Nanotechnology Based Delivery Systems of Drugs Currently Used to Treat Alzheimer’s Disease

Author(s): Niloufar Choubdar*, Sara Avizheh

Journal Name: Nanoscience & Nanotechnology-Asia

Volume 10 , Issue 3 , 2020

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Graphical Abstract:


Alzheimer’s Disease (AD) is one of the most common forms of dementia affecting over 46 million people, according to AD International. Over the past few decades, there has been considerable interest in developing nanomedicines. Using nanocarriers, the therapeutic compound could be delivered to the site of action where it gets accumulated. This accumulation, therefore, reduces the required doses for therapy. Alternatively, using nanocarriers decreases the side effects. Nanotechnology has had a great contribution in developing Drug Delivery Systems (DDS). These DDS could function as reservoirs for sustained drug release or control the pharmacokinetics and biodistribution of the drugs. In the current review, we have collected 38 original research articles using nanotechnology as DDS for the clinically used cholinesterase inhibitor drugs donepezil (DPZ), Rivastigmine (Riv), and galantamine (Gal) used for AD treatment from 2002 to 2017 from Scopus and PubMed databases. Regarding DDS used for DPZ, most of the research in recent years dealt with polymeric nanoparticles (NPs) including Poly-D, L-Lactide-Co-Glycolide (PLGA), and chitosans (CHs), then Liposomes (LPs), nanogels, and natural products, respectively. In terms of Riv most of the research performed was focused on polymeric NPs including PLGA, polylactic acid (PLA), Poly-Ε-Caprolactone (PCL), poly-alkyl-cyanoacrylates, CH, gelatin and then LPs. The highest application of NPs in regard to Gal was related to modified LPs and polymeric NPs. Polymeric NPs demonstrate safety, higher stability in biological fluids and against enzymatic metabolism, biocompatibility, bioavailability, and improved encapsulation efficacy. LPs, another major delivery system used, demonstrate biocompatibility, ease of surface modification, and amphiphilic nature.

Keywords: Alzheimer's disease, nanomedicines, donepezil, rivastigmine, galantamine, drug delivery systems, nanotechnology, nanocarrier.

Alzheimer’s Association. 2017 Alzheimer’s disease facts and figures. Alzheimers Dement., 2017, 13(4), 325-373.
Francis, P.T.; Palmer, A.M.; Snape, M.; Wilcock, G.K. The cholinergic hypothesis of Alzheimer’s disease: A review of progress. J. Neurol. Neuro. Surg. Psychiatry, 1999, 66(2), 137-147.
Wilkinson, D.G.; Francis, P.T.; Schwam, E.; Payne-Parrish, J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease. Drugs Aging, 2004, 21(7), 453-478.
Huang, Y.; Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell, 2012, 148(6), 1204-1222.
Doggui, S.; Dao, L.; Ramassamy, C. Potential of drug-loaded nanoparticles for Alzheimer’s disease: Diagnosis, prevention and treatment. Ther. Deliv., 2012, 3(9), 1026-1027.
Campos-Bedolla, P.; Walter, F.R.; Veszelka, S.; Deli, M.A. Role of the blood–brain barrier in the nutrition of the central nervous system. Arch. Med. Res., 2014, 45(8), 610-638.
Fazil, M. Shadab, Baboota, S.; Sahni, J.K.; Ali, J. Nanotherapeutics for Alzheimer’s disease (AD): Past, present and future. J. Drug Target., 2012, 20(2), 97-113.
Wilkinson, D.G.; Francis, P.T.; Schwam, E.; Payne-Parrish, J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease. Drugs Aging, 2014, 21(7), 453-478.
Glaser, T.; Han, I.; Wu, L.; Zeng, X. Targeted nanotechnology in glioblastoma multiforme. Front. Pharmacol., 2017, 8(166), 1-14.
