Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs

Journal of Controlled Release - Tập 281 - Trang 139-177 - 2018
Mukta Agrawal1, Swarnlata Saraf2, Shailendra Saraf2,3, Sophia G. Antimisiaris4,5, Mahavir Bhupal Chougule6,7,8, Sunday A. Shoyele9, Amit Alexander1
1Rungta College of Pharmaceutical Sciences and Research, Kohka-Kurud Road, Bhilai, Chhattisgarh 490024, India
2University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh 492010, India
3Durg University, Govt. Vasudev Vaman Patankar Girls' P.G. College Campus, Raipur, Naka, Durg, Chhattisgarh 491 001, India
4Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras, Rio 26510, Greece
5FORTH/ICE-HT, Institute of Chemical Engineering, Rio, 25104 Patras, Greece
6Translational Bio-pharma Engineering Nanodelivery Research Laboratory, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS 38677, USA
7Pii Center for Pharmaceutical Technology, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS, USA
8National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, Universityof Mississippi, University, MS, USA
9Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA

Tài liệu tham khảo

Wen, 2017, Nanotechnology-based drug delivery systems for Alzheimer's disease management: technical, industrial, and clinical challenges, J. Control. Release, 245, 95, 10.1016/j.jconrel.2016.11.025 Lista, 2015, Paths to Alzheimer's disease prevention: from modifiable risk factors to biomarker enrichment strategies, J. Nutr. Health Aging, 19, 154, 10.1007/s12603-014-0515-3 2015 Alzheimer's disease facts and figures, 2015, Alzheimer's & dementia, J. Alzheimer's Assoc., 11, 332 Folch, 2016, Current research therapeutic strategies for Alzheimer’s disease treatment, Neural Plast., 2016, 15, 10.1155/2016/8501693 Fettelschoss, 2014, Vaccination against Alzheimer disease: an update on future strategies, Hum. Vaccines Immunotherapeutics, 10, 847, 10.4161/hv.28183 Prince, 2016, Improving healthcare for people living with dementia, 140 2017 Alzheimer's disease facts and figures, 2017, vol. 13, 325 Mohammadi, 2011, Modulation of H2O2-induced mitogen-activated protein kinases activation and cell death in SK-N-MC cells by EUK134, a salen derivative, Basic Clin. Pharmacol. Toxicol., 108, 378, 10.1111/j.1742-7843.2010.00664.x Di Stefano, 2011, Drug delivery strategies for Alzheimer's disease treatment, Expert Opin. Drug Deliv., 8, 581, 10.1517/17425247.2011.561311 Brambilla, 2012, PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation: toward engineering of functional nanomedicines for Alzheimer's disease, ACS Nano, 6, 5897, 10.1021/nn300489k Parihar, 2004, Alzheimer's disease pathogenesis and therapeutic interventions, J. Clin. Neurosci., 11, 456, 10.1016/j.jocn.2003.12.007 Agrawal, 2018, Recent advancements in the field of nanotechnology for the delivery of anti-Alzheimer drug in the brain region, Expert Opin. Drug Deliv., 10.1080/17425247.2018.1471058 Nagpal, 2013, Drug targeting to brain: a systematic approach to study the factors, parameters and approaches for prediction of permeability of drugs across BBB, Expert Opin. Drug Deliv., 10, 927, 10.1517/17425247.2013.762354 Begley, 2004, Delivery of therapeutic agents to the central nervous system: the problems and the possibilities, Pharmacol. Ther., 104, 29, 10.1016/j.pharmthera.2004.08.001 Brasnjevic, 2009, Delivery of peptide and protein drugs over the blood-brain barrier, Prog. Neurobiol., 87, 212, 10.1016/j.pneurobio.2008.12.002 Su, 2006, Drug delivery across the blood–brain barrier: why is it difficult? How to measure and improve it?, Expert Opin. Drug Deliv., 3, 419, 10.1517/17425247.3.3.419 Agrawal, 2017, Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease, J. Control. Release, 260, 61, 10.1016/j.jconrel.2017.05.019 Lochhead, 2015, Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration, J. Cereb. Blood Flow Metab., 35, 371, 10.1038/jcbfm.2014.215 van Sorge, 2012, Defense at the border: the blood-brain barrier versus bacterial foreigners, Future Microbiol, 7, 383, 10.2217/fmb.12.1 Bitter, 2011, Nasal drug delivery in humans, Curr. Probl. Dermatol., 40, 20, 10.1159/000321044 Jiang, 2011, Intranasal delivery of stem cells to the brain, Expert Opin. Drug Deliv., 8, 623, 10.1517/17425247.2011.566267 Chapman, 2013, Intranasal treatment of central nervous system dysfunction in humans, Pharm. Res., 30, 2475, 10.1007/s11095-012-0915-1 Frey, 1997, Delivery of 125I-NGF to the brain via the olfactory route, Drug Deliv., 4, 87, 10.3109/10717549709051878 Chen, 1998, Delivery of nerve growth factor to the brain via the olfactory pathway, J. Alzheimer's Dis., 1, 35, 10.3233/JAD-1998-1102 Lochhead, 2012, Intranasal delivery of biologics to the central nervous system, Adv. Drug Deliv. Rev., 64, 614, 10.1016/j.addr.2011.11.002 Danielyan, 2009, Intranasal delivery of cells to the brain, Eur. J. Cell Biol., 88, 315, 10.1016/j.ejcb.2009.02.001 Danielyan, 2011, Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease, Rejuvenation Res., 14, 3, 10.1089/rej.2010.1130 Kulkarni, 2011, Modulation of anxiety behavior by intranasally administered vaccinia virus complement control protein and curcumin in a mouse model of Alzheimer's disease, Curr. Alzheimer Res., 8, 95, 10.2174/156720511794604598 Hussain, 1998, Intranasal drug delivery, Adv. Drug Deliv. Rev., 29, 39, 10.1016/S0169-409X(97)00060-4 Sood, 2014, Intranasal therapeutic strategies for management of Alzheimer's disease, J. Drug Target., 22, 279, 10.3109/1061186X.2013.876644 Fortuna, 2014, Intranasal delivery of systemic-acting drugs: small-molecules and biomacromolecules, Eur. J. Pharm. Biopharm., 88, 8, 10.1016/j.ejpb.2014.03.004 Grassin-Delyle, 2012, Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids, Pharmacol. Ther., 134, 366, 10.1016/j.pharmthera.2012.03.003 Kisan, 2007, Nasal drug delivery system-factors affecting and applications, Curr. Drug Ther., 2, 27, 10.2174/157488507779422374 II, 1991 Frey, 2012 van den Berg, 2004, Uptake of melatonin into the cerebrospinal fluid after nasal and intravenous delivery: studies in rats and comparison with a human study, Pharm. Res., 21, 799, 10.1023/B:PHAM.0000026431.55383.69 Al-Ghananeem, 2002, Targeted brain delivery of 17 beta-estradiol via nasally administered water soluble prodrugs, AAPS PharmSciTech, 3, 10.1208/pt030105 Dhuria, 2010, Intranasal delivery to the central nervous system: mechanisms and experimental considerations, J. Pharm. Sci., 99, 1654, 10.1002/jps.21924 Hanafy, 2016, Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: future potential contribution in Alzheimer's disease management, Drug Deliv., 23, 3111, 10.3109/10717544.2016.1153748 Hanafy, 2015, Complexation as an