Osmotin-loaded magnetic nanoparticles with electromagnetic guidance for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregated amyloid beta (Aβ) in the brain. Here, we describe for the first time the development of a new, pioneering nanotechnology-based drug delivery approach for potential therapies for neurodegenerative diseases, particularly AD. We demonstrated the delivery of fluorescent carboxyl magnetic Nile Red particles (FMNPs) to the brains of normal mice using a functionalized magnetic field (FMF) composed of positive- and negative-pulsed magnetic fields generated by electromagnetic coils. The FMNPs successfully reached the brain in a few minutes and showed evidence of blood-brain barrier (BBB) crossing. Moreover, the best FMF conditions were found for inducing the FMNPs to reach the cortex and hippocampus regions. Under the same FMF conditions, dextran-coated Fe3O4 magnetic nanoparticles (MNPs) loaded with osmotin (OMNP) were transported to the brains of Aβ1-42-treated mice. Compared with native osmotin, the OMNP potently attenuates Aβ1-42-induced synaptic deficits, Aβ accumulation, BACE-1 expression and tau hyperphosphorylation. This magnetic drug delivery approach can be extended to preclinical and clinical use and may advance the chances of success in the treatment of neurological disorders like AD in the future.

[1]  G. Rosania,et al.  Pulsed magnetic field improves the transport of iron oxide nanoparticles through cell barriers. , 2013, ACS nano.

[2]  T. Xia,et al.  Toxic Potential of Materials at the Nanolevel , 2006, Science.

[3]  Carl K. Hoh,et al.  Targeting and retention of magnetic targeted carriers (MTCs) enhancing intra-arterial chemotherapy , 1999 .

[4]  B. Liang,et al.  Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease* , 2010, The Journal of Biological Chemistry.

[5]  P Wust,et al.  Morbidity and quality of life during thermotherapy using magnetic nanoparticles in locally recurrent prostate cancer: Results of a prospective phase I trial , 2007, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[6]  Eva Yuhua Kuo,et al.  Increase in Evans blue dye extravasation into the brain in the late developmental stage , 2012, Neuroreport.

[7]  P. Hasegawa,et al.  Antifungal activity of tobacco osmotin has specificity and involves plasma membrane permeabilization , 1996 .

[8]  D. Selkoe.  The molecular pathology of Alzheimer's disease , 1991, Neuron.

[9]  Lei Han,et al.  Construction of Novel Brain-Targeting Gene Delivery System by Natural Magnetic Nanoparticles , 2011 .

[10]  R Weissleder,et al.  Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver. , 1988, Radiology.

[11]  Brian P. Grady,et al.  Magnetic Assisted Transport of PLGA Nanoparticles Through a Human Round Window Membrane Model , 2010 .

[12]  E. Landau,et al.  Synaptic Stimulation of mTOR Is Mediated by Wnt Signaling and Regulation of Glycogen Synthetase Kinase-3 , 2011, The Journal of Neuroscience.

[13]  E. Tiffany-Castiglioni,et al.  Evaluation of neurotoxic potential by use of in vitro systems , 2005, Expert opinion on drug metabolism & toxicology.

[14]  L. Buée,et al.  P1–062: Alzheimer's disease–like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits , 2006, The American journal of pathology.

[15]  M. Kim,et al.  Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus , 2015, Scientific Reports.

[16]  W. Bentley,et al.  Towards oriented assembly of proteins onto magnetic nanoparticles , 2008 .

[17]  Roy S Herbst,et al.  Targeted drug delivery strategies to treat lung metastasis , 2009, Expert opinion on drug delivery.

[18]  P. Hasegawa,et al.  Characterization of osmotin : a thaumatin-like protein associated with osmotic adaptation in plant cells. , 1987, Plant physiology.

[19]  A. Saria,et al.  Evans blue fluorescence: quantitative and morphological evaluation of vascular permeability in animal tissues , 1983, Journal of Neuroscience Methods.

[20]  D. Leslie-Pelecky,et al.  Iron oxide nanoparticles for sustained delivery of anticancer agents. , 2005, Molecular pharmaceutics.

