Oral and Intra-nasal Administration of Nanoparticles in the Cerebral Ischemia Treatment in Animal Experiments: Considering its Advantages and Disadvantages

Firoozeh       Alavian; Nasrin       Shams
Abstract

Background: Over the past few decades, nanotechnology has dramatically advanced; from the precise strategies of synthesizing modern nanostructures to methods of entry into the body. Using nanotechnology in diagnosis, drug delivery, determining signaling pathways, and tissue engineering is great hope for the treatment of stroke. The drug-carrying nanoparticles are a way to increase drug absorption through the mouth or nose in treating the stroke.
Objective: In this article, in addition to explaining pros and cons of oral and intra-nasal administration of nanoparticles in the brain ischemia treatment of animal models, the researchers introduce some articles in this field and briefly mentioned their work outcomes.
Methods: A number of relevant published articles 183 were initially collected from three popular databases including PubMed, Google Scholar, and Scopus. The articles not closely related to the main purpose of the present work were removed from the study process. The present data set finally included 125 published articles.
Results: Direct delivery of the drug to the animal brain through the mouth and nose has more therapeutic effects than systemic delivery of drugs. The strategy of adding drugs to the nanoparticles complex can potentially improve the direct delivery of drugs to the CNS.
Conclusion: Despite the limitations of oral and intra-nasal routes, the therapeutic potential of oral and intra-nasal administration of nano-medicines is high in cerebral ischemia treatment.
Keywords: Nanoparticles, stroke, oral, intra-nasal, treatment, CNS, rat.
Graphical Abstract

[1] 
Control CfD, Prevention.. National diabetes fact sheet: National estimates and general in-formation on diabetes and prediabetes in the United States 2011 2011; 201(1): 2568-9.
[2] 
Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. Lancet Neurol  2007; 6(2): 182-7.
[http://dx.doi.org/10.1016/S1474-4422(07)70031-5] [PMID: 17239805] 
[3] 
Alavian F, Hajizadeh S, Bigdeli MR, Javan M. The role of protein kinase C in ischemic tolerance induced by hyperoxia in rats with stroke. EXCLI J  2012; 11: 188-97.
[PMID: 27385957] 
[4] 
Alavian F, Ghiasvand S. Protective effects of jujube extract against permeability of Blood-Brain Barrier (BBB), and the activity of glutathione peroxidase and catalase in stroke model. Majallah-i Danishkadah-i Pizishki-i Isfahan  2018; 36(475): 379-85.
[5] 
Schinkel AH, Smit JJ, van Tellingen O, 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. Cell  1994; 77(4): 491-502.
[http://dx.doi.org/10.1016/0092-8674(94)90212-7] [PMID: 7910522] 
[6] 
Misra A, Ganesh S, Shahiwala A, Shah SP. Drug delivery to the central nervous system: a review. J Pharm Pharm Sci  2003; 6(2): 252-73.
[PMID: 12935438] 
[7] 
Ulbrich K, Hekmatara T, Herbert E, Kreuter J. Transferrin- and transferrin-receptor-antibody-modified nanoparticles enable drug delivery across the blood-brain barrier (BBB). Eur J Pharm Biopharm  2009; 71(2): 251-6.
[http://dx.doi.org/10.1016/j.ejpb.2008.08.021] [PMID: 18805484] 
[8] 
Lao F, Chen L, Li W, et al. Fullerene nanoparticles selectively enter oxidation-damaged cerebral microvessel endothelial cells and inhibit JNK-related apoptosis. ACS Nano  2009; 3(11): 3358-68.
[http://dx.doi.org/10.1021/nn900912n] [PMID: 19839607] 
[9] 
Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: Mechanisms of controlling drug release. Chem Rev  2016; 116(4): 2602-63.
[http://dx.doi.org/10.1021/acs.chemrev.5b00346] [PMID: 26854975] 
[10] 
Pathak Y. Recent Developments in nanoparticulate drug delivery systems drug delivery nanoparticles formulation and characterization.  CRC Press 2016; pp. 19-33.
[11] 
Warheit DB. Nanoparticles. Mater Today  2004; 7(2): 32-5.
[http://dx.doi.org/10.1016/S1369-7021(04)00081-1] 
[12] 
Alavian F. Drug Abuse Treatment through gene manipulation using nanomedicine. Curr Pharmacogenomics Person Med  2018; 16(182): 1-10.