approach to entrap cationic drugs into cationic nanoparticles administered intranasally for Alzheimer's disease management: preparation and detection in rat brain, Drug Dev. Ind. Pharm., 41, 2055, 10.3109/03639045.2015.1062897 Bhattacharya, 2015, Nasal application of the Galantamine pro-drug Memogain slows down plaque deposition and ameliorates behavior in 5X familial Alzheimer's disease mice, J. Alzheimer's Dis., 46, 123, 10.3233/JAD-142421 Li, 2012, Pharmacokinetic behavior and efficiency of acetylcholinesterase inhibition in rat brain after intranasal administration of galanthamine hydrobromide loaded flexible liposomes, Environ. Toxicol. Pharmacol., 34, 272, 10.1016/j.etap.2012.04.012 Yang, 2013, Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration, Int. J. Pharm., 452, 344, 10.1016/j.ijpharm.2013.05.009 Fazil, 2012, Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting, Eur. J. Pharm. Sci., 47, 6, 10.1016/j.ejps.2012.04.013 Liu, 2013, Lactoferrin-modified PEG-co-PCL nanoparticles for enhanced brain delivery of NAP peptide following intranasal administration, Biomaterials, 34, 3870, 10.1016/j.biomaterials.2013.02.003 Maurice, 2013, Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Abeta(2)(5)(−)(3)(5) non-transgenic mouse model of Alzheimer's disease, J. Psychopharmacol., 27, 1044, 10.1177/0269881113494939 Feng, 2012, Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of beta-amyloid and ibotenic acid into the bilateral hippocampus, Int. J. Pharm., 423, 226, 10.1016/j.ijpharm.2011.12.008 Zhang, 2014, Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease, Int. J. Pharm., 461, 192, 10.1016/j.ijpharm.2013.11.049 Gao, 2007, Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with wheat germ agglutinin following intranasal administration, J. Control. Release, 121, 156, 10.1016/j.jconrel.2007.05.026 Picone, 2016, Ionizing radiation-engineered nanogels as insulin nanocarriers for the development of a new strategy for the treatment of Alzheimer's disease, Biomaterials, 80, 179, 10.1016/j.biomaterials.2015.11.057 Chen, 2014, Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Abeta level and microglia activation in the brains of 3xTg-AD mice, Exp. Neurol., 261, 610, 10.1016/j.expneurol.2014.06.004 Mao, 2016, Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice, Aging Cell, 15, 893, 10.1111/acel.12498 Salameh, 2015, Central nervous system delivery of intranasal insulin: mechanisms of uptake and effects on cognition, J. Alzheimer's Dis., 47, 715, 10.3233/JAD-150307 Craft, 2012, Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial, Arch. Neurol., 69, 29, 10.1001/archneurol.2011.233 Wu, 2012, A novel small Odorranalectin-bearing cubosomes: preparation, brain delivery and pharmacodynamic study on amyloid-beta(2)(5)(−)(3)(5)-treated rats following intranasal administration, Eur. J. Pharm. Biopharm., 80, 368, 10.1016/j.ejpb.2011.10.012 Qian, 2014, Development, characterization and application of in situ gel systems for intranasal delivery of tacrine, Int. J. Pharm., 468, 272, 10.1016/j.ijpharm.2014.04.015 Bhavna, 2014, Donepezil nanosuspension intended for nose to brain targeting: in vitro and in vivo safety evaluation, Int. J. Biol. Macromol., 67, 418, 10.1016/j.ijbiomac.2014.03.022 Meng, 2018, Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer's disease, Int. J. Nanomedicine, 13, 705, 10.2147/IJN.S151474 Wang, 2011, Huperzine A activates Wnt/beta-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model, Neuropsychopharmacology, 36, 1073, 10.1038/npp.2010.245 Kumar, 2008, Intranasal nanoemulsion based brain targeting drug delivery system of risperidone, Int. J. Pharm., 358, 285, 10.1016/j.ijpharm.2008.03.029 Elnaggar, 2015, Intranasal piperine-loaded chitosan nanoparticles as brain-targeted therapy in Alzheimer's disease: optimization, biological efficacy, and potential toxicity, J. Pharm. Sci., 104, 3544, 10.1002/jps.24557 Lin, 2016, Intranasal Administration of a Polyethylenimine-Conjugated Scavenger Peptide Reduces Amyloid-beta Accumulation in a mouse model of Alzheimer's disease, J. Alzheimer's Dis., 53, 1053, 10.3233/JAD-151024 Guo, 2013, Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease, Neurobiol. Aging, 34, 562, 10.1016/j.neurobiolaging.2012.05.009 Fine, 2015, Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation, Neurosci. Lett., 584, 362, 10.1016/j.neulet.2014.11.013 Hanson, 2012, Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice, Drug Deliv. Transl. Res., 2, 160, 10.1007/s13346-011-0050-2 Guo, 2015, Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1alpha pathway on the brain of APP/PS1 transgenic mice, Front. Aging Neurosci., 7, 104, 10.3389/fnagi.2015.00104 Muntimadugu, 2016, Intranasal delivery of nanoparticle encapsulated tarenflurbil: a potential brain targeting strategy for Alzheimer's disease, Eur. J. Pharm. Sci., 92, 224, 10.1016/j.ejps.2016.05.012 Zheng, 2015, Intranasal H102 peptide-loaded liposomes for brain delivery to treat Alzheimer's disease, Pharm. Res., 32, 3837, 10.1007/s11095-015-1744-9 Yang, 2014, Enhancement of the nonamyloidogenic pathway by exogenous NGF in an Alzheimer transgenic mouse model, Neuropeptides, 48, 233, 10.1016/j.npep.2014.04.005 Capsoni, 2012, Intranasal "painless" human nerve growth factor [corrected] slows amyloid neurodegeneration and prevents memory deficits in app X PS1 mice, PLoS One, 7, 10.1371/annotation/97b6c799-1ebc-4e7b-8f86-47c1130dc00e Capsoni, 2009, Delivery of NGF to the brain: intranasal versus ocular administration in anti-NGF transgenic mice, J. Alzheimer's Dis., 16, 371, 10.3233/JAD-2009-0953 De Rosa, 2005, Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice, Proc. Natl. Acad. Sci. U. S. A., 102, 3811, 10.1073/pnas.0500195102 Vaz, 2017, Development of nasal lipid nanocarriers containing curcumin for brain targeting, J. Alzheimers Dis., 59, 961, 10.3233/JAD-160355 Chen, 2013, Enhanced brain targeting of curcumin by intranasal administration of a thermosensitive poloxamer hydrogel, J. Pharm. Pharmacol., 65, 807, 10.1111/jphp.12043 Wang, 2012, Formulation and evaluation of microemulsion-based in situ ion-sensitive gelling systems for intranasal administration of curcumin, J. Drug Target., 20, 831, 10.3109/1061186X.2012.719230 Lungare, 2016, Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery, Int. J. Pharm., 513, 280, 10.1016/j.ijpharm.2016.09.042 Nasr, 2016, Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery, Drug Deliv., 23, 1444, 10.3109/10717544.2015.1092619 Crowe, 2018, Mechanism of intranasal drug delivery directly to the brain, Life Sci., 195, 44, 10.1016/j.lfs.2017.12.025 Merkus, 1998, Nasal mucociliary clearance as a factor in nasal drug