Nanotechnology approaches to crossing the blood-brain barrier and drug delivery to the CNS

Nanotechnologies are materials and devices that have a functional organization in at least one dimension on the nanometer (one billionth of a meter) scale, ranging from a few to about 100 nanometers. Nanoengineered materials and devices aimed at biologic applications and medicine in general, and neuroscience in particular, are designed fundamentally to interface and interact with cells and their tissues at the molecular level. One particularly important area of nanotechnology application to the central nervous system (CNS) is the development of technologies and approaches for delivering drugs and other small molecules such as genes, oligonucleotides, and contrast agents across the blood brain barrier (BBB). The BBB protects and isolates CNS structures (i.e. the brain and spinal cord) from the rest of the body, and creates a unique biochemical and immunological environment. Clinically, there are a number of scenarios where drugs or other small molecules need to gain access to the CNS following systemic administration, which necessitates being able to cross the BBB. Nanotechnologies can potentially be designed to carry out multiple specific functions at once or in a predefined sequence, an important requirement for the clinically successful delivery and use of drugs and other molecules to the CNS, and as such have a unique advantage over other complimentary technologies and methods. This brief review introduces emerging work in this area and summarizes a number of example applications to CNS cancers, gene therapy, and analgesia.

[1]  J. Pappenheimer,et al.  Active transport of Diodrast and phenolsulfonphthalein from cerebrospinal fluid to blood. , 1961, The American journal of physiology.

[2]  W H Oldendorf,et al.  Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. , 1971, The American journal of physiology.

[3]  E. Bárány Inhibition by hippurate and probenecid of in vitro uptake of iodipamide and o-iodohippurate. A composite uptake system for iodipamide in choroid plexus, kidney cortex and anterior uvea of several species. , 1972, Acta physiologica Scandinavica.

[4]  E. Bárány The liver-like anion transport system in rabbit kidney, uvea and choroid plexus. I. Selectivity of some inhibitors, direction of transport, possible physiological substrates. , 1973, Acta physiologica Scandinavica.

[5]  H. Davson,et al.  Transport of sulfate in the rabbit's brain , 1973 .

[6]  D. Calne,et al.  Penicillin transport from cerebrospinal fluid , 1976, Neurology.

[7]  K D Pettigrew,et al.  Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. , 1978, The American journal of physiology.

[8]  K. Pettigrew,et al.  Drug entry into the brain , 1979, Brain Research.

[9]  W. Pardridge,et al.  Transport of steroid hormones through the rat blood-brain barrier. Primary role of albumin-bound hormone. , 1979, The Journal of clinical investigation.

[10]  V A Levin,et al.  Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. , 1980, Journal of medicinal chemistry.

[11]  G. Goldstein,et al.  Polarity of the blood-brain barrier: Distribution of enzymes between the luminal and antiluminal membranes of brain capillary endothelial cells , 1980, Brain Research.

[12]  C. Patlak,et al.  Efflux of radiolabeled polyethylene glycols and albumin from rat brain. , 1981, The American journal of physiology.

[13]  T. Tsuruo,et al.  Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. , 1981, Cancer research.

[14]  S. Adler,et al.  Electrical charge. Its role in the pathogenesis and prevention of experimental membranous nephropathy in the rabbit. , 1983, The Journal of clinical investigation.

[15]  S. Rapoport,et al.  An in situ brain perfusion technique to study cerebrovascular transport in the rat. , 1984, The American journal of physiology.

[16]  M. Center,et al.  Adriamycin resistance in HL60 cells in the absence of detectable P-glycoprotein. , 1987, Biochemical and biophysical research communications.

[17]  W. Pardridge,et al.  Absorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport. , 1987, The Journal of biological chemistry.

[18]  A. Leo,et al.  Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design. , 1987, Journal of pharmaceutical sciences.

[19]  R Griffiths,et al.  Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. , 1988, Journal of medicinal chemistry.

[20]  Peter Riederer,et al.  Transition Metals, Ferritin, Glutathione, and Ascorbic Acid in Parkinsonian Brains , 1989, Journal of neurochemistry.

[21]  W. Pardridge,et al.  Transport of histone through the blood-brain barrier. , 1989, The Journal of pharmacology and experimental therapeutics.

[22]  S. P. Gupta,et al.  QSAR studies on drugs acting at the central nervous system , 1989 .

[23]  Hugh Davson,et al.  History of the Blood-Brain Barrier Concept , 1989 .

[24]  M. Epstein,et al.  Cotransport of sodium and chloride by the adult mammalian choroid plexus. , 1990, The American journal of physiology.

