Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases.

The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed.

[1]  R. Ransohoff,et al.  Development, maintenance and disruption of the blood-brain barrier , 2013, Nature Medicine.

[2]  Catarina Gomes,et al.  Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. , 2011, Biochimica et biophysica acta.

[3]  Sei-Young Lee,et al.  Shaping nano-/micro-particles for enhanced vascular interaction in laminar flows , 2009, Nanotechnology.

[4]  Dan Peer,et al.  Precision nanomedicine in neurodegenerative diseases. , 2014, ACS nano.

[5]  John Hardy,et al.  The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal , 2009, Journal of neurochemistry.

[6]  Peng Shi,et al.  Remote modulation of neural activities via near-infrared triggered release of biomolecules. , 2015, Biomaterials.

[7]  Andrew Emili,et al.  Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. , 2012, Journal of the American Chemical Society.

[8]  J. Cano,et al.  Blood–brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons , 2007, Journal of neurochemistry.

[9]  H. Fernandez,et al.  Updates in the medical management of Parkinson disease , 2012, Cleveland Clinic Journal of Medicine.

[10]  Keishiro Tomoda,et al.  Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. , 2008, Colloids and surfaces. B, Biointerfaces.

[11]  P. Hof,et al.  Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson’s disease cases , 1996, Acta Neuropathologica.

[12]  L. Garcia-Segura,et al.  Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease , 2014, Front. Cell. Neurosci..

[13]  W. Thies,et al.  2013 Alzheimer's disease facts and figures , 2013, Alzheimer's & Dementia.

[14]  D. Begley,et al.  Albumin nanoparticles targeted with Apo E enter the CNS by transcytosis and are delivered to neurones. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[15]  Patrick Couvreur,et al.  A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood–Brain Barrier and Provides Neuroprotection , 2009, The Journal of Neuroscience.

[16]  Quanyin Hu,et al.  B6 peptide-modified PEG-PLA nanoparticles for enhanced brain delivery of neuroprotective peptide. , 2013, Bioconjugate chemistry.

[17]  H. Przuntek,et al.  Integrity of the blood–cerebrospinal fluid barrier in early Parkinson's disease , 2001, Neuroscience Letters.

[18]  William A Banks,et al.  Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[19]  Jun Chen,et al.  Lipoprotein-based nanoparticles rescue the memory loss of mice with Alzheimer's disease by accelerating the clearance of amyloid-beta. , 2014, ACS nano.

[20]  Maxime Culot,et al.  A Stable and Reproducible Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells , 2014, PloS one.

[21]  H. Davies,et al.  Glucose-Coated Gold Nanoparticles Transfer across Human Brain Endothelium and Enter Astrocytes In Vitro , 2013, PLoS ONE.

[22]  Mark E. Davis,et al.  Mechanism of active targeting in solid tumors with transferrin-containing gold nanoparticles , 2009, Proceedings of the National Academy of Sciences.

[23]  Fernando Albericio,et al.  Improving the brain delivery of gold nanoparticles by conjugation with an amphipathic peptide. , 2010, Nanomedicine.

[24]  Sukant Khurana,et al.  Evaluation of Models of Parkinson's Disease , 2016, Front. Neurosci..

[25]  Thomas Knobloch,et al.  Targeting the insulin receptor: nanoparticles for drug delivery across the blood–brain barrier (BBB) , 2011, Journal of drug targeting.

[26]  W. Wan,et al.  The potential mechanisms of Aβ-receptor for advanced glycation end-products interaction disrupting tight junctions of the blood-brain barrier in Alzheimer's disease , 2014, The International journal of neuroscience.

[27]  Sookja K. Chung,et al.  Caveolin‐1 regulates nitric oxide‐mediated matrix metalloproteinases activity and blood–brain barrier permeability in focal cerebral ischemia and reperfusion injury , 2012, Journal of neurochemistry.

[28]  P. Couvreur,et al.  Squalenoyl Adenosine Nanoparticles provide Neuroprotection after Stroke and Spinal Cord Injury , 2014, Nature nanotechnology.