delivery, Adv. Drug Deliv. Rev., 29, 13, 10.1016/S0169-409X(97)00059-8 Vyas, 2006, Intranasal mucoadhesive microemulsions of clonazepam: preliminary studies on brain targeting, J. Pharm. Sci., 95, 570, 10.1002/jps.20480 William, 2016, Intranasal drug delivery bypasses the blood–brain barrier, Neurol. Rev., 24, 40 Einer-Jensen, 2005, Counter-current transfer in reproductive biology, Reproduction (Cambridge, England), 129, 9, 10.1530/rep.1.00278 Illum, 2000, Transport of drugs from the nasal cavity to the central nervous system, Eur. J. Pharm. Sci., 11, 1, 10.1016/S0928-0987(00)00087-7 Kristensson, 1971, Uptake of exogenous proteins in mouse olfactory cells, Acta Neuropathol., 19, 145, 10.1007/BF00688493 Alexander, 2012, Approaches for breaking the barriers of drug permeation through transdermal drug delivery, J. Control. Release, 164, 26, 10.1016/j.jconrel.2012.09.017 Florence, 1997, The oral absorption of micro- and nanoparticulates: neither exceptional nor unusual, Pharm. Res., 14, 259, 10.1023/A:1012029517394 Lockman, 2002, Nanoparticle technology for drug delivery across the blood-brain barrier, Drug Dev. Ind. Pharm., 28, 1, 10.1081/DDC-120001481 Ugwoke, 2001, The biopharmaceutical aspects of nasal mucoadhesive drug delivery, J. Pharm. Pharmacol., 53, 3, 10.1211/0022357011775145 Pires, 2018, Nanosystems in nose-to-brain drug delivery: a review of non-clinical brain targeting studies, J. Control. Release, 270, 89, 10.1016/j.jconrel.2017.11.047 Scheibe, 2008, Intranasal administration of drugs, Arch. Otolaryngol., 134, 643, 10.1001/archotol.134.6.643 Djupesland, 2006, Breath actuated device improves delivery to target sites beyond the nasal valve, Laryngoscope, 116, 466, 10.1097/01.MLG.0000199741.08517.99 Reger, 2008, Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults, J. Alzheimer's Dis., 13, 323, 10.3233/JAD-2008-13309 Van den Berg, 2003, Hydroxocobalamin uptake into the cerebrospinal fluid after nasal and intravenous delivery in rats and humans, J. Drug Target., 11, 325, 10.1080/10611860310001640075 Kumar, 2008, Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting, J. Drug Target., 16, 806, 10.1080/10611860802476504 Alexander, 2016, Recent expansion of pharmaceutical nanotechnologies and targeting strategies in the field of phytopharmaceuticals for the delivery of herbal extracts and bioactives, J. Control. Release, 241, 110, 10.1016/j.jconrel.2016.09.017 Bhattacharya, 2014, Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer's disease, PLoS One, 9, 10.1371/journal.pone.0089454 Atanasova, 2015, Galantamine derivatives with indole moiety: docking, design, synthesis and acetylcholinesterase inhibitory activity, Bioorg. Med. Chem., 23, 5382, 10.1016/j.bmc.2015.07.058 Farlow, 2001, Pharmacokinetic profiles of current therapies for Alzheimer's disease: implications for switching to galantamine, Clin. Ther., 23, A13, 10.1016/S0149-2918(01)80164-8 Contestabile, 2011, The history of the cholinergic hypothesis, Behav. Brain Res., 221, 334, 10.1016/j.bbr.2009.12.044 Patel, 2011, Combination therapy for Alzheimer's disease, Drugs Aging, 28, 539, 10.2165/11591860-000000000-00000 Ezoulin, 2008, Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK-N-SH cells, Neurotoxicology, 29, 270, 10.1016/j.neuro.2007.11.004 de Bruin, 2006, Beneficial effects of galantamine on performance in the object recognition task in Swiss mice: deficits induced by scopolamine and by prolonging the retention interval, Pharmacol. Biochem. Behav., 85, 253, 10.1016/j.pbb.2006.08.007 Oh, 2006, Skin permeation of retinol in tween 20-based deformable liposomes: in-vitro evaluation in human skin and keratinocyte models, J. Pharm. Pharmacol., 58, 161, 10.1211/jpp.58.2.0002 Matharu, 2009, Galantamine inhibits beta-amyloid aggregation and cytotoxicity, J. Neurol. Sci., 280, 49, 10.1016/j.jns.2009.01.024 Zhang, 2004, Galantamine blocks cloned Kv2.1, but not Kv1.5 potassium channels, brain research, Mol. Brain Res., 131, 136, 10.1016/j.molbrainres.2004.08.010 Chen, 2012, Modern methods for delivery of drugs across the blood–brain barrier, Adv. Drug Deliv. Rev., 64, 640, 10.1016/j.addr.2011.11.010 Galgatte, 2014, Development of in situ gel for nasal delivery: design, optimization, in vitro and in vivo evaluation, Drug Deliv., 21, 62, 10.3109/10717544.2013.849778 Bhatt, 2015, Development, characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntington's disease, Drug Deliv., 22, 931, 10.3109/10717544.2014.880860 Ravi, 2015, Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization, Drug Deliv., 22, 903, 10.3109/10717544.2013.860501 Elgadir, 2015, Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems: a review, J. Food Drug Anal., 23, 619, 10.1016/j.jfda.2014.10.008 Ong, 2014, Nose-to-brain drug delivery by nanoparticles in the treatment of neurological disorders, Curr. Med. Chem., 21, 4247, 10.2174/0929867321666140716103130 Baldrick, 2010, The safety of chitosan as a pharmaceutical excipient, Regul. Toxicol. Pharmacol., 56, 290, 10.1016/j.yrtph.2009.09.015 Bamrungsap, 2012, Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system, Nanomedicine (London, England), 7, 1253, 10.2217/nnm.12.87 Alexander, 2015, A comparative study of chitosan and poloxamer based thermosensitive hydrogel for the delivery of PEGylated melphalan conjugates, Drug Dev. Ind. Pharm., 41, 1954, 10.3109/03639045.2015.1011167 Alexander, 2014, Formulation and evaluation of chitosan-based long-acting injectable hydrogel for PEGylated melphalan conjugate, J. Pharm. Pharmacol., 66, 1240, 10.1111/jphp.12262 Dash, 2010, Kinetic modeling on drug release from controlled drug delivery systems, Acta Pol. Pharm., 67, 217 Maelicke, 2010, Memogain is a galantamine pro-drug having dramatically reduced adverse effects and enhanced efficacy, J. Mol. Neurosci., 40, 135, 10.1007/s12031-009-9269-5 Cicinelli, 1996, Nasal spray vs oral administration of bromocriptine: pharmacology and effect on serum prolactin in puerperal women, J. Endocrinol. Investig., 19, 427, 10.1007/BF03349887 Anand, 2014, Therapeutics of Alzheimer's disease: past, present and future, Neuropharmacology, 76, 27, 10.1016/j.neuropharm.2013.07.004 Costantino, 2007, Intranasal delivery: physicochemical and therapeutic aspects, Int. J. Pharm., 337, 1, 10.1016/j.ijpharm.2007.03.025 Touitou, 2000, Ethosomes - novel vesicular carriers for enhanced delivery: characterization and skin penetration properties, J. Control. Release, 65, 403, 10.1016/S0168-3659(99)00222-9 Touitou, 2001, Intracellular delivery mediated by an ethosomal carrier, Biomaterials, 22, 3053, 10.1016/S0142-9612(01)00052-7 Elsayed, 2006, Deformable liposomes and ethosomes: mechanism of enhanced skin delivery, Int. J. Pharm., 