[25]  W. Pardridge,et al.  Beta-endorphin chimeric peptides: transport through the blood-brain barrier in vivo and cleavage of disulfide linkage by brain. , 1990, Endocrinology.

[26]  W. Pardridge,et al.  Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. , 1990, The Journal of pharmacology and experimental therapeutics.

[27]  N. Kaplowitz,et al.  Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat. , 1990, The Journal of clinical investigation.

[28]  R. Deane,et al.  Transport of Lead‐203 at the Blood‐Brain Barrier During Short Cerebrovascular Perfusion with Saline in the Rat , 1990, Journal of neurochemistry.

[29]  W. Pardridge,et al.  Enhanced cellular uptake of biotinylated antisense oligonucleotide or peptide mediated by avidin, a cationic protein , 1991, FEBS letters.

[30]  N. Bleehen,et al.  Resistance modification by PSC-833, a novel non-immunosuppressive cyclosporin A , 1991 .

[31]  T. Terasaki,et al.  Transport mechanism of a new behaviorally highly potent adrenocorticotropic hormone (ACTH) analog, ebiratide, through the blood-brain barrier. , 1991, The Journal of pharmacology and experimental therapeutics.

[32]  R. Starzyk,et al.  Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[33]  T. Terasaki,et al.  In‐vivo Blood‐brain Barrier Transport of a Novel Adrenocorticotropic Hormone Analogue, Ebiratide, Demonstrated by Brain Microdialysis and Capillary Depletion Methods , 1992, The Journal of pharmacy and pharmacology.

[34]  W. Pardridge,et al.  Biotin delivery to brain with a covalent conjugate of avidin and a monoclonal antibody to the transferrin receptor. , 1992, The Journal of pharmacology and experimental therapeutics.

[35]  H. Vinters,et al.  Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Kansy,et al.  Hydrogen-Bonding Capacity and Brain Penetration , 1992, Chimia (Basel).

[37]  R. Conradi,et al.  The relationship between peptide structure and transport across epithelial cell monolayers , 1992 .

[38]  C. S. Patlak,et al.  Secretion and Bulk Flow of Interstitial Fluid , 1992 .

[39]  G M Cohen,et al.  Quinone chemistry and toxicity. , 1992, Toxicology and applied pharmacology.

[40]  U. Bickel,et al.  Pharmacologic effects in vivo in brain by vector-mediated peptide drug delivery. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[41]  A. Granholm,et al.  Delivery of Trophic Factors to the Primate Brain , 1993, Experimental Neurology.

[42]  P. Wigler,et al.  Inhibition of the multidrug resistance efflux pump. , 1993, Biochimica et biophysica acta.

[43]  W. Scheithauer,et al.  Clinical trials of agents that reverse multidrug resistance. A literature review , 1993, Cancer.

[44]  S. Lightman,et al.  Transport into retina measured by short vascular perfusion in the rat. , 1993, The Journal of physiology.

[45]  Michael H. Abraham,et al.  Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes , 2010 .

[46]  F. Bloom,et al.  Blood-brain barrier penetration and in vivo activity of an NGF conjugate. , 1993, Science.

[47]  V. Hruby,et al.  Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J. H. Beijnen,et al.  Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs , 1994, Cell.

[49]  D. Hipfner,et al.  Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs. , 1994, Cancer research.

[50]  W. Pardridge,et al.  Use of neutral avidin improves pharmacokinetics and brain delivery of biotin bound to an avidin-monoclonal antibody conjugate. , 1994, The Journal of pharmacology and experimental therapeutics.

[51]  Michael H. Abraham,et al.  Physicochemical analysis of the factors governing distribution of solutes between blood and brain , 1994 .

[52]  B. Lannes Peptide drug delivery to the brain. Raven Press, Oxford (1991), 1 vol, 357 p. , 1994 .

[53]  J. Kordower,et al.  Intravenous administration of a transferrin receptor antibody-nerve growth factor conjugate prevents the degeneration of cholinergic striatal neurons in a model of Huntington disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Meier,et al.  Expression cloning of a rat liver Na(+)-independent organic anion transporter. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[55]  C R Ganellin,et al.  Predicting the brain-penetrating capability of histaminergic compounds. , 1994, Drug design and discovery.

[56]  Harpreet S. Chadha,et al.  Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain. , 1994, Journal of pharmaceutical sciences.

[57]  F. Baas,et al.  The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[58]  D. Keppler,et al.  The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. , 1994, The Journal of biological chemistry.

[59]  R T Borchardt,et al.  The effect of verapamil on the transport of peptides across the blood-brain barrier in rats: kinetic evidence for an apically polarized efflux mechanism. , 1995, The Journal of pharmacology and experimental therapeutics.