[13] 
Petkar KC, Chavhan SS, Agatonovik-Kustrin S, Sawant K. Nanostructured materials in drug and gene delivery: A review of the state of the art 
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v28.i2.10] 
[14] 
Prabhu S, Poulose EK. Silver nanoparticles: Mechanism of antimicrobial action, synthesis, medical applications, and toxicity effects. Int Nano Lett  2012; 2(1): 32.
[http://dx.doi.org/10.1186/2228-5326-2-32] 
[15] 
Kittelson DB. Engines and nanoparticles: A review. J Aerosol Sci  1998; 29(5-6): 575-88.
[http://dx.doi.org/10.1016/S0021-8502(97)10037-4] 
[16] 
Mohanraj V, Chen Y. Nanoparticles-a review. Trop J Pharm Res  2006; 5(1): 561-73.
[17] 
Kango S, Kalia S, Celli A, Njuguna J, Habibi Y, Kumar R. Surface modification of inorganic nanoparticles for development of organic–inorganic nanocomposites-A review. Prog Polym Sci  2013; 38(8): 1232-61.
[http://dx.doi.org/10.1016/j.progpolymsci.2013.02.003] 
[18] 
Khlebtsov N, Dykman L. Biodistribution and toxicity of engineered gold nanoparticles: a review of in vitro and in vivo studies. Chem Soc Rev  2011; 40(3): 1647-71.
[http://dx.doi.org/10.1039/C0CS00018C] [PMID: 21082078] 
[19] 
Jain PK, Huang X, El-Sayed IH, El-Sayed MA. Review of some interesting surface plasmon resonance-enhanced properties of noble metal nanoparticles and their applications to biosystems. Plasmonics  2007; 2(3): 107-18.
[http://dx.doi.org/10.1007/s11468-007-9031-1] 
[20] 
Wolfram J, Zhu M, Yang Y, et al. Safety of nanoparticles in medicine. Curr Drug Targets  2015; 16(14): 1671-81.
[http://dx.doi.org/10.2174/1389450115666140804124808] [PMID: 26601723] 
[21] 
Ferro-Flores G, Ocampo-García BE, Santos-Cuevas CL, Morales-Avila E, Azorín-Vega E. Multifunctional radiolabeled nanoparticles for targeted therapy. Curr Med Chem  2014; 21(1): 124-38.
[http://dx.doi.org/10.2174/09298673113209990218] [PMID: 23992338] 
[22] 
Jiskoot W, van Schie RM, Carstens MG, Schellekens H. Immunological risk of injectable drug delivery systems. Pharm Res  2009; 26(6): 1303-14.
[http://dx.doi.org/10.1007/s11095-009-9855-9] [PMID: 19247815] 
[23] 
Li M, Al-Jamal KT, Kostarelos K, Reineke J. Physiologically based pharmacokinetic modeling of nanoparticles. ACS Nano  2010; 4(11): 6303-17.
[http://dx.doi.org/10.1021/nn1018818] [PMID: 20945925] 
[24] 
Patel J, Patel A. Toxicity of Nanomaterials on the Liver, Kidney, and Spleen. CRC Press: Boca Raton, FL 2015.
[25] 
Donaldson K, Tran L, Jimenez LA, et al. Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure. Part Fibre Toxicol  2005; 2(1): 10.
[http://dx.doi.org/10.1186/1743-8977-2-10] [PMID: 16242040] 
[26] 
Lamprecht A, Schäfer U, Lehr C-M. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res  2001; 18(6): 788-93.
[http://dx.doi.org/10.1023/A:1011032328064] [PMID: 11474782] 
[27] 
Park MV, Neigh AM, Vermeulen JP, et al. The effect of particle size on the cytotoxicity, inflammation, developmental toxicity and genotoxicity of silver nanoparticles. Biomaterials  2011; 32(36): 9810-7.
[http://dx.doi.org/10.1016/j.biomaterials.2011.08.085] [PMID: 21944826] 
[28] 
Hoet PH, Brüske-Hohlfeld I, Salata OV. Nanoparticles - known and unknown health risks. J Nanobiotechnology  2004; 2(1): 12.
[http://dx.doi.org/10.1186/1477-3155-2-12] [PMID: 15588280] 
[29] 
Kettiger H, Schipanski A, Wick P, Huwyler J. Engineered nanomaterial uptake and tissue distribution: from cell to organism. Int J Nanomedicine  2013; 8: 3255-69.
[PMID: 24023514] 
[30] 
Cho M, Cho W-S, Choi M, et al. The impact of size on tissue distribution and elimination by single intravenous injection of silica nanoparticles. Toxicol Lett  2009; 189(3): 177-83.