[21]  Ton Duc Do,et al.  Guidance of Magnetic Nanocontainers for Treating Alzheimer's Disease Using an Electromagnetic, Targeted Drug-Delivery Actuator. , 2016, Journal of biomedical nanotechnology.

[22]  Larry R Squire,et al.  Spatial memory, recognition memory, and the hippocampus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  L. Squire.  Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. , 1992, Psychological review.

[24]  A. S. Moses,et al.  Imaging and drug delivery using theranostic nanoparticles. , 2010, Advanced drug delivery reviews.

[25]  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.

[26]  H. Y. Lee,et al.  Novel osmotin attenuates glutamate-induced synaptic dysfunction and neurodegeneration via the JNK/PI3K/Akt pathway in postnatal rat brain , 2014, Cell Death and Disease.

[27]  J. Kopeček.  Polymer-drug conjugates: origins, progress to date and future directions. , 2013, Advanced drug delivery reviews.

[28]  Andras Lakatos,et al.  Superparamagnetic Iron Oxide-Labeled Schwann Cells and Olfactory Ensheathing Cells Can Be Traced In Vivo by Magnetic Resonance Imaging and Retain Functional Properties after Transplantation into the CNS , 2004, The Journal of Neuroscience.

[29]  S. Lipton,et al.  Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease , 2014, Molecular Neurodegeneration.

[30]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Nair,et al.  Magnetic nanoformulation of azidothymidine 5’-triphosphate for targeted delivery across the blood–brain barrier , 2010, International journal of nanomedicine.

[32]  T. Nagai,et al.  Magnetic targeting after femoral artery administration and biocompatibility assessment of superparamagnetic iron oxide nanoparticles. , 2008, Journal of biomedical materials research. Part A.

[33]  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.

[34]  B. Strooper,et al.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics , 2011, Nature Reviews Drug Discovery.

[35]  T. Nabeshima,et al.  β-Amyloid (1–42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex , 2004, Behavioural Brain Research.

[36]  Walter H Backes,et al.  Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease. , 2016, Radiology.

[37]  B. Cornelissen,et al.  A tobacco mosaic virus-induced tobacco protein is homologous to the sweet-tasting protein thaumatin , 1986, Nature.

[38]  R. Cunha,et al.  Adenosine A2A Receptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway , 2009, The Journal of Neuroscience.

[39]  H. Y. Lee,et al.  Neuroprotective effect of osmotin against ethanol-induced apoptotic neurodegeneration in the developing rat brain , 2014, Cell Death and Disease.

[40]  P. Wong,et al.  Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease , 2003, Nature Medicine.

[41]  T. M. Sutherland,et al.  Increased permeability of the capillaries of the rat heart to the plasma albumin with asphyxiation and with perfusion , 1966, The Journal of physiology.

[42]  Dormer Kenneth,et al.  Epithelial internalization of superparamagnetic nanoparticles and response to external magnetic field , 2005 .

[43]  S. Hébert,et al.  Hypothermia-induced hyperphosphorylation: a new model to study tau kinase inhibitors , 2012, Scientific Reports.

[44]  Arthur W. Toga,et al.  Blood-Brain Barrier Breakdown in the Aging Human Hippocampus , 2015, Neuron.

[45]  M. Moore,et al.  Do nanoparticles present ecotoxicological risks for the health of the aquatic environment? , 2006, Environment international.

[46]  G. Oberdörster,et al.  Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles , 2005, Environmental health perspectives.

[47]  Yuan Yuan Zhang,et al.  The permeability of SPION over an artificial three-layer membrane is enhanced by external magnetic field , 2006, Journal of nanobiotechnology.

[48]  Tae-Jong Yoon,et al.  Toxicity and tissue distribution of magnetic nanoparticles in mice. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[49]  M. Tabaton,et al.  Amyloid-β₄₂ activates the expression of BACE1 through the JNK pathway. , 2011, Journal of Alzheimer's disease : JAD.

[50]  R. Weissleder,et al.  Clinical application of superparamagnetic iron oxide to MR imaging of tissue perfusion in vascular liver tumors. , 1990, Radiology.

[51]  C. Robic,et al.  Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. , 2008, Chemical reviews.