[60]  U. Bickel,et al.  In vivo cleavability of a disulfide-based chimeric opioid peptide in rat brain. , 1995, Bioconjugate chemistry.

[61]  P. Borst,et al.  Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. , 1995, The Journal of clinical investigation.

[62]  W. Pardridge Vector-mediated peptide drug delivery to the brain. , 1995, Advanced drug delivery reviews.

[63]  J. Kreuter,et al.  Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles) , 1995, Brain Research.

[64]  W. Pardridge,et al.  Pharmacokinetics and organ clearance of a 3'-biotinylated, internally [32P]-labeled phosphodiester oligodeoxynucleotide coupled to a neutral avidin/monoclonal antibody conjugate. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[65]  U. Bickel Antibody delivery through the blood-brain barrier. , 1995, Advanced drug delivery reviews.

[66]  W. Pardridge,et al.  Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[67]  P. Chou,et al.  Multidrug resistance gene expression in childhood medulloblastoma: correlation with clinical outcome and DNA ploidy in 29 patients. , 1995, Pediatric neurosurgery.

[68]  Y. Rustum,et al.  MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors. , 1996, The American journal of pathology.

[69]  R. Evers,et al.  Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells. , 1996, The Journal of clinical investigation.

[70]  Hugh Davson,et al.  Physiology of the CSF and Blood-Brain Barriers , 1996 .

[71]  W. Dalton,et al.  Serum can inhibit reversal of multidrug resistance by chemosensitisers. , 1996, European journal of cancer.

[72]  D. Keppler,et al.  Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump. , 1996, Cancer research.

[73]  Michał J. Markuszewski,et al.  Brain/blood distribution described by a combination of partition coefficient and molecular mass , 1996 .

[74]  W. Wels,et al.  Target Cell-specific DNA Transfer Mediated by a Chimeric Multidomain Protein , 1996, The Journal of Biological Chemistry.

[75]  D. Keppler,et al.  The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion. , 1996, Advances in enzyme regulation.

[76]  W. Pardridge,et al.  Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system. , 1996, The Journal of pharmacology and experimental therapeutics.

[77]  K. Nakamura,et al.  Thermodynamic aspects of hydrophobicity and the blood-brain barrier permeability studied with a gel filtration chromatography. , 1996, Journal of medicinal chemistry.

[78]  A. Granholm,et al.  Systemic Administration of a Nerve Growth Factor Conjugate Reverses Age-Related Cognitive Dysfunction and Prevents Cholinergic Neuron Atrophy , 1996, The Journal of Neuroscience.

[79]  S. Cole,et al.  ATP-dependent 17-Estradiol 17-(-D-Glucuronide) Transport by Multidrug Resistance Protein (MRP) , 1996, The Journal of Biological Chemistry.

[80]  R. Starzyk,et al.  Enhanced uptake of rsCD4 across the rodent and primate blood-brain barrier after conjugation to anti-transferrin receptor antibodies. , 1996, The Journal of pharmacology and experimental therapeutics.

[81]  D. Scherman,et al.  Functional Expression of P‐Glycoprotein in an Immortalised Cell Line of Rat Brain Endothelial Cells, RBE4 , 1996, Journal of neurochemistry.

[82]  B. Zlokovic,et al.  Evidence for the Existence of a Sodium-dependent Glutathione (GSH) Transporter , 1996, The Journal of Biological Chemistry.

[83]  M. Kool,et al.  Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. , 1997, Cancer research.

[84]  D. Keppler,et al.  The canalicular multidrug resistance protein, cMRP/MRP2, a novel conjugate export pump expressed in the apical membrane of hepatocytes. , 1997, Advances in enzyme regulation.

[85]  P. Meier,et al.  Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[86]  W. Banks,et al.  Acute modulation of active carrier-mediated brain-to-blood transport of corticotropin-releasing hormone. , 1997, The American journal of physiology.

[87]  B. Sikic,et al.  Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein , 1997, Cancer Chemotherapy and Pharmacology.

[88]  S. Morrison,et al.  Functional and pharmacokinetic properties of antibody-avidin fusion proteins. , 1997, Journal of immunology.

[89]  W. Banks,et al.  Selective, Physiological Transport of Insulin Across the Blood-Brain Barrier: Novel Demonstration by Species-Specific Radioimmunoassays , 1997, Peptides.

[90]  U. Bickel,et al.  Brain Microvascular and Astrocyte Localization of P‐Glycoprotein , 1997, Journal of neurochemistry.

[91]  Y. Sai,et al.  Structure-internalization relationship for adsorptive-mediated endocytosis of basic peptides at the blood-brain barrier. , 1997, The Journal of pharmacology and experimental therapeutics.