[29]  P. Couraud,et al.  Instruction of Circulating Endothelial Progenitors In Vitro towards Specialized Blood-Brain Barrier and Arterial Phenotypes , 2014, PloS one.

[30]  Patrick Couvreur,et al.  Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26. , 2005, Bioconjugate chemistry.

[31]  Tong-ying Jiang,et al.  Trimethylated chitosan-conjugated PLGA nanoparticles for the delivery of drugs to the brain. , 2010, Biomaterials.

[32]  Mikio Shoji,et al.  Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease , 2001, The Journal of Neuroscience.

[33]  A. Mccarthy.  Development , 1996, Current Opinion in Neurobiology.

[34]  K. Dawson,et al.  Imaging approach to mechanistic study of nanoparticle interactions with the blood-brain barrier. , 2014, ACS nano.

[35]  D D Allen,et al.  Nanoparticle Technology for Drug Delivery Across the Blood-Brain Barrier , 2002, Drug development and industrial pharmacy.

[36]  H. Winn,et al.  Regulation of cerebral vasculature in normal and ischemic brain , 2008, Neuropharmacology.

[37]  M. Motiei,et al.  Transport of nanoparticles through the blood-brain barrier for imaging and therapeutic applications. , 2014, Nanoscale.

[38]  J. Koenderink.  Q… , 2014, Les noms officiels des communes de Wallonie, de Bruxelles-Capitale et de la communaute germanophone.

[39]  D. Kaufer,et al.  Blood-brain barrier in health and disease. , 2015, Seminars in cell & developmental biology.

[40]  Qizhi Zhang,et al.  Dual-functional nanoparticles targeting amyloid plaques in the brains of Alzheimer's disease mice. , 2014, Biomaterials.

[41]  Yoon Kyung Choi,et al.  Blood-neural barrier: its diversity and coordinated cell-to-cell communication. , 2008, BMB reports.

[42]  E. Hirsch,et al.  Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. , 2008, The Journal of clinical investigation.

[43]  Yu-hua Chen,et al.  Microglial TNF-α-Dependent Elevation of MHC Class I Expression on Brain Endothelium Induced by Amyloid-Beta Promotes T Cell Transendothelial Migration , 2013, Neurochemical Research.

[44]  B. Långström,et al.  Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport , 2009, Drug Metabolism and Disposition.

[45]  Y. Ishida,et al.  Regional distributions of manganese, iron, copper, and zinc in the brains of 6-hydroxydopamine-induced parkinsonian rats , 2005, Analytical and bioanalytical chemistry.

[46]  Paul R. Lockman,et al.  Nanoparticle Surface Charges Alter Blood–Brain Barrier Integrity and Permeability , 2004, Journal of drug targeting.

[47]  Y Agid,et al.  Expression of lactoferrin receptors is increased in the mesencephalon of patients with Parkinson disease. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Miyata,et al.  Neurogenesis in the circumventricular organs of adult mouse brains , 2013, Journal of neuroscience research.

[49]  W. Luk,et al.  Boosting Brain Uptake of a Therapeutic Antibody by Reducing Its Affinity for a Transcytosis Target , 2011, Science Translational Medicine.

[50]  P. Mcgeer,et al.  Inflammation and neurodegeneration in Parkinson's disease. , 2004, Parkinsonism & related disorders.

[51]  N. Inestrosa,et al.  Peroxisome Proliferator-activated Receptors and Alzheimer's Disease: Hitting the Blood–Brain Barrier , 2013, Molecular Neurobiology.

[52]  Mark E. Davis,et al.  Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor , 2013, Proceedings of the National Academy of Sciences.

[53]  V. Janardhan,et al.  Mechanisms of ischemic brain injury , 2004, Current cardiology reports.

[54]  Xue-song Liu,et al.  Protective effects of cationic bovine serum albumin-conjugated PEGylated tanshinone IIA nanoparticles on cerebral ischemia. , 2013, Biomaterials.