Faraji, A.H.; Wipf, P. Nanoparticles in cellular drug delivery. Bioorganic. Med. Chem., 2009, 17(8), 2950-2962.
Alam, M.I.; Beg, S.; Samad, A.; Baboota, S.; Kohli, K.; Ali, J.; Ahuja, A.; Akbar, M. Strategy for effective brain drug delivery. Eur. J. Pharm. Sci., 2010, 40(5), 385-403.
Jann, M.W. Rivastigmine, a new generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacother., 2000, 20(1), 1-12.
Birks, J.S.; Chong, L.Y.; Grimley Evans, J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst. Rev., 2009, 4, 1.
Wen, M.M.; El-Salamouni, N.S.; El-Refaie, W.M.; Hazzah, H.A.; Ali, M.M.; Tosi, G.; Farid, R.M.; Blanco-Prieto, M.J.; Billa, N.; Hanafy, A.S. Nanotechnology-based drug delivery systems for Alzheimer’s disease management: Technical, industrial, and clinical challenges. J. Control. Release, 2016, 245, 95-107.
Lilienfeld, S. Galantamine - a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer’s disease. CNS Drug Rev., 2002, 8(2), 159-176.
Defilippi, J.L.; Crismon, M.L. Drug interactions with cholinesterase inhibitors. Drugs Aging, 2003, 20(6), 437-444.
Jann, M.W.; Shirley, K.L.; Small, G.W. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin. Pharmacokinet., 2002, 41(10), 719-739.
Loy, C. Schneider, L. Galantamine for Alzheimer’s disease and mild cognitive impairment. Cochrane Database Syst. Rev., 2002, 3 CD001747
Seltzer, B. Donepezil: an update. Expert Opin. Pharmacother., 2007, 8(7), 1011-1023.
Safari, J.; Zarnegar, Z. Advanced drug delivery systems: Nanotechnology of health design A review. J. Saudi Chem. Soc., 2014, 18(2), 85-99.
Mohammad, D.; Chan, P.; Bradley, J.; Lanctôt, K.; Herrmann, N. Acetylcholinesterase inhibitors for treating dementia symptoms-a safety evaluation. Expert Opin. Drug Saf., 2017, 16(9), 1009-1019.
Zhang, H.; Zhai, Y.; Wang, J.; Zhai, G. New progress and prospects: The application of nanogel in drug delivery. Mater. Sci. Eng. C, 2016, 60, 560-568.
Fanun, M. Microemulsions as delivery systems. ‎. Curr. Opin. Colloid Interface Sci., 2012, 17(5), 306-313.
Callender, S.P.; Mathews, J.A.; Kobernyk, K.; Wettig, S.D. Microemulsion utility in pharmaceuticals: Implications for multi-drug delivery. Int. J. Pharm., 2017, 526, 425-422.
de Souza, L.G.; Rennó, M.N.; Figueroa-Villar, J.D. Coumarins as cholinesterase inhibitors: A review. Chem. Biol. Interact., 2016, 254, 11-23.
Sahoo, S.K.; Labhasetwar, V. Nanotech approaches to drug delivery and imaging. Drug Discov. Today, 2003, 8(24), 1112-1120.
Wilczewska, A.Z.; Niemirowicz, K.; Markiewicz, K.H.; Car, H. Nanoparticles as drug delivery systems. Pharmacol. Rep., 2012, 64(5), 1020-1037.
Suri, S.S.; Fenniri, H.; Singh, B. Nanotechnology-based drug delivery systems. J. Occup. Med. Toxicol., 2007, 2(1), 16.
Allen, T.M.; Cullis, P.R. Drug delivery systems: Entering the mainstream. Science, 2004, 303(5665), 1818-1822.
Bhushan, B. Introduction to nanotechnology. In: Springer handbook of nanotechnology; Berlin: Heidelberg; Springer-Verlag, 2010; pp. 1-13.
Springer, New York, NY, 2008, vol. 9, . Springer, New York, NY, 2008, vol. 9, .