[92]  Harpreet S. Chadha,et al.  Molecular Factors Influencing Drug Transfer across the Blood‐Brain Barrier , 1997, The Journal of pharmacy and pharmacology.

[93]  U. Bickel,et al.  Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[94]  Antioxidant defense of the brain: a role for astrocytes. , 1997, Canadian journal of physiology and pharmacology.

[95]  J. Beijnen,et al.  Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. , 1997, The Journal of clinical investigation.

[96]  W. Pardridge,et al.  Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor. , 1997, The Journal of clinical investigation.

[97]  T. Yamashita,et al.  Cloning and Functional Expression of a Brain Peptide/Histidine Transporter* , 1997, The Journal of Biological Chemistry.

[98]  H. Galla,et al.  Evidence for an asymmetrical uptake of L-carnitine in the blood-brain barrier in vitro. , 1997, Biochemical and biophysical research communications.

[99]  P. Magistretti,et al.  Expression of monocarboxylate transporter mRNAs in mouse brain: support for a distinct role of lactate as an energy substrate for the neonatal vs. adult brain. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[100]  A. Smith,et al.  Availability of PSC833, a substrate and inhibitor of P-glycoproteins, in various concentrations of serum. , 1998, Journal of the National Cancer Institute.

[101]  W Vaalburg,et al.  Complete in vivo reversal of P‐glycoprotein pump function in the blood‐brain barrier visualized with positron emission tomography , 1998, British journal of pharmacology.

[102]  Y. Sugiyama,et al.  Efflux of taurocholic acid across the blood-brain barrier: interaction with cyclic peptides. , 1998, The Journal of pharmacology and experimental therapeutics.

[103]  D. Begley,et al.  The effect of drug lipophilicity on P-glycoprotein-mediated colchicine efflux at the blood-brain barrier. , 1998, International journal of clinical pharmacology and therapeutics.

[104]  D. A. Kharkevich,et al.  Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study. , 1998, Journal of microencapsulation.

[105]  R. Bergmann,et al.  Mrp1 Multidrug Resistance‐Associated Protein and P‐Glycoprotein Expression in Rat Brain Microvessel Endothelial Cells , 1998, Journal of neurochemistry.

[106]  R. Yokel,et al.  Aluminum transport out of brain extracellular fluid is proton dependent and inhibited by mersalyl acid, suggesting mediation by the monocarboxylate transporter (MCT1). , 1998, Toxicology.

[107]  W. Pardridge,et al.  Enhanced endocytosis in cultured human breast carcinoma cells and in vivo biodistribution in rats of a humanized monoclonal antibody after cationization of the protein. , 1998, The Journal of pharmacology and experimental therapeutics.

[108]  T. Tsuruo,et al.  Characterization of efflux transport of organic anions in a mouse brain capillary endothelial cell line. , 1998, The Journal of pharmacology and experimental therapeutics.

[109]  S. Goldstein,et al.  IAM retention and blood brain barrier penetration , 1998 .

[110]  J. Nezu,et al.  Molecular and Functional Identification of Sodium Ion-dependent, High Affinity Human Carnitine Transporter OCTN2* , 1998, The Journal of Biological Chemistry.

[111]  D. Miller,et al.  Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells. , 1998, Biochemical and biophysical research communications.

[112]  B. Sabel,et al.  Nanoparticle technology for delivery of drugs across the blood-brain barrier. , 1998, Journal of pharmaceutical sciences.

[113]  Y. Sai,et al.  Design and Synthesis of Peptides Passing through the Blood-Brain Barrier , 1998 .

[114]  Y. Sugiyama,et al.  Hepatobiliary transport kinetics of HSR-903, a new quinolone antibacterial agent. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[115]  J. Barrio,et al.  Effects of Large Neutral Amino Acid Concentrations on 6-[F-18]Fluoro-L-DOPA Kinetics , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[116]  W. Pardridge,et al.  Retention of biologic activity of human epidermal growth factor following conjugation to a blood-brain barrier drug delivery vector via an extended poly(ethylene glycol) linker. , 1999, Bioconjugate chemistry.

[117]  W. Pardridge,et al.  Neuroprotection with noninvasive neurotrophin delivery to the brain. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[118]  G Pradal,et al.  Electron microscopy study of intrahepatic ultrasmall superparamagnetic iron oxide kinetics in the rat. Relation with magnetic resonance imaging , 1999, Biology of the cell.