[http://dx.doi.org/10.1016/j.toxlet.2009.04.017] [PMID: 19397964] 
[31] 
De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials  2008; 29(12): 1912-9.
[http://dx.doi.org/10.1016/j.biomaterials.2007.12.037] [PMID: 18242692] 
[32] 
Ong W-Y, Shalini S-M, Costantino L. Nose-to-brain drug delivery by nanoparticles in the treatment of neurological disorders. Curr Med Chem  2014; 21(37): 4247-56.
[http://dx.doi.org/10.2174/0929867321666140716103130] [PMID: 25039773] 
[33] 
Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release  2001; 70(1-2): 1-20.
[http://dx.doi.org/10.1016/S0168-3659(00)00339-4] [PMID: 11166403] 
[34] 
Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science  2004; 303(5665): 1818-22.
[http://dx.doi.org/10.1126/science.1095833] [PMID: 15031496] 
[35] 
Ting Y, Jiang Y, Ho C-T, Huang Q. Common delivery systems for enhancing in vivo bioavailability and biological efficacy of nutraceuticals. J Funct Foods  2014; 7: 112-28.
[http://dx.doi.org/10.1016/j.jff.2013.12.010] 
[36] 
Kakkar V, Muppu SK, Chopra K, Kaur IP. Curcumin loaded solid lipid nanoparticles: an efficient formulation approach for cerebral ischemic reperfusion injury in rats. Eur J Pharm Biopharm  2013; 85(3 Pt A): 339-45.
[http://dx.doi.org/10.1016/j.ejpb.2013.02.005] [PMID: 23454202] 
[37] 
Ahmad N, Ahmad R, Naqvi AA, et al. Rutin-encapsulated chitosan nanoparticles targeted to the brain in the treatment of Cerebral Ischemia. Int J Biol Macromol  2016; 91: 640-55.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.06.001] [PMID: 27264648] 
[38] 
Zhang J, Han X, Li X, et al. Core-shell hybrid liposomal vesicles loaded with panax notoginsenoside: preparation, characterization and protective effects on global cerebral ischemia/reperfusion injury and acute myocardial ischemia in rats. Int J Nanomedicine  2012; 7: 4299-310.
[http://dx.doi.org/10.2147/IJN.S32385] [PMID: 22915851] 
[39] 
Yadav A, Sunkaria A, Singhal N, Sandhir R. Resveratrol loaded solid lipid nanoparticles attenuate mitochondrial oxidative stress in vascular dementia by activating Nrf2/HO-1 pathway. Neurochem Int  2018; 112: 239-54.
[http://dx.doi.org/10.1016/j.neuint.2017.08.001] [PMID: 28782592] 
[40] 
Ghosh A, Sarkar S, Mandal AK, Das N. Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats. PLoS One  2013; 8(4) e57735
[http://dx.doi.org/10.1371/journal.pone.0057735] [PMID: 23620721] 
[41] 
Mutoh T, Mutoh T, Taki Y, Ishikawa T. Therapeutic potential of natural product-based oral nanomedicines for stroke prevention. J Med Food  2016; 19(6): 521-7.
[http://dx.doi.org/10.1089/jmf.2015.3644] [PMID: 27136062] 
[42] 
Mittal D, Ali A, Md S, Baboota S, Sahni JK, Ali J. Insights into direct nose to brain delivery: current status and future perspective. Drug Deliv  2014; 21(2): 75-86.
[http://dx.doi.org/10.3109/10717544.2013.838713] [PMID: 24102636] 
[43] 
Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm  2009; 379(1): 146-57.
[http://dx.doi.org/10.1016/j.ijpharm.2009.06.019] [PMID: 19555750] 
[44] 
Ahmad N, Umar S, Ashafaq M, et al. A comparative study of PNIPAM nanoparticles of curcumin, demethoxycurcumin, and bisdemethoxycurcumin and their effects on oxidative stress markers in experimental stroke. Protoplasma  2013; 250(6): 1327-38.
[http://dx.doi.org/10.1007/s00709-013-0516-9] [PMID: 23784381] 
[45] 
des Rieux A, Fievez V, Garinot M, Schneider Y-J, Préat V. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release  2006; 116(1): 1-27.
[http://dx.doi.org/10.1016/j.jconrel.2006.08.013] [PMID: 17050027] 
[46] 
Shahbazi M-A, Santos HA. Improving oral absorption via drug-loaded nanocarriers: absorption mechanisms, intestinal models and rational fabrication. Curr Drug Metab  2013; 14(1): 28-56.
