Nanotechnologies: a strategy to overcome blood-brain barrier.

The possibility to treat central nervous system (CNS) disorders is strongly limited by the poor access of many therapeutic agent to the target tissues. This is mainly due to the presence of the blood-brain barrier (BBB), formed by a complex interplay of endothelial cells, astrocyte and pericytes, through which only selected molecules can passively diffuse to reach CNS. Drug pharmacokinetics and biodistribution can be changed by using nanotechnology, in order to improve drug accumulation into the action site and to limit the drug release in the healthy tissues. When the CNS diseases are characterised by BBB altered permeability, an enhanced drug delivery into the brain can be achieved by using nanocarriers. Moreover, modification of nanocarrier surface with specific endogenous or exogenous ligands can promote enhanced BBB crossing, also in case of unaltered endothelium. This review summarizes the most meaningful advances in the field of nanotechnology for brain delivery of therapeutics.

[1]  D. Stewart,et al.  Review: Molecular pathogenesis of blood–brain barrier breakdown in acute brain injury , 2011, Neuropathology and applied neurobiology.

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

[3]  Yao Qin,et al.  In vitro and in vivo investigation of glucose-mediated brain-targeting liposomes , 2010, Journal of drug targeting.

[4]  M A Vandelli,et al.  Sialic acid and glycopeptides conjugated PLGA nanoparticles for central nervous system targeting: In vivo pharmacological evidence and biodistribution. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[5]  J. Kreuter,et al.  Drug delivery to the brain using surfactant-coated poly(lactide-co-glycolide) nanoparticles: influence of the formulation parameters. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[6]  A. Sigal,et al.  Pegylated nanoliposomes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune encephalomyelitis , 2009, Journal of Neuroimmunology.

[7]  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.

[8]  I. Romero,et al.  P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β , 2009, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  H. Tsukada,et al.  Liposome-encapsulated hemoglobin reduces the size of cerebral infarction in rats: effect of oxygen affinity. , 2009, Artificial organs.

[10]  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.

[11]  D. V. Kohli,et al.  Transferrin-conjugated liposomal system for improved delivery of 5-fluorouracil to brain , 2008 .

[12]  L. Rivers,et al.  Inflammation and dephosphorylation of the tight junction protein occludin in an experimental model of multiple sclerosis , 2007, Neuroscience.

[13]  H. Koprowski,et al.  Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models , 2007, Proceedings of the National Academy of Sciences.

[14]  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.

[15]  P. Carvey,et al.  Blood–Brain Barrier Pathology in Alzheimer's and Parkinson's Disease: Implications for Drug Therapy , 2007, Cell transplantation.

[16]  Patrick Couvreur,et al.  Translocation of poly(ethylene glycol-co-hexadecyl)cyanoacrylate nanoparticles into rat brain endothelial cells: role of apolipoproteins in receptor-mediated endocytosis. , 2007, Biomacromolecules.

[17]  P. Couvreur,et al.  Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells , 2007, Cellular and Molecular Life Sciences.

[18]  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.

[19]  T. Ishida,et al.  Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[20]  Xinguo Jiang,et al.  Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles. , 2006, International journal of pharmaceutics.

[21]  D. Mager,et al.  Effect of Repetitive Administration of Doxorubicin-Containing Liposomes on Plasma Pharmacokinetics and Drug Biodistribution in a Rat Brain Tumor Model , 2005, Clinical Cancer Research.

[22]  G. Tosi,et al.  Peptide-derivatized biodegradable nanoparticles able to cross the blood-brain barrier. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

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

[24]  P. Couvreur,et al.  A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles , 2005, Cellular and Molecular Life Sciences.

[25]  D. V. Kohli,et al.  Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil , 2005, Journal of drug targeting.

[26]  V. Shenoy,et al.  Tumour targeting: biological factors and formulation advances in injectable lipid nanoparticles , 2005, The Journal of pharmacy and pharmacology.

[27]  Berislav V. Zlokovic,et al.  Neurovascular mechanisms of Alzheimer's neurodegeneration , 2005, Trends in Neurosciences.

[28]  R. Müller,et al.  Polysorbate-stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain: Comparison of plasma protein adsorption patterns , 2005, Journal of drug targeting.

[29]  M. Hope,et al.  Immunogenicity and Rapid Blood Clearance of Liposomes Containing Polyethylene Glycol-Lipid Conjugates and Nucleic Acid , 2005, Journal of Pharmacology and Experimental Therapeutics.

[30]  M. C. Papadopoulos,et al.  Molecular mechanisms of brain tumor edema , 2004, Neuroscience.

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

[32]  A. Schätzlein,et al.  Glucose-targeted niosomes deliver vasoactive intestinal peptide (VIP) to the brain. , 2004, International journal of pharmaceutics.

[33]  R. Mumper,et al.  Paclitaxel nanoparticles for the potential treatment of brain tumors. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[34]  R. Murthy,et al.  Etoposide-incorporated tripalmitin nanoparticles with different surface charge: Formulation, characterization, radiolabeling, and biodistribution studies , 2004, The AAPS Journal.

[35]  T. Suhara,et al.  Factors governing the in vivo tissue uptake of transferrin-coupled polyethylene glycol liposomes in vivo. , 2004, International journal of pharmaceutics.

[36]  W. Pardridge,et al.  Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter. , 2004, Human gene therapy.

[37]  Karsten Mäder,et al.  Investigations on the structure of solid lipid nanoparticles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[38]  S. McQuaid,et al.  Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood–brain barrier leakage and active demyelination , 2003, The Journal of pathology.