322, 60, 10.1016/j.ijpharm.2006.05.027 Oh, 2006, Galantamine increases excitability of CA1 hippocampal pyramidal neurons, Neuroscience, 137, 113, 10.1016/j.neuroscience.2005.08.063 Lee, 2005, Effect of edge activators on the formation and transfection efficiency of ultradeformable liposomes, Biomaterials, 26, 205, 10.1016/j.biomaterials.2004.02.020 Elsayed, 2007, Deformable liposomes and ethosomes as carriers for skin delivery of ketotifen, Die Pharmazie, 62, 133 Jain, 2003, Transfersomes—a novel vesicular carrier for enhanced transdermal delivery: development, characterization, and performance evaluation, Drug Dev. Ind. Pharm., 29, 1013, 10.1081/DDC-120025458 Hallschmid, 2008, Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders, Regul. Pept., 149, 79, 10.1016/j.regpep.2007.06.012 Rodrigues Simoes, 2014, Donepezil: an important prototype to the design of new drug candidates for Alzheimer's disease, Mini Rev. Med. Chem., 14, 2, 10.2174/1389557513666131119201353 Kása, 1997, The cholinergic system in Alzheimer's disease, Prog. Neurobiol., 52, 511, 10.1016/S0301-0082(97)00028-2 Noetzli, 2013, Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease, Clin. Pharmacokinet., 52, 225, 10.1007/s40262-013-0038-9 Calvo, 1997, Chitosan and chitosan/ethylene oxide-propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines, Pharm. Res., 14, 1431, 10.1023/A:1012128907225 Spencer, 1998, Rivastigmine. A review of its use in Alzheimer's disease, Drugs Aging, 13, 391, 10.2165/00002512-199813050-00005 Gauthier, 2006, Aggressive course of disease in dementia, Alzheimer's Dement., 2, 210, 10.1016/j.jalz.2006.03.002 Cummings, 2007, Pharmacokinetic rationale for the rivastigmine patch, Neurology, 69, S10, 10.1212/01.wnl.0000281846.40390.50 Tenovuo, 2005, Central acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury-clinical experience in 111 patients, Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 29, 61, 10.1016/j.pnpbp.2004.10.006 Venkatesh, 2007, Strategies to improve tolerability of rivastigmine: a case series, Curr. Med. Res. Opin., 23, 93, 10.1185/030079906X162791 Ali, 2015, Adverse effects of cholinesterase inhibitors in dementia, according to the Pharmacovigilance databases of the United-States and Canada, PLoS One, 10, 10.1371/journal.pone.0144337 Trabulo, 2010, Cell-penetrating peptides-mechanisms of cellular uptake and generation of delivery systems, Pharmaceuticals (Basel, Switzerland), 3, 961, 10.3390/ph3040961 Zhang, 2009, Endocytosis and membrane potential are required for HeLa cell uptake of R.I.-CKTat9, a retro-inverso tat cell penetrating peptide, Mol. Pharm., 6, 836, 10.1021/mp800121f Ma, 2011, Distinct transduction modes of arginine-rich cell-penetrating peptides for cargo delivery into tumor cells, Int. J. Pharm., 419, 200, 10.1016/j.ijpharm.2011.08.001 Torchilin, 2008, Tat peptide-mediated intracellular delivery of pharmaceutical nanocarriers, Adv. Drug Deliv. Rev., 60, 548, 10.1016/j.addr.2007.10.008 Vila, 2002, Design of biodegradable particles for protein delivery, J. Control. Release, 78, 15, 10.1016/S0168-3659(01)00486-2 Aktaş, 2005, Preparation and in vitro evaluation of chitosan nanoparticles containing a caspase inhibitor, Int. J. Pharm., 298, 378, 10.1016/j.ijpharm.2005.03.027 Ritger, 1987, A simple equation for description of solute release II. Fickian and anomalous release from swellable devices, J. Control. Release, 5, 37, 10.1016/0168-3659(87)90035-6 Porporatto, 2005, Local and systemic activity of the polysaccharide chitosan at lymphoid tissues after oral administration, J. Leukoc. Biol., 78, 62, 10.1189/jlb.0904541 Borchard, 1996, The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro, J. Control. Release, 39, 131, 10.1016/0168-3659(95)00146-8 Tosi, 2007, Targeting the central nervous system: in vivo experiments with peptide-derivatized nanoparticles loaded with Loperamide and Rhodamine-123, J. Control. Release, 122, 1, 10.1016/j.jconrel.2007.05.022 Vergoni, 2009, Nanoparticles as drug delivery agents specific for CNS: in vivo biodistribution, Nanomedicine, 5, 369, 10.1016/j.nano.2009.02.005 Taraschenko, 2005, Actions of tacrine and galanthamine on histamine-N-methyltransferase, Methods Find. Exp. Clin. Pharmacol., 27, 161, 10.1358/mf.2005.27.3.890872 FDA, 2018, Drug database Hartvig, 1990, Clinical pharmacokinetics of intravenous and oral 9-amino-1,2,3,4-tetrahydroacridine, tacrine, Eur. J. Clin. Pharmacol., 38, 259, 10.1007/BF00315027 Madden, 1995, Clinical pharmacokinetics of tacrine, Clin. Pharmacokinet., 28, 449, 10.2165/00003088-199528060-00003 O'Brien, 1991, Effects of tetrahydroaminoacridine on liver function in patients with Alzheimer's disease, Age Ageing, 20, 129, 10.1093/ageing/20.2.129 Qizilbash, 1998, Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists' collaboration, JAMA, 280, 1777, 10.1001/jama.280.20.1777 Patocka, 2008, Possible role of hydroxylated metabolites of tacrine in drug toxicity and therapy of Alzheimer's disease, Curr. Drug Metab., 9, 332, 10.2174/138920008784220619 Wong, 2010, Intranasal delivery—modification of drug metabolism and brain disposition, Pharm. Res., 27, 1208, 10.1007/s11095-010-0127-5 Jogani, 2008, Intranasal mucoadhesive microemulsion of tacrine to improve brain targeting, Alzheimer Dis. Assoc. Disord., 22, 116, 10.1097/WAD.0b013e318157205b Illum, 2002, Intranasal delivery of morphine, J. Pharmacol. Exp. Ther., 301, 391, 10.1124/jpet.301.1.391 Watts, 2009, PecSys: in situ gelling system for optimised nasal drug delivery, Expert Opin. Drug Deliv., 6, 543, 10.1517/17425240902939135 Anderson, 2001, Understanding drug release from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels, J. Control. Release, 70, 157, 10.1016/S0168-3659(00)00341-2 Jeong, 2002, Thermosensitive sol-gel reversible hydrogels, Adv. Drug Deliv. Rev., 54, 37, 10.1016/S0169-409X(01)00242-3 Li, 2011, Thermosensitive hydrogels for drug delivery, Expert Opin. Drug Deliv., 8, 991, 10.1517/17425247.2011.581656 Alexander, 2014, Saraf, polyethylene glycol (PEG)-poly(N-isopropylacrylamide) (PNIPAAm) based thermosensitive injectable hydrogels for biomedical applications, Eur. J. Pharm. Biopharm., 88, 575, 10.1016/j.ejpb.2014.07.005 Escobar-Chavez, 2006, Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations, J. Pharm. Pharm. Sci., 9, 339 Ruel-Gariepy, 2004, In situ-forming hydrogels—review of temperature-sensitive systems, Eur. J. Pharm. Biopharm., 58, 409, 10.1016/j.ejpb.2004.03.019 Gilbert, 1986, Drug release from Pluronic F-127 gels, Int. J. Pharm., 32, 223, 10.1016/0378-5173(86)90182-1 Baloglu, 2011, In-situ gel formulations of econazole nitrate: preparation and in-vitro and in-vivo evaluation, J. Pharm. Pharmacol., 