[http://dx.doi.org/10.2174/138920013804545133] [PMID: 22497568] 
[47] 
Müller RH, Rühl D, Runge SA. Biodegradation of solid lipid nanoparticles as a function of lipase incubation time. Int J Pharm  1996; 144(1): 115-21.
[http://dx.doi.org/10.1016/S0378-5173(96)04731-X] 
[48] 
Jani P, Halbert GW, Langridge J, Florence AT. Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency. J Pharm Pharmacol  1990; 42(12): 821-6.
[http://dx.doi.org/10.1111/j.2042-7158.1990.tb07033.x] [PMID: 1983142] 
[49] 
Mehnert W, Mäder K. Solid lipid nanoparticles: Production, characterization and applications. Adv Drug Deliv Rev  2012; 64: 83-101.
[http://dx.doi.org/10.1016/j.addr.2012.09.021] [PMID: 11311991] 
[50] 
Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Release  2008; 127(2): 97-109.
[http://dx.doi.org/10.1016/j.jconrel.2007.12.018] [PMID: 18313785] 
[51] 
Freitas C, Müller RH. Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLN™) dispersions. Int J Pharm  1998; 168(2): 221-9.
[http://dx.doi.org/10.1016/S0378-5173(98)00092-1] 
[52] 
Gastaldi L, Battaglia L, Peira E, et al. Solid lipid nanoparticles as vehicles of drugs to the brain: current state of the art. Eur J Pharm Biopharm  2014; 87(3): 433-44.
[http://dx.doi.org/10.1016/j.ejpb.2014.05.004] [PMID: 24833004] 
[53] 
Martins SM, Sarmento B, Nunes C, Lúcio M, Reis S, Ferreira DC. Brain targeting effect of camptothecin-loaded solid lipid nanoparticles in rat after intravenous administration. Eur J Pharm Biopharm  2013; 85(3 Pt A): 488-502.
[http://dx.doi.org/10.1016/j.ejpb.2013.08.011] [PMID: 23994244] 
[54] 
Kakkar V, Mishra AK, Chuttani K, Kaur IP. Proof of concept studies to confirm the delivery of curcumin loaded solid lipid nanoparticles (C-SLNs) to brain. Int J Pharm  2013; 448(2): 354-9.
[http://dx.doi.org/10.1016/j.ijpharm.2013.03.046] [PMID: 23558314] 
[55] 
Kakkar V, Kaur IP. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol  2011; 49(11): 2906-13.
[http://dx.doi.org/10.1016/j.fct.2011.08.006] [PMID: 21889563] 
[56] 
Kakkar V, Kaur IP. Antidepressant activity of Curcumin loaded Solid Lipid Nanoparticles (C-SLNs) in mice. Am J Pharm Res  2012; 2(3): 729-36.
[57] 
Virgili M, Contestabile A. Partial neuroprotection of in vivo excitotoxic brain damage by chronic administration of the red wine antioxidant agent, trans-resveratrol in rats. Neurosci Lett  2000; 281(2-3): 123-6.
[http://dx.doi.org/10.1016/S0304-3940(00)00820-X] [PMID: 10704758] 
[58] 
Gülçin İ. Antioxidant properties of resveratrol: a structure–activity insight. Innov Food Sci Emerg Technol  2010; 11(1): 210-8.
[http://dx.doi.org/10.1016/j.ifset.2009.07.002] 
[59] 
Tosun I, Inkaya AN. Resveratrol as a health and disease benefit agent. Food Rev Int  2009; 26(1): 85-101.
[http://dx.doi.org/10.1080/87559120802525459] 
[60] 
Gupta C, Sharma G, Chan D. Resveratrol: A chemo-preventative agent with diverse applications.  Prakash D, Sharma G. Phytochemicals of Nutraceutical Importance..  2014; pp. 47-60.
[61] 
Jardim FR, de Rossi FT, Nascimento MX, et al. Resveratrol and brain mitochondria: A review. Mol Neurobiol  2018; 55(3): 2085-101.
[http://dx.doi.org/10.1007/s12035-017-0448-z] [PMID: 28283884] 
[62] 
Novakovic A, Gojkovic-Bukarica L, Peric M, et al. The mechanism of endothelium-independent relaxation induced by the wine polyphenol resveratrol in human internal mammary artery. J Pharmacol Sci  2006; 101(1): 85-90.
[http://dx.doi.org/10.1254/jphs.FP0050863] [PMID: 16682785] 
[63] 
Vidavalur R, Otani H, Singal PK, Maulik N. Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Exp Clin Cardiol  2006; 11(3): 217-25.
