhanced delivery of different molecular weight tracers of gadolinium-tagged polylysine. J Neurosci Methods 2013; 219: 169-75.
226. Asthagiri AR, Walbridge S, Heiss JD, Lonser RR. Effect of concentration on the accuracy of convective imaging distribution of a gadolinium-based surrogate tracer. J Neurosurg 2011; 115: 467-73.
227. Sampson JH, Brady M, Raghavan R, et al. Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecularweight molecules after intracerebral convection-enhanced delivery in humans. Neurosurgery 2011; 69: 668-76.
228. Barua NU, Bienemann AS, Woolley M, et al. Convectionenhanced delivery of MANF -volume of distribution analysis in porcine putamen and substantia nigra. J Neurol Sci 2015; 357: 264-9.
229. Chen MY, Hoffer A, Morrison PF, et al. Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system. J Neurosurg 2005; 103: 311-9.
230. Szerlip NJ, Walbridge S, Yang L, et al. Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles. J Neurosurg 2007; 107: 560-7.
231. Dickinson PJ, LeCouteur RA, Higgins RJ, et al. Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: laboratory investigation. J Neurosurg 2008; 108: 989-98.
232. Arshad A, Yang B, Bienemann AS, et al. Convection-enhanced delivery of carboplatin PLGA nanoparticles for the treatment of glioblastoma. PLoS One 2015; 10: e0132266.
233. Mastorakos P, Zhang C, Berry S, et al. Highly PEGylated DNA nanoparticles provide uniform and widespread gene transfer in the brain. Adv Healthc Mater 2015; 4: 1023-33.
234. Foley CP, Nishimura N, Neeves KB, Schaffer CB, Olbricht WL. Real-time imaging of perivascular transport of nanoparticles during convection-enhanced delivery in the rat cortex. Ann Biomed Eng 2012; 40: 292-303.
235. Ksendzovsky A, Walbridge S, Saunders RC, Asthagiri AR, Heiss JD, Lonser RR. Convection-enhanced delivery of M13 bacteriophage to the brain. J Neurosurg 2012; 117: 197-203.
236. Kenny GD, Bienemann AS, Tagalakis AD, et al. Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain. Biomaterials 2013; 34: 9190-200.
237. Thorne RG, Nicholson C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci USA 2006; 103: 5567-72.
238. Nance EA, Woodworth GF, Sailor KA, et al. A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci Transl Med 2012; 4: 149ra19.
239. Lidar Z, Mardor Y, Jonas T, et al. Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg 2004; 100: 472-9.
240. Patel SJ, Shapiro WR, Laske DW, et al. Safety and feasibility of convection-enhanced delivery of Cotara for the treatment of malignant glioma: initial experience in 51 patients. Neurosurgery 2005; 56: 1243-52; discussion 52-3.
241. Carpentier A, Laigle-Donadey F, Zohar S, et al. Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol 2006; 8: 60-6.
242. Carpentier A, Metellus P, Ursu R, et al. Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro Oncol 2010; 12: 401-8.
243. Weber F, Asher A, Bucholz R, et al. Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol 2003; 64: 125-37.
244. Laske DW, Youle RJ, Oldfield EH. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med 1997; 3: 1362-8.
245. Weaver M, Laske DW. Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol 2003; 65: 3-13.
246. Kunwar S, Prados MD, Chang SM, et al. Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol 2007; 25: 837-44.
247. Vogelbaum MA, Sampson JH, Kunwar S, et al. Convectionenhanced delivery of cintredekin besudotox (interleukin-13-PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: phase 1 study of final safety results. Neurosurgery 2007; 61: 1031-7; discussion 7-8.
248. Kunwar S, Chang S, Westphal M, et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol 2010; 12: 871-81.
249. Sampson JH, Archer G, Pedain C, et al. Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg 2010; 113: 301-9.
250. Chen MY, Lonser RR, Morrison PF, Governale LS, Oldfield EH. Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg 1999; 90: 315-20.
251. Sampson JH, Akabani G, Archer GE, et al. Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. Neuro Oncol 2008; 10: 320-9.
252. Morrison PF, Chen MY, Chadwick RS, Lonser RR, Oldfield EH. Focal delivery during direct infusion to brain: role of flow rate, catheter diameter, and tissue mechanics. Am J Physiol 1999; 277: R1218-29.
253. White E, Bienemann A, Malone J, et al. An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery. J Neurosci Methods 2011; 199: 87-97.
254. Krauze MT, Saito R, Noble C, et al. Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 2005; 103: 923-9.
255. Rosenbluth KH, Luz M, Mohr E, Mittermeyer S, Bringas J, Bankiewicz KS. Design of an in-dwelling cannula for convectionenhanced delivery. J Neurosci Methods 2011; 196: 118-23.
256. Oh S, Odland R, Wilson SR, et al. Improved distribution of small molecules and viral vectors in the murine brain using a hollow fiber catheter. J Neurosurg 2007; 107: 568-77.