63, 1274, 10.1111/j.2042-7158.2011.01315.x Jitendra, 2008, In situ mucoadhesive nasal gels of metoclopramide hydrochloride: preformulation and formulation studies, J. Pharm. Res., 1, 88 Bhandwalkar, 2013, Thermoreversible nasal in situ gel of venlafaxine hydrochloride: formulation, characterization, and pharmacodynamic evaluation, AAPS PharmSciTech, 14, 101, 10.1208/s12249-012-9893-1 Yun, 1999, Development of a thermo-reversible insulin liquid suppository with bioavailability enhancement, Int. J. Pharm., 189, 137, 10.1016/S0378-5173(99)00227-6 Bhalerao, 2009, Nasal Mucoadhesive in situ gel of ondansetron hydrochloride, Indian J. Pharm. Sci., 71, 711 Chen, 2010, Preparation of nasal temperature-sensitive in situ gel of Radix Bupleuri and evaluation of the febrile response mechanism, Drug Dev. Ind. Pharm., 36, 490, 10.3109/03639040903264371 Majithiya, 2006, Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan, AAPS PharmSciTech, 67 Moore, 2000, Experimental investigation and mathematical modeling of Pluronic F127 gel dissolution: drug release in stirred systems, J. Control. Release, 67, 191, 10.1016/S0168-3659(00)00215-7 Cho, 2011, Poloxamer/cyclodextrin/chitosan-based thermoreversible gel for intranasal delivery of fexofenadine hydrochloride, J. Pharm. Sci., 100, 681, 10.1002/jps.22314 Sharma, 2012, Efficacy of Risperidone in managing maladaptive behaviors for children with autistic Spectrum disorder: a meta-analysis, J. Pediatr. Health Care, 26, 291, 10.1016/j.pedhc.2011.02.008 2014 Vyas, 2005, Intranasal drug delivery for brain targeting, Curr. Drug Deliv., 2, 165, 10.2174/1567201053586047 Mathison, 1998, Nasal route for direct delivery of solutes to the central nervous system: fact or fiction?, J. Drug Target., 5, 415, 10.3109/10611869808997870 Chow, 1999, Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats, J. Pharm. Sci., 88, 754, 10.1021/js9900295 Zhang, 2004, Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain, Int. J. Pharm., 275, 85, 10.1016/j.ijpharm.2004.01.039 Hardy, 2002, The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics, Science (New York, N.Y.), 297, 353, 10.1126/science.1072994 Walsh, 2002, Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo, Nature, 416, 535, 10.1038/416535a Bush, 2003, The metallobiology of Alzheimer's disease, Trends Neurosci., 26, 207, 10.1016/S0166-2236(03)00067-5 Lovell, 1998, Copper, iron and zinc in Alzheimer's disease senile plaques, J. Neurol. Sci., 158, 47, 10.1016/S0022-510X(98)00092-6 Strozyk, 2009, Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid, Neurobiol. Aging, 30, 1069, 10.1016/j.neurobiolaging.2007.10.012 Zhang, 2010, Altered expression and distribution of zinc transporters in APP/PS1 transgenic mouse brain, Neurobiol. Aging, 31, 74, 10.1016/j.neurobiolaging.2008.02.018 Atwood, 2003, Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta, Brain Res. Brain Res. Rev., 43, 1, 10.1016/S0165-0173(03)00174-7 Jiang, 2009, Ternary complexes of iron, amyloid-beta, and nitrilotriacetic acid: binding affinities, redox properties, and relevance to iron-induced oxidative stress in Alzheimer's disease, Biochemistry, 48, 7939, 10.1021/bi900907a Moreira, 2010, Detection and localization of markers of oxidative stress by in situ methods: application in the study of Alzheimer disease, Methods Mol. Biol. (Clifton, N.J.), 610, 419, 10.1007/978-1-60327-029-8_25 Castellani, 2004, Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease, Ageing Res. Rev., 3, 319, 10.1016/j.arr.2004.01.002 Lovell, 2004, Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3, J. Alzheimer's Dis., 6, 659, 10.3233/JAD-2004-6610 Pratico, 2000, Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease, Am. J. Med., 109, 577, 10.1016/S0002-9343(00)00547-7 Sayre, 2001, Chemistry and biochemistry of oxidative stress in neurodegenerative disease, Curr. Med. Chem., 8, 721, 10.2174/0929867013372922 Cherny, 2001, Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice, Neuron, 30, 665, 10.1016/S0896-6273(01)00317-8 Crapper McLachlan, 1991, Intramuscular desferrioxamine in patients with Alzheimer's disease, Lancet (London, England), 337, 1304, 10.1016/0140-6736(91)92978-B Whitnall, 2006, Iron: a new target for pharmacological intervention in neurodegenerative diseases, Semin. Pediatr. Neurol., 13, 186, 10.1016/j.spen.2006.08.008 House, 2004, Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease, J. Alzheimer's Dis., 6, 291, 10.3233/JAD-2004-6310 Morse, 2004, FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein, J. Mol. Neurosci., 24, 129, 10.1385/JMN:24:1:129 Avramovich-Tirosh, 2007, Neurorescue activity, APP regulation and amyloid-beta peptide reduction by novel multi-functional brain permeable iron- chelating- antioxidants, M-30 and green tea polyphenol, EGCG, Curr. Alzheimer Res., 4, 403, 10.2174/156720507781788927 Cuajungco, 2000, Metal chelation as a potential therapy for Alzheimer's disease, Ann. N. Y. Acad. Sci., 920, 292, 10.1111/j.1749-6632.2000.tb06938.x Freedman, 1988, Neurotoxicity associated with deferoxamine therapy, Toxicology, 49, 283, 10.1016/0300-483X(88)90010-8 Lindner, 1995, Influence of hepatic artery occlusion and desferrioxamine on liver-tumour growth, Int. J. Cancer, 63, 592, 10.1002/ijc.2910630421 Shachar, 2004, Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats, Neuropharmacology, 46, 254, 10.1016/j.neuropharm.2003.09.005 May, 1983, 5 the present status of chelating agents in medicine, 225, 10.1016/S0079-6468(08)70220-0 Hanson, 2009, Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke, J. Pharmacol. Exp. Ther., 330, 679, 10.1124/jpet.108.149807 Esch, 1990, Cleavage of amyloid beta peptide during constitutive processing of its precursor, Science (New York, N.Y.), 248, 1122, 10.1126/science.2111583 Arendash, 2004, Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer's disease: linkage of poorer cognitive performance to tau pathology in forebrain, Brain Res., 1012, 29, 10.1016/j.brainres.2004.02.081 Cai, 2012, Roles of glycogen synthase kinase 3 in Alzheimer's disease, Curr. Alzheimer Res., 9, 864, 10.2174/156720512802455386 Zhu, 2007, Causes of oxidative stress in Alzheimer disease, Cell. Mol. Life Sci., 64, 2202, 10.1007/s00018-007-7218-4 Tonin, 2010, Long-chain 3-hydroxy fatty acids accumulating in LCHAD and MTP deficiencies induce oxidative stress in rat brain, Neurochem. Int., 56, 930, 10.1016/j.neuint.2010.03.025 Domingo, 2006, Aluminum and other metals in Alzheimer's disease: a review of potential therapy with chelating agents, J. Alzheimer's Dis., 331, 10.3233/JAD-2006-102-315 Rafii, 2009, Recent developments in Alzheimer's disease therapeutics, BMC Med., 7, 7, 10.1186/1741-7015-7-7 