[55]  Arturo Alvarez-Buylla,et al.  Neurogenesis in Adult Subventricular Zone , 2002, The Journal of Neuroscience.

[56]  S. Reinhardt,et al.  A Novel Blood-Brain Barrier Co-Culture System for Drug Targeting of Alzheimer’s Disease: Establishment by Using Acitretin as a Model Drug , 2014, PloS one.

[57]  Linyin Feng,et al.  Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model , 2010, Journal of the Neurological Sciences.

[58]  Anil Kumar,et al.  A review on animal models of stroke: An update , 2016, Brain Research Bulletin.

[59]  R. Müller,et al.  Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly(butyl cyanoacrylate) nanoparticles: revisiting the role of surfactants. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[60]  Jun Wang,et al.  The Interaction of Amyloid β and the Receptor for Advanced Glycation Endproducts Induces Matrix Metalloproteinase-2 Expression in Brain Endothelial Cells , 2011, Cellular and Molecular Neurobiology.

[61]  A. Pisani,et al.  Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease , 2012, Journal of Neuroinflammation.

[62]  D. Van Dam,et al.  Animal models in the drug discovery pipeline for Alzheimer's disease , 2011, British journal of pharmacology.

[63]  F. Cupaioli,et al.  Engineered nanoparticles. How brain friendly is this new guest? , 2014, Progress in Neurobiology.

[64]  Fang Liu,et al.  Conjugation of Functionalized SPIONs with Transferrin for Targeting and Imaging Brain Glial Tumors in Rat Model , 2012, PloS one.

[65]  J. Arenillas,et al.  Matrix Metalloproteinase-9 Pretreatment Level Predicts Intracranial Hemorrhagic Complications After Thrombolysis in Human Stroke , 2003, Circulation.

[66]  J. Kreuter,et al.  Covalent attachment of apolipoprotein A-I and apolipoprotein B-100 to albumin nanoparticles enables drug transport into the brain. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[67]  E. Matsubara,et al.  Lipoprotein‐free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer's disease and Down's syndrome , 1999, Annals of neurology.

[68]  J. Kreuter,et al.  Drug delivery to the central nervous system by polymeric nanoparticles: what do we know? , 2014, Advanced drug delivery reviews.

[69]  D. Dexter,et al.  Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment. , 1999, Advances in experimental medicine and biology.

[70]  S. Warach,et al.  Evidence of Reperfusion Injury, Exacerbated by Thrombolytic Therapy, in Human Focal Brain Ischemia Using a Novel Imaging Marker of Early Blood–Brain Barrier Disruption , 2004, Stroke.

[71]  Julie A. Schneider,et al.  Evidence for angiogenesis in Parkinson’s disease, incidental Lewy body disease, and progressive supranuclear palsy , 2011, Journal of Neural Transmission.

[72]  Katya Tsaioun,et al.  ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective , 2009, BMC neurology.

[73]  Rajendra Kumar Shukla,et al.  Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats. , 2015, ACS nano.

[74]  V. Janardhan,et al.  Blood–brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke , 2012, Neurology.

[75]  Anirvan Ghosh,et al.  Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle , 2014, Neuron.

[76]  David Eidelberg,et al.  Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson's Disease , 2008, The Journal of Neuroscience.

[77]  P. Scheltens,et al.  Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene , 2012, EJNMMI Research.

[78]  Dong Chen,et al.  The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. , 2011, ACS nano.

[79]  Samir Mitragotri,et al.  Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium , 2013, Proceedings of the National Academy of Sciences.

[80]  E. Murphy,et al.  Lipopolysaccharide-induced blood brain barrier permeability is enhanced by alpha-synuclein expression , 2013, Neuroscience Letters.

[81]  J. Woulfe,et al.  Striatal Blood–Brain Barrier Permeability in Parkinson'S Disease , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[82]  E. Barbu,et al.  The potential for nanoparticle-based drug delivery to the brain: overcoming the blood-brain barrier. , 2009, Expert opinion on drug delivery.