[PMID: 18651034] 
[64] 
Shigematsu S, Ishida S, Hara M, et al. Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. Free Radic Biol Med  2003; 34(7): 810-7.
[http://dx.doi.org/10.1016/S0891-5849(02)01430-2] [PMID: 12654468] 
[65] 
Chun-Fu W, Jing-Yu Y, Fang W, Xiao-Xiao W. Resveratrol: Botanical origin, pharmacological activity and applications. Chin J Nat Med  2013; 11(1): 1-15.
[66] 
Bellaver B, Souza DG, Souza DO, Quincozes-Santos A. Resveratrol increases antioxidant defenses and decreases proinflammatory cytokines in hippocampal astrocyte cultures from newborn, adult and aged Wistar rats. Toxicol In Vitro  2014; 28(4): 479-84.
[http://dx.doi.org/10.1016/j.tiv.2014.01.006] [PMID: 24462605] 
[67] 
Shin JA, Lee H, Lim Y-K, Koh Y, Choi JH, Park E-M. Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke. J Neuroimmunol  2010; 227(1-2): 93-100.
[http://dx.doi.org/10.1016/j.jneuroim.2010.06.017] [PMID: 20655115] 
[68] 
Amri A, Chaumeil JC, Sfar S, Charrueau C. Administration of resveratrol: What formulation solutions to bioavailability limitations? J Control Release  2012; 158(2): 182-93.
[http://dx.doi.org/10.1016/j.jconrel.2011.09.083] [PMID: 21978644] 
[69] 
Davidov-Pardo G, McClements DJ. Resveratrol encapsulation: designing delivery systems to overcome solubility, stability and bioavailability issues. Trends Food Sci Technol  2014; 38(2): 88-103.
[http://dx.doi.org/10.1016/j.tifs.2014.05.003] 
[70] 
Sandhir R, Yadav A, Sunkaria A, Singhal N. Nano-antioxidants: An emerging strategy for intervention against neurodegenerative conditions. Neurochem Int  2015; 89: 209-26.
[http://dx.doi.org/10.1016/j.neuint.2015.08.011] [PMID: 26315960] 
[71] 
Neves AR, Queiroz JF, Reis S. Brain-targeted delivery of resveratrol using solid lipid nanoparticles functionalized with apolipoprotein E. J Nanobiotechnology  2016; 14(1): 27.
[http://dx.doi.org/10.1186/s12951-016-0177-x] [PMID: 27061902] 
[72] 
Blasi P, Giovagnoli S, Schoubben A, Ricci M, Rossi C. Solid lipid nanoparticles for targeted brain drug delivery. Adv Drug Deliv Rev  2007; 59(6): 454-77.
[http://dx.doi.org/10.1016/j.addr.2007.04.011] [PMID: 17570559] 
[73] 
Jose S, Anju SS, Cinu TA, Aleykutty NA, Thomas S, Souto EB. In vivo pharmacokinetics and biodistribution of resveratrol-loaded solid lipid nanoparticles for brain delivery. Int J Pharm  2014; 474(1-2): 6-13.
[http://dx.doi.org/10.1016/j.ijpharm.2014.08.003] [PMID: 25102112] 
[74] 
Alfieri A, Srivastava S, Siow RC, Modo M, Fraser PA, Mann GE. Targeting the Nrf2-Keap1 antioxidant defence pathway for neurovascular protection in stroke. J Physiol  2011; 589(17): 4125-36.
[http://dx.doi.org/10.1113/jphysiol.2011.210294] [PMID: 21646410] 
[75] 
Cicero AF, Vitale G, Savino G, Arletti R. Panax notoginseng (Burk.) effects on fibrinogen and lipid plasma level in rats fed on a high-fat diet. Phytother Res  2003; 17(2): 174-8.
[http://dx.doi.org/10.1002/ptr.1262] [PMID: 12601683] 
[76] 
Zhao G-R, Xiang Z-J, Ye T-X, Yuan Y-J, Guo Z-X. Antioxidant activities of Salvia miltiorrhiza and Panax notoginseng. Food Chem  2006; 99(4): 767-74.
[http://dx.doi.org/10.1016/j.foodchem.2005.09.002] 
[77] 
Ng TB. Pharmacological activity of sanchi ginseng (Panax notoginseng). J Pharm Pharmacol  2006; 58(8): 1007-19.