Sinha, R.; Kim, G.J.; Nie, S.; Shin, D.M. Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery. Mol. Cancer Ther., 2006, 5(8), 1909-1917.
Farokhzad, O.C.; Langer, R. Impact of nanotechnology on drug delivery. ACS Nano, 2009, 3(1), 16-20.
Han, M.; He, C.X.; Fang, Q.L.; Yang, X.C.; Diao, Y.Y.; Xu, D.H.; He, Q.J.; Hu, Y.Z.; Liang, W.Q.; Yang, B. Gao, J.Q. A novel camptothecin derivative incorporated in nano-carrier induced distinguished improvement in solubility, stability and anti-tumor activity both in vitro and in vivo. Pharm. Res., 2009, 26(4), 926-935.
Wu, J.; Chu, C.C. Water insoluble cationic poly (ester amide) s: synthesis, characterization and applications. J. Mater. Chem. B., 2013, 1(3), 353-360.
Huang, X.; Brazel, C.S. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J. Control. Release, 2001, 73(2-3), 121-136.
Kataoka, K.; Harada, A.; Nagasaki, Y. Block copolymer micelles for drug delivery: Design, characterization and biological significance. Adv. Drug Deliv. Rev., 2012, 64, 37-48.
Torchilin, V.P. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov., 2005, 4(2), 145.
Panyam, J.; Labhasetwar, V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Deliv. Rev., 2003, 55(3), 329-347.
Brigger, I.; Dubernet, C.; Couvreur, P. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev., 2012, 64, 24-36.
Desai, M.P.; Labhasetwar, V.; Amidon, G.L.; Levy, R.J. Gastrointestinal uptake of biodegradable microparticles: Effect of particle size. ‎. Pharm. Res., 1996, 13(12), 1838-1845.
Desai, M.P.; Labhasetwar, V.; Walter, E.; Levy, R.J.; Amidon, G.L. The mechanism of uptake of biodegradable microparticles in Caco-2 cells is size dependent. . Pharm. Res., 1997, 14(11), 1568-1573.
Panyam, J.; Sahoo, S.K.; Prabha, S.; Bargar, T.; Labhasetwar, V. Fluorescence and electron microscopy probes for cellular and tissue uptake of poly (D, L-lactide-co-glycolide) nanoparticles. Int. J. Pharm., 2003, 262(1-2), 1-11.
Thomas, M.; Klibanov, A.M. Conjugation to gold nanoparticles enhances polyethylenimine’s transfer of plasmid DNA into mammalian cells. Proc. Natl. Acad. Sci., 2003, 100(16), 9138-9143.
Lanza, G.M.; Yu, X.; Winter, P.M.; Abendschein, D.R.; Karukstis, K.K.; Scott, M.J.; Chinen, L.K.; Fuhrhop, R.W.; Scherrer, D.E.; Wickline, S.A. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: Implications for rational therapy of restenosis. Circulation, 2002, 106(22), 2842-2847.
Lamprecht, A.; Ubrich, N.; Yamamoto, H.; Schäfer, U.; Takeuchi, H.; Maincent, P.; Kawashima, Y.; Lehr, C.M. Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease. J. Pharmacol. Exp. Ther., 2001, 299(2), 775-781.
Scherer, F.; Anton, M.; Schillinger, U.; Henke, J.; Bergemann, C.; Krüger, A.; Gänsbacher, B.; Plank, C. Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo. Gene Ther., 2002, 9(2), 102.
Nevozhay, D.; Kańska, U.; Budzyńska, R.; Boratyński, J. Current status of research on conjugates and related drug delivery systems in the treatment of cancer and other diseases. Posteb. Hig. Med. Dosw., 2007, 61, 350-360.
Monsky, W.L.; Fukumura, D.; Gohongi, T.; Ancukiewcz, M.; Weich, H.A.; Torchilin, V.P.; Yuan, F.; Jain, R.K. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res., 1999, 59(16), 4129-4135.