[83]  G. Fricker,et al.  Delivery of nanoparticles to the brain detected by fluorescence microscopy. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[84]  Penny A. MacDonald,et al.  The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson's disease: support from functional MRI. , 2011, Brain : a journal of neurology.

[85]  Stuart Kyle,et al.  Nanotechnology for the Detection and Therapy of Stroke , 2014, Advanced healthcare materials.

[86]  J. Kreuter,et al.  Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB). , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[87]  I. Pienaar,et al.  Disruption of the blood-brain barrier in Parkinson's disease: curse or route to a cure? , 2014, Frontiers in bioscience.

[88]  Elizabeth Nance,et al.  A Dense Poly(Ethylene Glycol) Coating Improves Penetration of Large Polymeric Nanoparticles Within Brain Tissue , 2012, Science Translational Medicine.

[89]  C. Greer,et al.  Blood vessels form a migratory scaffold in the rostral migratory stream , 2009, The Journal of comparative neurology.

[90]  A. Paillard,et al.  Influence of surface charge and inner composition of porous nanoparticles to cross blood-brain barrier in vitro. , 2007, International journal of pharmaceutics.

[91]  T. Aminabhavi,et al.  Quinoline-n-butylcyanoacrylate-based nanoparticles for brain targeting for the diagnosis of Alzheimer's disease. , 2010, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[92]  J. Bart,et al.  Blood–brain barrier dysfunction in parkinsonian midbrain in vivo , 2005, Annals of neurology.

[93]  E. Hirsch,et al.  The Iron-Binding Protein Lactoferrin Protects Vulnerable Dopamine Neurons from Degeneration by Preserving Mitochondrial Calcium Homeostasis , 2013, Molecular Pharmacology.

[94]  J. Haorah,et al.  Blood–brain Barrier: Structural Components and Function Under Physiologic and Pathologic Conditions , 2006, Journal of Neuroimmune Pharmacology.

[95]  Jin Xie,et al.  Nanoparticle-based theranostic agents. , 2010, Advanced drug delivery reviews.

[96]  Mark D. Huffman,et al.  AHA Statistical Update Heart Disease and Stroke Statistics — 2012 Update A Report From the American Heart Association WRITING GROUP MEMBERS , 2010 .

[97]  W. Pardridge,et al.  Blood-brain barrier transport and brain metabolism of adenosine and adenosine analogs. , 1994, The Journal of pharmacology and experimental therapeutics.

[98]  A. Hafezi-Moghadam,et al.  ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. , 2007, American journal of physiology. Cell physiology.

[99]  Barbara Ruozi,et al.  Polymeric nanoparticles for the drug delivery to the central nervous system , 2008, Expert opinion on drug delivery.

[100]  P. Couraud,et al.  Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation , 2012, Fluids and Barriers of the CNS.

[101]  D. Matias,et al.  The impact of microglial activation on blood-brain barrier in brain diseases , 2014, Front. Cell. Neurosci..

[102]  Samir Mitragotri,et al.  Flow and adhesion of drug carriers in blood vessels depend on their shape: a study using model synthetic microvascular networks. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[103]  B. Zlokovic.  Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders , 2011, Nature Reviews Neuroscience.

[104]  David J. Begley,et al.  Structure and function of the blood–brain barrier , 2010, Neurobiology of Disease.

[105]  E. Hirsch,et al.  Changes in vascularization in substantia nigra pars compacta of monkeys rendered parkinsonian , 2005, Journal of Neural Transmission.

[106]  M. Dehouck,et al.  Stem Cell-Based Human Blood-Brain Barrier Models for Drug Discovery and Delivery. , 2016, Trends in biotechnology.

[107]  A. Bartels.  Blood-brain barrier P-glycoprotein function in neurodegenerative disease. , 2011, Current pharmaceutical design.

[108]  J. García-Verdugo,et al.  A specialized vascular niche for adult neural stem cells. , 2008, Cell stem cell.

[109]  D VanDam,et al.  Animal models in the drug discovery pipeline for Alzheimer's disease. , 2011 .