[http://dx.doi.org/10.1211/jpp.58.8.0001] [PMID: 16872547] 
[78] 
Liu J, Wang Y, Qiu L, Yu Y, Wang C. Saponins of Panax notoginseng: chemistry, cellular targets and therapeutic opportunities in cardiovascular diseases. Expert Opin Investig Drugs  2014; 23(4): 523-39.
[http://dx.doi.org/10.1517/13543784.2014.892582] [PMID: 24555869] 
[79] 
Wang T, Guo R, Zhou G, et al. Traditional uses, botany, phytochemistry, pharmacology and toxicology of Panax notoginseng (Burk.) F.H. Chen: A review. J Ethnopharmacol  2016; 188: 234-58.
[http://dx.doi.org/10.1016/j.jep.2016.05.005] [PMID: 27154405] 
[80] 
Duan L, Xiong X, Hu J, Liu Y, Li J, Wang J. Panax notoginseng saponins for treating coronary artery disease: A functional and mechanistic overview. Front Pharmacol  2017; 8: 702.
[http://dx.doi.org/10.3389/fphar.2017.00702] [PMID: 29089889] 
[81] 
Kim D-H. Chemical Diversity of Panax ginseng, Panax quinquifolium, and Panax notoginseng. J Ginseng Res  2012; 36(1): 1-15.
[http://dx.doi.org/10.5142/jgr.2012.36.1.1] [PMID: 23717099] 
[82] 
Lee J, Lee E, Kim D, Lee J, Yoo J, Koh B. Studies on absorption, distribution and metabolism of ginseng in humans after oral administration. J Ethnopharmacol  2009; 122(1): 143-8.
[http://dx.doi.org/10.1016/j.jep.2008.12.012] [PMID: 19146939] 
[83] 
Kim H, Lee JH, Kim JE, et al. Micro-/nano-sized delivery systems of ginsenosides for improved systemic bioavailability. J Ginseng Res  2018; 42(3): 361-9.
[http://dx.doi.org/10.1016/j.jgr.2017.12.003] [PMID: 29983618] 
[84] 
Qiu J, Cai G, Liu X, Ma D. αvβ3 integrin receptor specific peptide modified, salvianolic acid B and panax notoginsenoside loaded nanomedicine for the combination therapy of acute myocardial ischemia. Biomed Pharmacother  2017; 96: 1418-26.
[http://dx.doi.org/10.1016/j.biopha.2017.10.086] [PMID: 29079344] 
[85] 
Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces  2010; 75(1): 1-18.
[http://dx.doi.org/10.1016/j.colsurfb.2009.09.001] [PMID: 19782542] 
[86] 
Sahoo SK, Misra R, Parveen S. Nanoparticles: A boon to drug delivery, therapeutics, diagnostics and imaging. Nanomedicine in Cancer: Pan Stanford  2017; 75(1): 73-124.
[87] 
Bamrungsap S, Zhao Z, Chen T, et al. Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system. Nanomedicine (Lond)  2012; 7(8): 1253-71.
[http://dx.doi.org/10.2217/nnm.12.87] [PMID: 22931450] 
[88] 
Zhang J, Guan P, Wang T, Chang D, Jiang T, Wang S. Freeze-dried liposomes as potential carriers for ocular administration of cytochrome c against selenite cataract formation. J Pharm Pharmacol  2009; 61(9): 1171-8.
[http://dx.doi.org/10.1211/jpp.61.09.0006] [PMID: 19703366] 
[89] 
Cartea ME, Francisco M, Soengas P, Velasco P. Phenolic compounds in Brassica vegetables. Molecules  2010; 16(1): 251-80.
[http://dx.doi.org/10.3390/molecules16010251] [PMID: 21193847] 
[90] 
Albini A, Tosetti F, Li VW, Noonan DM, Li WW. Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol  2012; 9(9): 498-509.
[http://dx.doi.org/10.1038/nrclinonc.2012.120] [PMID: 22850752] 
[91] 
Guardia T, Rotelli AE, Juarez AO, Pelzer LE. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco  2001; 56(9): 683-7.
[http://dx.doi.org/10.1016/S0014-827X(01)01111-9] [PMID: 11680812] 
[92] 
Hassimotto NMA, Genovese MI, Lajolo FM. Antioxidant activity of dietary fruits, vegetables, and commercial frozen fruit pulps. J Agric Food Chem  2005; 53(8): 2928-35.
[http://dx.doi.org/10.1021/jf047894h] [PMID: 15826041] 
[93] 
Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol  2008; 585(2-3): 325-37.