Maeda, H. The enhanced permeability and retention (EPR) effect in tumor vasculature: The key role of tumor-selective macromolecular drug targeting. Adv. Enzym. Regul., 2001, 41, 189-207.
Sahoo, S.K.; Sawa, T.; Fang, J.; Tanaka, S.; Miyamoto, Y.; Akaike, T.; Maeda, H. Pegylated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with tumor-targeting capacity. Bioconjug. Chem., 2002, 13(5), 1031-1038.
Ai, J.; Biazar, E.; Jafarpour, M.; Montazeri, M.; Majdi, A.; Aminifard, S.; Zafari, M.; Akbari, H.R.; Rad, H.G. Nanotoxicology and nanoparticle safety in biomedical designs. Int. J. Nanomedicine, 2011, 6, 1117.
Cole, A.J.; Yang, V.C.; David, A.E. Cancer theranostics: The rise of targeted magnetic nanoparticles. Trends Biotechnol., 2011, 29(7), 323-332.
Groneberg, D.A.; Rabe, K.F.; Fischer, A. Novel concepts of neuropeptide-based drug therapy: Vasoactive intestinal polypeptide and its receptors. Eur. J. Pharmacol., 2006, 533(1-3), 182-194.
Grady, W.M. Epigenetic events in the colorectum and in colon cancer. 2005, 33(Pt 4), 684-688.
Muggia, F.; Hamilton, A. Phase III data on Caelyx® in ovarian cancer. Eur. J. Cancer, 2001, 37, 15-18.
Northfelt, D.W.; Martin, F.J.; Working, P.; Volberding, P.A.; Russell, J.; Newman, M.; Amantea, M.A.; Kaplan, L.D. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: Pharmacokinetics, tumor localization, and safety in patients with AIDS-Related Kaposi’s sarcoma. J. Clin. Pharmacol., 1996, 36(1), 55-63.
Olsen, E.; Duvic, M.; Frankel, A.; Kim, Y.; Martin, A.; Vonderheid, E.; Jegasothy, B.; Wood, G.; Gordon, M.; Heald, P.; Oseroff, A. Pivotal phase III trial of two dose levels of denileukindiftitox for the treatment of cutaneous T-cell lymphoma. J. Clin. Oncol., 2001, 19(2), 376-388.
Rosen, O.; Müller, H.J.; Gökbuget, N.; Langer, W.; Peter, N.; Schwartz, S.; Hähling, D.; Hartmann, F.; Ittel, T.H.; Mück, R.; Rothmann, F. Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: A pilot study. Br. J. Haematol., 2003, 123(5), 836-841.
lue, P.; Rouzier-Panis, R.; Raffanel, C.; Sabo, R.; Gupta, S.K.; Salfi, M.; Jacobs, S.; Clement, R.P. A dose-ranging study of pegylated interferon Alfa-2b and Ribavirin in chronic hepatitis C. Hepatology, 2000, 32(3), 647-653.
Panyam, J.; Labhasetwar, V. Sustained cytoplasmic delivery of drugs with intracellular receptors using biodegradable nanoparticles. Mol. Pharm., 2004, 1(1), 77-84.
Prabha, S.; Labhasetwar, V. Nanoparticle-mediated wild-type p53 gene delivery results in sustained antiproliferative activity in breast cancer cells. Mol. Pharm., 2004, 1(3), 211-219.
Prabha, S.; Labhasetwar, V. Critical determinants in PLGA/PLA nanoparticle-mediated gene expression. Pharm. Res., 2004, 21(2), 354-364.
Murakami, H.; Kobayashi, M.; Takeuchi, H.; Kawashima, Y. Preparation of poly (DL-lactide-co-glycolide) nanoparticles by modified spontaneous emulsification solvent diffusion method. ‎. Int. J. Pharm., 1999, 187(2), 143-152.