[110]  N. Abbott,et al.  Brain to blood efflux transport of adenosine: blood–brain barrier studies in the rat , 2004, Journal of neurochemistry.

[111]  Jinfeng Hou,et al.  P-Glycoprotein Mediated Efflux Limits the Transport of the Novel Anti-Parkinson's Disease Candidate Drug FLZ across the Physiological and PD Pathological In Vitro BBB Models , 2014, PloS one.

[112]  Warren C W Chan,et al.  Design and potential application of PEGylated gold nanoparticles with size-dependent permeation through brain microvasculature. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[113]  Jesse D. Sengillo,et al.  GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration , 2015, Nature Neuroscience.

[114]  Rongqin Huang,et al.  Neuroprotection in a 6‐hydroxydopamine‐lesioned Parkinson model using lactoferrin‐modified nanoparticles , 2009, The journal of gene medicine.

[115]  I. Grundke‐Iqbal,et al.  Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease , 2008, FEBS letters.

[116]  S. Vincent,et al.  Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood–brain barrier , 2004, Experimental Neurology.

[117]  E. Hirsch,et al.  Blood vessels change in the mesencephalon of patients with Parkinson's disease , 1999, The Lancet.

[118]  M. Masserini.  Nanoparticles for Brain Drug Delivery , 2013, ISRN biochemistry.

[119]  M Ferrari,et al.  Size and shape effects in the biodistribution of intravascularly injected particles. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[120]  A. Hofman,et al.  Cerebral hypoperfusion and clinical onset of dementia: The Rotterdam study , 2005, Annals of neurology.

[121]  D. Begley,et al.  Brain Targeting Of Nerve Growth Factor Using Poly(Butylcyanoacrylate) Nanoparticles , 2004 .

[122]  L. Ferreira,et al.  Nanomedicine boosts neurogenesis: new strategies for brain repair. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[123]  Qing-hui Zhou,et al.  Receptor-mediated abeta amyloid antibody targeting to Alzheimer's disease mouse brain. , 2011, Molecular pharmaceutics.

[124]  F. Calon,et al.  Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[125]  Yoshinobu Manome,et al.  Cell-Based in Vitro Blood–Brain Barrier Model Can Rapidly Evaluate Nanoparticles’ Brain Permeability in Association with Particle Size and Surface Modification , 2014, International journal of molecular sciences.

[126]  I. Mook‐Jung,et al.  Disruption of blood-brain barrier in Alzheimer disease pathogenesis , 2013, Tissue barriers.

[127]  W. Pardridge.  Drug Targeting to the Brain , 2007, Pharmaceutical Research.

[128]  Xinguo Jiang,et al.  Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: preparation, characterization and efficacy in Parkinson's disease. , 2011, International journal of pharmaceutics.

[129]  L. Pan,et al.  The effect of cationic albumin-conjugated PEGylated tanshinone IIA nanoparticles on neuronal signal pathways and neuroprotection in cerebral ischemia. , 2013, Biomaterials.

[130]  R. Egleton,et al.  Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. , 2001, American journal of physiology. Heart and circulatory physiology.

[131]  H. Davson.  Blood–brain barrier , 1977, Nature.

[132]  C. Xue,et al.  Role of P-glycoprotein in restricting the brain penetration of tanshinone IIA, a major active constituent from the root of Salvia miltiorrhiza Bunge, across the blood–brain barrier , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[133]  H. H. Marti,et al.  Matrix Metalloproteinase-9 Mediates Hypoxia-Induced Vascular Leakage in the Brain via Tight Junction Rearrangement , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[134]  Jun Qian,et al.  Overcoming the blood-brain barrier for delivering drugs into the brain by using adenosine receptor nanoagonist. , 2014, ACS nano.

[135]  T. Abbruscato,et al.  An in vitro model of ischemic stroke. , 2012, Methods in molecular biology.

[136]  D. Borchelt,et al.  SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein , 1999, Nature Neuroscience.

[137]  B. Hyman,et al.  Nanoparticles enhance brain delivery of blood–brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging , 2011, Proceedings of the National Academy of Sciences.