[52]  W. Statton,et al.  Structure in Vitreous Silicate Fibers as Shown by Small‐Angle Scattering of X‐Rays , 1960 .

[53]  L. Hersh,et al.  Substrate Activation of Insulin-degrading Enzyme (Insulysin) , 2003, Journal of Biological Chemistry.

[54]  G. Cole,et al.  Why Pleiotropic Interventions are Needed for Alzheimer's Disease , 2010, Molecular Neurobiology.

[55]  O. Steinwall,et al.  SELECTIVE VULNERABILITY OF THE BLOOD‐BRAIN BARRIER IN CHEMICALLY INDUCED LESIONS , 1966, Journal of neuropathology and experimental neurology.

[57]  K Mosbach,et al.  Preparation and application of magnetic polymers for targeting of drugs , 1979, FEBS letters.

[58]  H M Evans,et al.  THE ACTION OF VITAL STAINS BELONGING TO THE BENZIDINE GROUP. , 1914, Science.

[59]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[60]  T. Yoshino,et al.  Anti‐high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[61]  Catherine C. Berry,et al.  Functionalisation of magnetic nanoparticles for applications in biomedicine , 2003 .

[62]  M. Ohno,et al.  BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice , 2007, Neurobiology of Disease.

[63]  P. Sykes,et al.  Cellular transfer and AFM imaging of cancer cells using Bioimprint , 2006, Journal of nanobiotechnology.

[64]  D. Woodruff-Pak,et al.  Animal models of Alzheimer's disease: therapeutic implications. , 2008, Journal of Alzheimer's disease : JAD.

[65]  Jungwon Yoon,et al.  A Novel Electromagnetic Actuation System for Magnetic Nanoparticle Guidance in Blood Vessels , 2014, IEEE Transactions on Magnetics.

[66]  Scott E McNeil,et al.  Nanotechnology safety concerns revisited. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[67]  Vladimir P Torchilin,et al.  Passive and active drug targeting: drug delivery to tumors as an example. , 2010, Handbook of experimental pharmacology.

[68]  Huan Xu,et al.  Iron oxide @ polypyrrole nanoparticles as a multifunctional drug carrier for remotely controlled cancer therapy with synergistic antitumor effect. , 2013, ACS nano.

[69]  Mohsin Shah,et al.  Amphiphilic PHA-mPEG copolymeric nanocontainers for drug delivery: preparation, characterization and in vitro evaluation. , 2010, International journal of pharmaceutics.

[70]  A. Arrott,et al.  Magnetism in Medicine , 1960 .

[71]  M. Gregersen,et al.  THE DISAPPEARANCE OF T-1824 AND STRUCTURALLY RELATED DYES FROM THE BLOOD STREAM , 1943 .

[72]  Jungwon Yoon,et al.  A Novel Scheme for Nanoparticle Steering in Blood Vessels Using a Functionalized Magnetic Field , 2015, IEEE Transactions on Biomedical Engineering.

[73]  Robert N Grass,et al.  In vitro cytotoxicity of oxide nanoparticles: comparison to asbestos, silica, and the effect of particle solubility. , 2006, Environmental science & technology.

[74]  E. Neuwelt,et al.  Imaging, Distribution, and Toxicity of Superparamagnetic Iron Oxide Magnetic Resonance Nanoparticles in the Rat Brain and Intracerebral Tumor , 2005, Neurosurgery.

[75]  G. Hass,et al.  VITAL STAINING, SERUM ALBUMIN AND THE BLOOD‐BRAIN BARRIER , 1970, Journal of neuropathology and experimental neurology.

[76]  D. Butterfield,et al.  Oxidatively modified proteins in Alzheimer’s disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis , 2009, Acta Neuropathologica.

[77]  Adiponectin is Protective against Oxidative Stress Induced Cytotoxicity in Amyloid-Beta Neurotoxicity , 2012, PloS one.

[78]  Miqin Zhang,et al.  Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. , 2010, Advanced drug delivery reviews.

[79]  A. Curtis,et al.  Dextran and albumin derivatised iron oxide nanoparticles: influence on fibroblasts in vitro. , 2003, Biomaterials.