Wilcock, 2008, Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial, Lancet, 7, 483, 10.1016/S1474-4422(08)70090-5 Eriksen, 2003, NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo, J. Clin. Invest., 112, 440, 10.1172/JCI18162 Myriad Genetics Reports Results of U.S., 2008 Green, 2009, Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial, JAMA, 302, 2557, 10.1001/jama.2009.1866 Imbimbo, 2009, Why did tarenflurbil fail in Alzheimer's disease?, J. Alzheimer's Dis., 17, 757, 10.3233/JAD-2009-1092 Swami, 2015, Adenosine conjugated lipidic nanoparticles for enhanced tumor targeting, Int. J. Pharm., 486, 287, 10.1016/j.ijpharm.2015.03.065 Win, 2005, Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs, Biomaterials, 26, 2713, 10.1016/j.biomaterials.2004.07.050 Sahni, 2011, Neurotherapeutic applications of nanoparticles in Alzheimer's disease, J. Control. Release, 152, 208, 10.1016/j.jconrel.2010.11.033 Dora, 2012, Poly(ethylene glycol) hydroxystearate-based nanosized emulsions: effect of surfactant concentration on their formation and ability to solubilize quercetin, J. Biomed. Nanotechnol., 8, 202, 10.1166/jbn.2012.1380 Heurtault, 2002, A novel phase inversion-based process for the preparation of lipid nanocarriers, Pharm. Res., 19, 875, 10.1023/A:1016121319668 Balls, 2004, Progressing toward the reduction, refinement and replacement of laboratory animal procedures: thoughts on some encounters with Dr Iain purchase, Toxicol. In Vitro, 18, 165, 10.1016/S0887-2333(03)00145-0 Horvat, 2009, Sodium hyaluronate as a mucoadhesive component in nasal formulation enhances delivery of molecules to brain tissue, Eur. J. Pharm. Biopharm., 72, 252, 10.1016/j.ejpb.2008.10.009 Amri, 2012, Administration of resveratrol: what formulation solutions to bioavailability limitations?, J. Control. Release, 158, 182, 10.1016/j.jconrel.2011.09.083 Ved, 2011, Poly(ethylene oxide/propylene oxide) copolymer thermo-reversible gelling system for the enhancement of intranasal zidovudine delivery to the brain, Int. J. Pharm., 411, 1, 10.1016/j.ijpharm.2011.02.040 Alexander, 2013, Poly(ethylene glycol)-poly(lactic-co-glycolic acid) based thermosensitive injectable hydrogels for biomedical applications, J. Control. Release, 172, 715, 10.1016/j.jconrel.2013.10.006 Picone, 2011, Insulin-activated Akt rescues Abeta oxidative stress-induced cell death by orchestrating molecular trafficking, Aging Cell, 10, 832, 10.1111/j.1474-9726.2011.00724.x Zhao, 2008, Amyloid beta oligomers induce impairment of neuronal insulin receptors, FASEB J., 22, 246, 10.1096/fj.06-7703com Di Carlo, 2010, Insulin promotes survival of amyloid-beta oligomers Neuroblastoma damaged cells via Caspase 9 inhibition and Hsp70 Upregulation, J. Biomed. Biotechnol., 2010, 8, 10.1155/2010/147835 Chua, 2012, Impaired neuronal insulin signaling precedes Abeta42 accumulation in female AbetaPPsw/PS1DeltaE9 mice, J. Alzheimer's Dis., 29, 783, 10.3233/JAD-2012-111880 Benedict, 2004, Intranasal insulin improves memory in humans, Psychoneuroendocrinology, 29, 1326, 10.1016/j.psyneuen.2004.04.003 Banks, 2004, The source of cerebral insulin, Eur. J. Pharmacol., 490, 5, 10.1016/j.ejphar.2004.02.040 Schulingkamp, 2000, Insulin receptors and insulin action in the brain: review and clinical implications, Neurosci. Biobehav. Rev., 24, 855, 10.1016/S0149-7634(00)00040-3 Wu, 2010, Multifunctional hybrid nanogel for integration of optical glucose sensing and self-regulated insulin release at physiological pH, ACS Nano, 4, 4831, 10.1021/nn1008319 Dispenza, 2015, Radiation-engineered functional nanoparticles in aqueous systems, J. Nanosci. Nanotechnol., 15, 3445, 10.1166/jnn.2015.9865 Picone, 2017, Nose-to-brain delivery of insulin enhanced by a nanogel carrier, J. Control. Release, 270, 23, 10.1016/j.jconrel.2017.11.040 Thorne, 2001, Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations, Clin. Pharmacokinet., 40, 907, 10.2165/00003088-200140120-00003 Graff, 2005, Nasal drug administration: potential for targeted central nervous system delivery, J. Pharm. Sci., 94, 1187, 10.1002/jps.20318 Dufes, 2003, Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats, Int. J. Pharm., 255, 87, 10.1016/S0378-5173(03)00039-5 Kim, 2000, In vivo gene transfer to the mouse nasal cavity mucosa using a stable cationic lipid emulsion, Mol. Cells, 10, 142, 10.1007/s10059-000-0142-1 Nishimoto, 2004, Unravelling the role of Humanin, Trends Mol. Med., 10, 102, 10.1016/j.molmed.2004.01.001 Niikura, 2004, Humanin: after the discovery, Mol. Neurobiol., 30, 327, 10.1385/MN:30:3:327 Mamiya, 2001, [Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo, Br. J. Pharmacol., 134, 1597, 10.1038/sj.bjp.0704429 Tajima, 2005, A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice, J. Neurosci. Res., 79, 714, 10.1002/jnr.20391 Garg, 2007, Cubosomes: an overview, Biol. Pharm. Bull., 30, 350, 10.1248/bpb.30.350 Li, 2007, Anti-infection peptidomics of amphibian skin, Mol. Cell. Proteomics, 6, 882, 10.1074/mcp.M600334-MCP200 Li, 2008, Odorranalectin is a small peptide lectin with potential for drug delivery and targeting, PLoS One, 3, 10.1371/journal.pone.0002381 Melgarejo Moreno, 1998, Olfactory epithelium of the rat. Lectin-mediated histochemical studies, An. Otorrinolaringol. Iberoam., 25, 471 Lundh, 1989, Lectin-binding pattern of neuroepithelial and respiratory epithelial cells in the mouse nasal cavity, Histochem. J., 21, 33, 10.1007/BF01002469 Spicer, 2001, Novel process for producing cubic liquid crystalline nanoparticles (Cubosomes), Langmuir, 17, 5748, 10.1021/la010161w Yue, 2007, Huperzine a in rat plasma and CSF following intranasal administration, Int. J. Pharm., 337, 127, 10.1016/j.ijpharm.2006.12.029 Tao, 2006, Preparation of huperzine A nasal in situ gel and evaluation of its brain targeting following intranasal administration, Yao xue xue bao, 41, 1104 Zhao, 2007, Drug brain distribution following intranasal administration of Huperzine a in situ gel in rats, Acta Pharmacol. Sin., 28, 273, 10.1111/j.1745-7254.2007.00486.x Majumdar, 2007, Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils, Mol. Biol. Cell, 18, 1490, 10.1091/mbc.e06-10-0975 Mitrasinovic, 2003, Microglial overexpression of the M-CSF receptor augments phagocytosis of opsonized Abeta, Neurobiol. Aging, 24, 807, 10.1016/S0197-4580(02)00237-3 Mitrasinovic, 2003, Macrophage colony stimulating factor promotes phagocytosis by murine microglia, Neurosci. Lett., 344, 185, 10.1016/S0304-3940(03)00474-9 Bartesaghi, 2005, Erythropoietin: a novel neuroprotective cytokine, Neurotoxicology, 26, 923, 10.1016/j.neuro.2005.01.016 Rabie, 2008, Brain protection by erythropoietin: a manifold task, Physiology (Bethesda, MD), 