[138]  S. Maeng,et al.  MMP-3 Contributes to Nigrostriatal Dopaminergic Neuronal Loss, BBB Damage, and Neuroinflammation in an MPTP Mouse Model of Parkinson's Disease , 2013, Mediators of inflammation.

[139]  Sungho Jin,et al.  Magnetic targeting of nanoparticles across the intact blood-brain barrier. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[140]  G. Enikolopov,et al.  Circumventricular organs: A novel site of neural stem cells in the adult brain , 2009, Molecular and Cellular Neuroscience.

[141]  C. Dickey,et al.  Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy , 2015, Acta neuropathologica communications.

[142]  A. Wu,et al.  The effects of Tanshinone IIA on blood-brain barrier and brain edema after transient middle cerebral artery occlusion in rats. , 2010, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[143]  V. Rotello,et al.  Modulating Pharmacokinetics, Tumor Uptake and Biodistribution by Engineered Nanoparticles , 2011, PloS one.

[144]  G. Rosenberg,et al.  Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. , 2011, Stroke.

[145]  Jeffrey F. Thompson,et al.  Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[146]  L. Badimón,et al.  Matrix metalloproteinase-9 pretreatment level predicts intracraneal hemorrhagic complications after thrombolysis in human stroke , 2004 .

[147]  H. Arias,et al.  The role of inflammation in Alzheimer's disease. , 2005, The international journal of biochemistry & cell biology.

[148]  R. Rosenwasser,et al.  Neurogenesis is enhanced by stroke in multiple new stem cell niches along the ventricular system at sites of high BBB permeability , 2015, Neurobiology of Disease.

[149]  Jijin Gu,et al.  The brain targeting mechanism of Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles. , 2012, Biomaterials.

[150]  A. Misra,et al.  Comparative receptor based brain delivery of tramadol-loaded poly(lactic-co-glycolic acid) nanoparticles. , 2012, Journal of biomedical nanotechnology.

[151]  I. Zuhorn,et al.  Surface characteristics of nanoparticles determine their intracellular fate in and processing by human blood-brain barrier endothelial cells in vitro. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[152]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[153]  D. Holtzman,et al.  Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. , 2000, The Journal of clinical investigation.

[154]  S. Lule,et al.  Systemically Administered Brain-Targeted Nanoparticles Transport Peptides across the Blood—Brain Barrier and Provide Neuroprotection , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[155]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[156]  L. Xiong,et al.  DDR1 may play a key role in destruction of the blood–brain barrier after cerebral ischemia–reperfusion , 2015, Neuroscience Research.

[157]  R. Yokel.  Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. , 2006, Journal of Alzheimer's disease : JAD.

[158]  T. Hibi,et al.  Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. , 2008, Pharmacology & therapeutics.

[159]  D. Frenkel,et al.  Designing super selectivity in multivalent nano-particle binding , 2011, Proceedings of the National Academy of Sciences.

[160]  Yunhui Liu,et al.  Specific Role of Tight Junction Proteins Claudin-5, Occludin, and ZO-1 of the Blood–Brain Barrier in a Focal Cerebral Ischemic Insult , 2011, Journal of Molecular Neuroscience.

[161]  J. Kreuter.  Drug targeting with nanoparticles , 1994, European Journal of Drug Metabolism and Pharmacokinetics.

[162]  Ann Marie Schmidt,et al.  RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain , 2003, Nature Medicine.

[163]  Leaf Huang,et al.  Nanoparticles evading the reticuloendothelial system: role of the supported bilayer. , 2009, Biochimica et biophysica acta.

[164]  Hartwig Wolburg,et al.  Tight junctions of the blood-brain barrier: development, composition and regulation. , 2002, Vascular pharmacology.

[165]  D. Breimer,et al.  Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood-brain barrier in vitro. , 2003, Microvascular research.

[166]  Ken Arai,et al.  Three-Dimensional Blood-Brain Barrier Model for in vitro Studies of Neurovascular Pathology , 2015, Scientific Reports.