[39]  R. Gold,et al.  Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis. , 2003, Brain : a journal of neurology.

[40]  A. Minagar,et al.  Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells , 2003, Multiple sclerosis.

[41]  F. Dosio,et al.  From Conventional to Stealth Liposomes a new Frontier in Cancer Chemotherapy , 2003, Tumori.

[42]  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.

[43]  H. Lee,et al.  Synthesis of Pegylated Immunonanoparticles , 2002, Pharmaceutical Research.

[44]  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.

[45]  W. Pardridge,et al.  Drug and gene targeting to the brain with molecular trojan horses , 2002, Nature Reviews Drug Discovery.

[46]  Peter Ramge,et al.  Apolipoprotein-mediated Transport of Nanoparticle-bound Drugs Across the Blood-Brain Barrier , 2002, Journal of drug targeting.

[47]  R. Cavalli,et al.  Intravenous Administration to Rabbits of Non-stealth and Stealth Doxorubicin-loaded Solid Lipid Nanoparticles at Increasing Concentrations of Stealth Agent: Pharmacokinetics and Distribution of Doxorubicin in Brain and Other Tissues , 2002, Journal of drug targeting.

[48]  P. Couvreur,et al.  PEGylated polycyanoacrylate nanoparticles as vector for drug delivery in prion diseases , 2001, Journal of Neuroscience Methods.

[49]  W. Pardridge,et al.  Receptor-Mediated Gene Targeting to Tissues In Vivo Following Intravenous Administration of Pegylated Immunoliposomes , 2001, Pharmaceutical Research.

[50]  P. Couvreur,et al.  Long-Circulating PEGylated Polycyanoacrylate Nanoparticles as New Drug Carrier for Brain Delivery , 2001, Pharmaceutical Research.

[51]  R. Kean,et al.  The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity1 , 2000, The Journal of Immunology.

[52]  R. Cavalli,et al.  Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats. , 2000, Pharmacological research.

[53]  R. Müller,et al.  Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[54]  M. Rafii,et al.  Agrin and microvascular damage in Alzheimer’s disease , 2000, Neurobiology of Aging.

[55]  J. Drewe,et al.  Endocytosis and Transcytosis of an Immunoliposome-Based Brain Drug Delivery System , 2000, Journal of drug targeting.

[56]  R. Kalaria The Blood‐Brain Barrier and Cerebrovascular Pathology in Alzheimer's Disease , 1999, Annals of the New York Academy of Sciences.

[57]  Buchwald,et al.  Recent advances in the brain targeting of neuropharmaceuticals by chemical delivery systems. , 1999, Advanced drug delivery reviews.

[58]  B. Sabel,et al.  Efficacy of Oral Dalargin-loaded Nanoparticle Delivery across the Blood–Brain Barrier , 1998, Peptides.

[59]  B. Engelhardt,et al.  E- and P-selectin are not involved in the recruitment of inflammatory cells across the blood-brain barrier in experimental autoimmune encephalomyelitis. , 1997, Blood.

[60]  R. Straubinger,et al.  Liposome-Mediated Therapy of Intracranial Brain Tumors in a Rat Model , 1997, Pharmaceutical Research.

[61]  W. Pardridge,et al.  Drug Delivery to the Brain , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

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

[63]  S. Chandler,et al.  Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview , 1997, Journal of Neuroimmunology.

[64]  J. Huwyler,et al.  Brain drug delivery of small molecules using immunoliposomes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[65]  A. Gabizon,et al.  Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. , 1995, Journal of neurosurgery.

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

[67]  U. Bickel,et al.  In vivo demonstration of subcellular localization of anti-transferrin receptor monoclonal antibody-colloidal gold conjugate in brain capillary endothelium. , 1994, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[68]  A. Gabizon,et al.  Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[69]  W. Pardridge,et al.  Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. , 1991, The Journal of pharmacology and experimental therapeutics.

[70]  T M Allen,et al.  Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. , 1991, Biochimica et biophysica acta.

[71]  T. Allen,et al.  Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. , 1989, Biochimica et biophysica acta.

[72]  A. Gabizon,et al.  Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[73]  Y. Eto,et al.  Liposome targeting to mouse brain: mannose as a recognition marker. , 1988, Biochemical and biophysical research communications.

[74]  M. Dehouck,et al.  Upregulation of the low density lipoprotein receptor at the blood-brain barrier: intercommunications between brain capillary endothelial cells and astrocytes , 1987, The Journal of cell biology.

[75]  W. Jefferies,et al.  Transferrin receptor on endothelium of brain capillaries , 1984, Nature.

[76]  A. Klip,et al.  Identification and characterization of the glucose transporter of the blood-brain barrier by cytochalasin B binding and immunological reactivity. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[77]  T. Reese,et al.  JUNCTIONS BETWEEN INTIMATELY APPOSED CELL MEMBRANES IN THE VERTEBRATE BRAIN , 1969, The Journal of cell biology.

[78]  Thomas S. Reese,et al.  FINE STRUCTURAL LOCALIZATION OF A BLOOD-BRAIN BARRIER TO EXOGENOUS PEROXIDASE , 1967, The Journal of cell biology.

[79]  A. Bangham,et al.  Diffusion of univalent ions across the lamellae of swollen phospholipids. , 1965, Journal of molecular biology.

[80]  Y. Kawashima,et al.  Brain targeting with surface-modified poly(D,L-lactic-co-glycolic acid) nanoparticles delivered via carotid artery administration. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[81]  A. Tsuji Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems , 2011, NeuroRX.

[82]  W. Pardridge,et al.  Global non-viral gene transfer to the primate brain following intravenous administration. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[83]  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.