23, 263 Nadam, 2007, Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus, Neurobiol. Dis., 25, 412, 10.1016/j.nbd.2006.10.009 Sanchez, 2009, Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons, Proc. Natl. Acad. Sci. U. S. A., 106, 9848, 10.1073/pnas.0901840106 Assaraf, 2007, Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment, J. Neuropathol. Exp. Neurol., 66, 389, 10.1097/nen.0b013e3180517b28 Lee, 2006, Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage, J. Neurochem., 96, 1728, 10.1111/j.1471-4159.2006.03697.x Bernaudin, 1999, A potential role for erythropoietin in focal permanent cerebral ischemia in mice, J. Cereb. Blood Flow Metab., 19, 643, 10.1097/00004647-199906000-00007 Sakanaka, 1998, In vivo evidence that erythropoietin protects neurons from ischemic damage, Proc. Natl. Acad. Sci. U. S. A., 95, 4635, 10.1073/pnas.95.8.4635 Celik, 2002, Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury, Proc. Natl. Acad. Sci. U. S. A., 99, 2258, 10.1073/pnas.042693799 Brines, 2000, Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury, Proc. Natl. Acad. Sci., 97, 10526, 10.1073/pnas.97.19.10526 Li, 2004, Beneficial effect of erythropoietin on experimental allergic encephalomyelitis, Ann. Neurol., 56, 767, 10.1002/ana.20274 Kumral, 2004, Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats, Behav. Brain Res., 153, 77, 10.1016/j.bbr.2003.11.002 Grunfeld, 2007, Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model, Exp. Neurol., 204, 260, 10.1016/j.expneurol.2006.11.002 Chong, 2005, Erythropoietin requires NF-kappaB and its nuclear translocation to prevent early and late apoptotic neuronal injury during beta-amyloid toxicity, Curr. Neurovasc. Res., 2, 387, 10.2174/156720205774962683 Ma, 2009, Erythropoietin protects PC12 cells from beta-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway, Neuropharmacology, 56, 1027, 10.1016/j.neuropharm.2009.02.006 Garcia-Rodriguez, 2009, The nasal route as a potential pathway for delivery of erythropoietin in the treatment of acute ischemic stroke in humans, TheScientificWorldJOURNAL, 9, 970, 10.1100/tsw.2009.103 Maurice, 1996, Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction, Brain Res., 706, 181, 10.1016/0006-8993(95)01032-7 Bies, 2004, Lectin-mediated drug targeting: history and applications, Adv. Drug Deliv. Rev., 56, 425, 10.1016/j.addr.2003.10.030 Said, 1970, Polypeptide with broad biological activity: isolation from small intestine, Science (New York, N.Y.), 169, 1217, 10.1126/science.169.3951.1217 Magistretti, 1981, Vasoactive intestinal polypeptide induces glycogenolysis in mouse cortical slices: a possible regulatory mechanism for the local control of energy metabolism, Proc. Natl. Acad. Sci. U. S. A., 78, 6535, 10.1073/pnas.78.10.6535 Muller, 1995, VIP as a cell-growth and differentiation neuromodulator role in neurodevelopment, Mol. Neurobiol., 10, 115, 10.1007/BF02740671 Brenneman, 1998, VIP neurotrophism in the central nervous system: multiple effectors and identification of a femtomolar-acting neuroprotective peptide, Ann. N. Y. Acad. Sci., 865, 207, 10.1111/j.1749-6632.1998.tb11180.x Conner, 2009, NGF is essential for hippocampal plasticity and learning, J. Neurosci., 29, 10883, 10.1523/JNEUROSCI.2594-09.2009 Sanchez-Ortiz, 2012, TrkA gene ablation in basal forebrain results in dysfunction of the cholinergic circuitry, J. Neurosci., 32, 4065, 10.1523/JNEUROSCI.6314-11.2012 Counts, 2011, Gender differences in neurotrophin and glutamate receptor expression in cholinergic nucleus basalis neurons during the progression of Alzheimer's disease, J. Chem. Neuroanat., 42, 111, 10.1016/j.jchemneu.2011.02.004 Morrison, 1986, Basic fibroblast growth factor supports the survival of cerebral cortical neurons in primary culture, Proc. Natl. Acad. Sci. U. S. A., 83, 7537, 10.1073/pnas.83.19.7537 Aoyagi, 1994, Characterization of basic fibroblast growth factor-mediated acceleration of axonal branching in cultured rat hippocampal neurons, Brain Res., 661, 117, 10.1016/0006-8993(94)91188-6 Terlau, 1990, Fibroblast growth factor enhances long-term potentiation in the hippocampal slice, Eur. J. Neurosc., Vol. 2, 973, 10.1111/j.1460-9568.1990.tb00009.x Sun, 2009, Basic fibroblast growth factor-enhanced neurogenesis contributes to cognitive recovery in rats following traumatic brain injury, Exp. Neurol., 216, 56, 10.1016/j.expneurol.2008.11.011 Yoshimura, 2003, FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice, J. Clin. Invest., 112, 1202, 10.1172/JCI16618 Kawamata, 1997, Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebralinfarction, Proc. Natl. Acad. Sci., 94, 8179, 10.1073/pnas.94.15.8179 Zechel, 2010, Expression and functions of fibroblast growth factor 2 (FGF-2) in hippocampal formation, Neuroscientist, 16, 357, 10.1177/1073858410371513 Stopa, 1990, Basic fibroblast growth factor in Alzheimer's disease, Biochem. Biophys. Res. Commun., 171, 690, 10.1016/0006-291X(90)91201-3 Mattson, 1997, Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives, Physiol. Rev., 77, 1081, 10.1152/physrev.1997.77.4.1081 Baskin, 1997, Altered apolipoprotein E secretion in cytokine treated human astrocyte cultures, J. Neurol. Sci., 148, 15, 10.1016/S0022-510X(96)05335-X Liu, 1999, Roles of p53, c-Myc, Bcl-2, Bax and caspases in glutamate-induced neuronal apoptosis and the possible neuroprotective mechanism of basic fibroblast growth factor, brain research, Mol. Brain Res., 71, 210, 10.1016/S0169-328X(99)00186-2 Illum, 2003, Nasal drug delivery—possibilities, problems and solutions, J. Control. Release, 87, 187, 10.1016/S0168-3659(02)00363-2 Wu, 2009, Lectins as tools in glycoconjugate research, Glycoconj. J., 26, 899, 10.1007/s10719-008-9119-7 Gabor, 2004, The lectin-cell interaction and its implications to intestinal lectin-mediated drug delivery, Adv. Drug Deliv. Rev., 56, 459, 10.1016/j.addr.2003.10.015 Pastor, 1992, Histochemical study of glycoconjugates in the nasal mucosa of the rat and Guinea pig, Histochem. J., 24, 727, 10.1007/BF01460825 Guzman-Casado, 2001, Myo-inositol hexasulphate and low molecular weight heparin binding to human acidic fibroblast growth factor: a calorimetric and FTIR study, Int. J. Biol. Macromol., 28, 305, 10.1016/S0141-8130(01)00131-3 Roghani, 1994, Heparin increases the affinity of basic fibroblast growth factor for its receptor but is not required for binding, J. Biol. Chem., 269, 3976, 10.1016/S0021-9258(17)41730-3 Chafekar, 2007, Branched KLVFF tetramers strongly potentiate inhibition of beta-amyloid aggregation, Chembiochem, 8, 1857, 10.1002/cbic.200700338 Lowe, 2001, Structure-function relationships for inhibitors of beta-amyloid toxicity containing the recognition