[119]  J. Kreuter,et al.  Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[120]  R. Löbenberg,et al.  Interaction of Poly(butylcyanoacrylate) Nanoparticles with the Blood-Brain Barrier in vivo and in vitro , 2001, Journal of drug targeting.

[121]  G. Vassal,et al.  Poly(ethylene glycol)-Coated Hexadecylcyanoacrylate Nanospheres Display a Combined Effect for Brain Tumor Targeting , 2002, Journal of Pharmacology and Experimental Therapeutics.

[122]  R. Müller,et al.  Lipid-Drug-Conjugate (LDC) Nanoparticles as Novel Carrier System for the Hydrophilic Antitrypanosomal Drug Diminazenediaceturate , 2002, Journal of drug targeting.

[123]  Patrick Couvreur,et al.  Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat , 2002, The European journal of neuroscience.

[124]  F. Calon,et al.  Intravenous nonviral gene therapy causes normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism. , 2003, Human gene therapy.

[125]  G. Pasternak,et al.  Improved Brain Uptake and Pharmacological Activity of Dalargin Using a Peptide-Vector-Mediated Strategy , 2003, Journal of Pharmacology and Experimental Therapeutics.

[126]  A. Sbarbati,et al.  In Vitro and In Vivo Study of Solid Lipid Nanoparticles Loaded with Superparamagnetic Iron Oxide , 2003, Journal of drug targeting.

[127]  T. Terasaki,et al.  Absorptive-Mediated Endocytosis of an Adrenocorticotropic Hormone (ACTH) Analogue, Ebiratide, into the Blood–Brain Barrier: Studies with Monolayers of Primary Cultured Bovine Brain Capillary Endothelial Cells , 1992, Pharmaceutical Research.

[128]  Akira Tsuji,et al.  Carrier-Mediated Intestinal Transport of Drugs , 1996, Pharmaceutical Research.

[129]  K. Geiger,et al.  Chemotherapy of glioblastoma in rats using doxorubicin‐loaded nanoparticles , 2004, International journal of cancer.

[130]  Si-Shen Feng,et al.  Nanoparticles of biodegradable polymers for clinical administration of paclitaxel. , 2004, Current medicinal chemistry.

[131]  H. Okada,et al.  Insulin Fragments as a Carrier for Peptide Delivery Across the Blood–Brain Barrier , 1994, Pharmaceutical Research.

[132]  T. Terasaki,et al.  In Vivo Transport of a Dynorphin-like Analgesic Peptide, E-2078, Through the Blood–Brain Barrier: An Application of Brain Microdialysis , 1991, Pharmaceutical Research.

[133]  Alexander V Kabanov,et al.  Nanogels for oligonucleotide delivery to the brain. , 2004, Bioconjugate chemistry.

[134]  P. Timmermans,et al.  Lipophilicity and brain disposition of clonidine and structurally related imidazolidines , 1977, Naunyn-Schmiedeberg's Archives of Pharmacology.

[135]  J. Kreuter,et al.  Significant Transport of Doxorubicin into the Brain with Polysorbate 80-Coated Nanoparticles , 1999, Pharmaceutical Research.

[136]  I. Arias,et al.  The biology of the P-glycoproteins , 2004, The Journal of Membrane Biology.

[137]  W. Pardridge,et al.  Combined Use of Carboxyl-Directed Protein Pegylation and Vector-Mediated Blood-Brain Barrier Drug Delivery System Optimizes Brain Uptake of Brain-Derived Neurotrophic Factor Following Intravenous Administration , 1998, Pharmaceutical Research.

[138]  D. A. Kharkevich,et al.  Delivery of Loperamide Across the Blood-Brain Barrier with Polysorbate 80-Coated Polybutylcyanoacrylate Nanoparticles , 1997, Pharmaceutical Research.

[139]  J. R. Kanwar Anti-inflammatory immunotherapy for multiple sclerosis/experimental autoimmune encephalomyelitis (EAE) disease. , 2005, Current medicinal chemistry.

[140]  N. Savaraj,et al.  Drug resistance in brain tumors , 2005, Journal of Neuro-Oncology.

[141]  Sungho Jin,et al.  Quantum Dot Applications to Neuroscience: New Tools for Probing Neurons and Glia , 2006, The Journal of Neuroscience.

[142]  S. Miller,et al.  Mechanisms of Immunopathology in Murine Models of Central Nervous System Demyelinating Disease1 , 2006, The Journal of Immunology.

[143]  Gabriel A Silva,et al.  Nanotechnology approaches for drug and small molecule delivery across the blood brain barrier. , 2007, Surgical neurology.

[144]  Harpreet S. Chadha,et al.  Applications of a Solvation Equation to Drug Transport Properties , 2008 .