[http://dx.doi.org/10.1016/j.ejphar.2008.03.008] [PMID: 18417116] 
[94] 
Perez-Vizcaino F, Duarte J, Andriantsitohaina R. Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols. Free Radic Res  2006; 40(10): 1054-65.
[http://dx.doi.org/10.1080/10715760600823128] [PMID: 17015250] 
[95] 
Formica JV, Regelson W. Review of the biology of Quercetin and related bioflavonoids. Food Chem Toxicol  1995; 33(12): 1061-80.
[http://dx.doi.org/10.1016/0278-6915(95)00077-1] [PMID: 8847003] 
[96] 
Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet  1993; 342(8878): 1007-11.
[http://dx.doi.org/10.1016/0140-6736(93)92876-U] [PMID: 8105262] 
[97] 
Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev  2001; 53(2): 283-318.
[PMID: 11356986] 
[98] 
Olivier J-C. Drug transport to brain with targeted nanoparticles. NeuroRx  2005; 2(1): 108-19.
[http://dx.doi.org/10.1602/neurorx.2.1.108] [PMID: 15717062] 
[99] 
Zhao LX, Liu AC, Yu SW, et al. The permeability of puerarin loaded poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 on the blood-brain barrier and its protective effect against cerebral ischemia/reperfusion injury. Biol Pharm Bull  2013; 36(8): 1263-70.
[http://dx.doi.org/10.1248/bpb.b12-00769] [PMID: 23902970] 
[100] 
Zhou F, Wang L, Liu P, et al. Puerarin protects brain tissue against cerebral ischemia/reperfusion injury by inhibiting the inflammatory response. Neural Regen Res  2014; 9(23): 2074-80.
[http://dx.doi.org/10.4103/1673-5374.147934] [PMID: 25657724] 
[101] 
Tian F, Xu L-H, Zhao W, Tian L-J, Ji X-L. The optimal therapeutic timing and mechanism of puerarin treatment of spinal cord ischemia-reperfusion injury in rats. J Ethnopharmacol  2011; 134(3): 892-6.
[http://dx.doi.org/10.1016/j.jep.2011.01.055] [PMID: 21296138] 
[102] 
Liu G, Liu Z, Yuan S. Recent advances in methods of puerarin biotransformation. Mini Rev Med Chem  2016; 16(17): 1392-402.
[http://dx.doi.org/10.2174/1389557516666160505114456] [PMID: 27145856] 
[103] 
Lockman PR, Mumper RJ, Khan MA, Allen DD. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm  2002; 28(1): 1-13.
[http://dx.doi.org/10.1081/DDC-120001481] [PMID: 11858519] 
[104] 
Agüeros M, Ruiz-Gatón L, Vauthier C, et al. Combined hydroxypropyl-β-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel. Eur J Pharm Sci  2009; 38(4): 405-13.
[http://dx.doi.org/10.1016/j.ejps.2009.09.010] [PMID: 19765652] 
[105] 
Loftsson T, Duchêne D. Cyclodextrins and their pharmaceutical applications. Int J Pharm  2007; 329(1-2): 1-11.
[http://dx.doi.org/10.1016/j.ijpharm.2006.10.044] [PMID: 17137734] 
[106] 
Vecsernyés M, Fenyvesi F, Bácskay I, Deli MA, Szente L, Fenyvesi É. Cyclodextrins, blood-brain barrier, and treatment of neurological diseases. Arch Med Res  2014; 45(8): 711-29.
[http://dx.doi.org/10.1016/j.arcmed.2014.11.020] [PMID: 25482528] 
[107] 
Gil ES, Li J, Xiao H, Lowe TL. Quaternary ammonium β-cyclodextrin nanoparticles for enhancing doxorubicin permeability across the in vitro blood-brain barrier. Biomacromolecules  2009; 10(3): 505-16.
[http://dx.doi.org/10.1021/bm801026k] [PMID: 19216528] 
[108] 
Tao HQ, Meng Q, Li MH, et al. HP-β-CD-PLGA nanoparticles improve the penetration and bioavailability of puerarin and enhance the therapeutic effects on brain ischemia-reperfusion injury in rats. Naunyn Schmiedebergs Arch Pharmacol  2013; 386(1): 61-70.
[http://dx.doi.org/10.1007/s00210-012-0804-5] [PMID: 23192284] 
[109] 
Pardeshi CV, Belgamwar VS. Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting. Expert Opin Drug Deliv  2013; 10(7): 957-72.