sequence KLVFF, Biochemistry, 40, 7882, 10.1021/bi002734u Findeis, 1999, Modified-peptide inhibitors of amyloid beta-peptide polymerization, Biochemistry, 38, 6791, 10.1021/bi982824n Tjernberg, 1996, Arrest of beta-amyloid fibril formation by a pentapeptide ligand, J. Biol. Chem., 271, 8545, 10.1074/jbc.271.15.8545 Soto, 1998, Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy, Nat. Med., 4, 822, 10.1038/nm0798-822 Adessi, 2003, Pharmacological profiles of peptide drug candidates for the treatment of Alzheimer's disease, J. Biol. Chem., 278, 13905, 10.1074/jbc.M211976200 Chang, 2009, A new amyloid-like beta-aggregate with amyloid characteristics, except fibril morphology, J. Mol. Biol., 385, 1257, 10.1016/j.jmb.2008.11.009 Iwata, 2005, Metabolism of amyloid-beta peptide and Alzheimer's disease, Pharmacol. Ther., 108, 129, 10.1016/j.pharmthera.2005.03.010 Aileen Funke, 2010, Oral treatment with the d-enantiomeric peptide D3 improves the pathology and behavior of Alzheimer's disease transgenic mice, ACS Chem. Neurosci., 1, 639, 10.1021/cn100057j Permanne, 2002, Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a beta-sheet breaker peptide, FASEB J., 16, 860, 10.1096/fj.01-0841fje Wiesehan, 2003, Selection of D-amino-acid peptides that bind to Alzheimer's disease amyloid peptide abeta1-42 by mirror image phage display, Chembiochem, 4, 748, 10.1002/cbic.200300631 Frydman-Marom, 2009, Cognitive-performance recovery of Alzheimer's disease model mice by modulation of early soluble amyloidal assemblies, Angew. Chem., 48, 1981, 10.1002/anie.200802123 Lin, 2014, Feasibility of beta-sheet breaker peptide-H102 treatment for Alzheimer's disease based on beta-amyloid hypothesis, PLoS One, 9 Benedict, 2007, Intranasal insulin to improve memory function in humans, Neuroendocrinology, 86, 136, 10.1159/000106378 Lotjonen, 2011, Fast and robust extraction of hippocampus from MR images for diagnostics of Alzheimer's disease, NeuroImage, 56, 185, 10.1016/j.neuroimage.2011.01.062 Hanson, 2008, Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease, BMC Neurosci., 9, S5, 10.1186/1471-2202-9-S3-S5 Thorne, 1995, Quantitative analysis of the olfactory pathway for drug delivery to the brain, Brain Res., 692, 278, 10.1016/0006-8993(95)00637-6 Illum, 2004, Is nose-to-brain transport of drugs in man a reality?, J. Pharm. Pharmacol., 56, 3, 10.1211/0022357022539 Ali, 2010, Potential of nanoparticulate drug delivery systems by intranasal administration, Curr. Pharm. Des., 16, 1644, 10.2174/138161210791164108 Verma, 2010, Effect of surface properties on nanoparticle-cell interactions, Small, 6, 12, 10.1002/smll.200901158 Gozes, 2003, From vasoactive intestinal peptide (VIP) through activity-dependent neuroprotective protein (ADNP) to NAP: a view of neuroprotection and cell division, J. Mol. Neurosci., 20, 315, 10.1385/JMN:20:3:315 Gozes, 2004, NAP mechanisms of neuroprotection, J. Mol. Neurosci., 24, 67, 10.1385/JMN:24:1:067 Gozes, 2005, NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP), CNS Drug Rev., 11, 353, 10.1111/j.1527-3458.2005.tb00053.x Bassan, 1999, Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide, J. Neurochem., 72, 1283, 10.1046/j.1471-4159.1999.0721283.x Zemlyak, 2000, A novel peptide prevents death in enriched neuronal cultures, Regul. Pept., 96, 39, 10.1016/S0167-0115(00)00198-1 Beni-Adani, 2001, A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice, J. Pharmacol. Exp. Ther., 296, 57 Allen, 1999, Cellular internalization of PCL(20)-b-PEO(44) block copolymer micelles, Biochim. Biophys. Acta, 1421, 32, 10.1016/S0005-2736(99)00108-X Chonpathompikunlert, 2010, Br. Ind. Biol. Res. Assoc., 48, 798 Sastre, 2012, Local and systemic safety of intranasal corticosteroids, J Investig Allergol Clin Immunol, 22, 1 Illum, 1994, Chitosan as a novel nasal delivery system for peptide drugs, Pharm. Res., 11, 1186, 10.1023/A:1018901302450 Elnaggar, 2015, Intranasal piperine-loaded chitosan nanoparticles as brain-targeted therapy in Alzheimer's disease: optimization, biological efficacy, and potential toxicity, J. Pharm. Sci., 104, 3544, 10.1002/jps.24557 Alexander, 2016, Understanding the role of Poloxamer 407 based Thermoreversible in situ gelling hydrogel for delivery of PEGylated Melphalan conjugate, Curr. Drug Deliv., 13, 621, 10.2174/1567201813666160204114000 Mistry, 2009, Nanoparticles for direct nose-to-brain delivery of drugs, Int. J. Pharm., 379, 146, 10.1016/j.ijpharm.2009.06.019 Zhang, 2012, Preparation and characterization of insulin-loaded bioadhesive PLGA nanoparticles for oral administration, Eur. J. Pharm. Sci., 45, 632, 10.1016/j.ejps.2012.01.002 McNay, 2010, Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance, Neurobiol. Learn. Mem., 93, 546, 10.1016/j.nlm.2010.02.002 Schioth, 2012, Brain insulin signaling and Alzheimer's disease: current evidence and future directions, Mol. Neurobiol., 46, 4, 10.1007/s12035-011-8229-6 Chiu, 2008, Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo, Neuron, 58, 708, 10.1016/j.neuron.2008.04.014 Benedict, 2007, Intranasal insulin improves memory in humans: superiority of insulin aspart, Neuropsychopharmacology, 32, 239, 10.1038/sj.npp.1301193 Steen, 2005, Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes?, J. Alzheimer's Dis., 7, 63, 10.3233/JAD-2005-7107 Benedict, 2011, Intranasal insulin as a therapeutic option in the treatment of cognitive impairments, Exp. Gerontol., 46, 112, 10.1016/j.exger.2010.08.026 Reger, 2008, Intranasal insulin improves cognition and modulates beta-amyloid in early AD, Neurology, 70, 440, 10.1212/01.WNL.0000265401.62434.36 De Felice, 2009, Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers, Proc. Natl. Acad. Sci. U. S. A., 106, 1971, 10.1073/pnas.0809158106 Lee, 2009, Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation, Neurobiol. Aging, 30, 377, 10.1016/j.neurobiolaging.2007.06.014 Freiherr, 2013, Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence, CNS drugs, 27, 505, 10.1007/s40263-013-0076-8 Reger, 2006, Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype, Neurobiol. Aging, 27, 451, 10.1016/j.neurobiolaging.2005.03.016 Rangasamy, 2015, Intranasal delivery of NEMO-binding domain peptide prevents memory loss in a mouse model of Alzheimer's disease, J. Alzheimer's Dis., 47, 385, 10.3233/JAD-150040 Hayden, 2012, NF-kappaB, the first quarter-century: remarkable progress and outstanding questions, Genes Dev., 26, 203, 10.1101/gad.183434.111 Oeckinghaus, 2011, Crosstalk in NF-kappaB signaling pathways, Nat. Immunol., 12, 695, 10.1038/ni.2065 May, 2000, Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex, Science (New York, N.Y.), 289, 1550, 10.1126/science.289.5484.1550