[http://dx.doi.org/10.1517/17425247.2013.790887] [PMID: 23586809] 
[110] 
Lu C-T, Zhao Y-Z, Wong HL, Cai J, Peng L, Tian X-Q. Current approaches to enhance CNS delivery of drugs across the brain barriers. Int J Nanomedicine  2014; 9: 2241-57.
[http://dx.doi.org/10.2147/IJN.S61288] [PMID: 24872687] 
[111] 
Dhuria SV, Hanson LR, Frey WH II. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci  2010; 99(4): 1654-73.
[http://dx.doi.org/10.1002/jps.21924] [PMID: 19877171] 
[112] 
Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci  2000; 11(1): 1-18.
[http://dx.doi.org/10.1016/S0928-0987(00)00087-7] [PMID: 10913748] 
[113] 
Arora P, Sharma S, Garg S. Permeability issues in nasal drug delivery. Drug Discov Today  2002; 7(18): 967-75.
[http://dx.doi.org/10.1016/S1359-6446(02)02452-2] [PMID: 12546871] 
[114] 
Johnson PH, Quay SC. Advances in nasal drug delivery through tight junction technology. Expert Opin Drug Deliv  2005; 2(2): 281-98.
[http://dx.doi.org/10.1517/17425247.2.2.281] [PMID: 16296754] 
[115] 
Illum L. Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems? J Pharm Sci  2007; 96(3): 473-83.
[http://dx.doi.org/10.1002/jps.20718] [PMID: 17117404] 
[116] 
Illum L. Nasal drug delivery--possibilities, problems and solutions. J Control Release  2003; 87(1-3): 187-98.
[http://dx.doi.org/10.1016/S0168-3659(02)00363-2] [PMID: 12618035] 
[117] 
Enogieru AB, Haylett W, Hiss DC, Bardien S, Ekpo OE. Rutin as a potent antioxidant: Implications for neurodegenerative disorders. Oxid Med Cell Longev  2018; 2018 6241017
[http://dx.doi.org/10.1155/2018/6241017] 
[118] 
Al-Dhabi NA, Arasu MV, Park CH, Park SU. An up-to-date review of rutin and its biological and pharmacological activities. EXCLI J  2015; 14: 59-63.
[PMID: 26535031] 
[119] 
Choi J-H, Kim D-W, Park S-E, et al. Anti-thrombotic effect of rutin isolated from Dendropanax morbifera Leveille. J Biosci Bioeng  2015; 120(2): 181-6.
[http://dx.doi.org/10.1016/j.jbiosc.2014.12.012] [PMID: 25777266] 
[120] 
Park JH, Saravanakumar G, Kim K, Kwon IC. Targeted delivery of low molecular drugs using chitosan and its derivatives. Adv Drug Deliv Rev  2010; 62(1): 28-41.
[http://dx.doi.org/10.1016/j.addr.2009.10.003] [PMID: 19874862] 
[121] 
Ding Y, Qiao Y, Wang M, et al. Enhanced neuroprotection of acetyl-11-keto-β-boswellic acid (AKBA)-loaded O-carboxymethyl chitosan nanoparticles through antioxidant and anti-inflammatory pathways. Mol Neurobiol  2016; 53(6): 3842-53.
[http://dx.doi.org/10.1007/s12035-015-9333-9] [PMID: 26162321] 
[122] 
Sarvaiya J, Agrawal YK. Chitosan as a suitable nanocarrier material for anti-Alzheimer drug delivery. Int J Biol Macromol  2015; 72: 454-65.
[http://dx.doi.org/10.1016/j.ijbiomac.2014.08.052] [PMID: 25199867] 
[123] 
Ameeduzzafar AJ, Ali J, Bhatnagar A, Kumar N, Ali A. Chitosan nanoparticles amplify the ocular hypotensive effect of cateolol in rabbits. Int J Biol Macromol  2014; 65: 479-91.
[http://dx.doi.org/10.1016/j.ijbiomac.2014.02.002] [PMID: 24530326] 
[124] 
Yu G, Liu L, Zhang P, Li Y. Protective effect of Curcumin on chronic cerebral ischemia by altering expression of α-synuclein in 2VO model. Mol Neurodegener  2012; 7: S33.
[http://dx.doi.org/10.1186/1750-1326-7-S1-S33] 
[125] 
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm  2007; 4(6): 807-18.
[http://dx.doi.org/10.1021/mp700113r] [PMID: 17999464] 
Cite As
Current Clinical Pharmacology

Oral and Intra-nasal Administration of Nanoparticles in the Cerebral Ischemia Treatment in Animal Experiments: Considering its Advantages and Disadvantages

Abstract

Graphical Abstract