Alyautdin, R.N.; Petrov, V.E.; Langer, K.; Berthold, A.; Kharkevich, D.A.; Kreuter, J. Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm. Res., 1997, 14(3), 325-328.
Alyaudtin, R.N.; Reichel, A.; Löbenberg, R.; Ramge, P.; Kreuter, J.; Begley, D.J. Interaction of poly (butylcyanoacrylate) nanoparticles with the blood-brain barrier in vivo and in vitro. J. Drug Target., 2001, 9(3), 209-221.
Kreuter, J.; Ramge, P.; Petrov, V.; Hamm, S.; Gelperina, S.E.; Engelhardt, B.; Alyautdin, R.; Von Briesen, H.; Begley, D.J. Direct evidence that polysorbate-80-coated poly (butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles. Pharm. Res., 2003, 20(3), 409-416.
Calvo, P.; Gouritin, B.; Chacun, H.; Desmaële, D.; D’angelo, J.; Noel, J.P.; Georgin, D.; Fattal, E.; Andreux, J.P.; Couvreur, P. Long-circulating PEGylatedpolycyanoacrylate nanoparticles as new drug carrier for brain delivery. Pharm. Res., 2001, 18(8), 1157-1166.
Calvo, P.; Gouritin, B.; Villarroya, H.; Eclancher, F.; Giannavola, C.; Klein, C.; Andreux, J.P.; Couvreur, P. Quantification and localization of PEGylatedpolycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat. Eur. J. Neurosci., 2002, 15(8), 1317-1326.
Papahadjopoulos, D. Liposomes and their uses in biology and medicine. Ann. NY. Acad. Sci., 1978, 308, 1.
Ryman, B. Liposomes and their uses in biology and medicine. Ann. N. Y. Acad. Sci., 1978, 308, 300-301.
Lasic, D.D.; Frederik, P.M.; Stuart, M.C.A.; Barenholz, Y.; McIntosh, T.J. Gelation of liposome interior A novel method for drug encapsulation. FEBS Lett., 1992, 312(2-3), 255-258.
Bangham, A.D. Surrogate cells or Trojan horses. The discovery of liposomes. BioEssays, 1995, 17(12), 1081-1088.
Müller, R.H.; Mehnert, W.; Lucks, J.S. Solid lipid nanoparticles (SLN): an alternative colloidal carrier system for controlled drug delivery. Eur. J. Pharm. Bio. pharm., 1995, 41(1), 62-69.
Schwarz, C.; Mehnert, W.; Lucks, J.S.; Müller, R.H. Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art. Eur. J. Pharm. Biopharm., 2000, 50(1), 161-177.
Siekmann, B.; Westesen, K. Submicron-sized parenteral carrier systems based on solid lipids. Pharm. Pharmacol. Lett, 1992, 1(3), 123-126.
Souto, E.B.; Wissing, S.A.; Barbosa, C.M.; Müller, R.H. Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery. . Int. J. Pharm., 2004, 278(1), 71-77.
Gasco, M.R. Method for producing solid lipid nanoesphereshave a narrow size distribution. U.S. Patent 5,250,236, Oct 5. 1993.
Müller, R.H.; Radtke, M.; Wissing, S.A. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug Deliv. Rev., 2002, 54, 131-155.
Attard, G.S.; Bartlett, P.N.; Coleman, N.R.; Elliott, J.M.; Owen, J.R.; Wang, J.H. Mesoporous platinum films from lyotropic liquid crystalline phases. Science, 1997, 278(5339), 838-840.
Armatas, G.S.; Kanatzidis, M.G. Mesostructured germanium with cubic pore symmetry. Nature, 2006, 441(7097), 1122-1125.
Sun, D.; Riley, A.E.; Cadby, A.J.; Richman, E.K.; Korlann, S.D.; Tolbert, S.H. Hexagonal nanoporous germanium through surfactant-driven self-assembly of Zintl clusters. Nature, 2006, 441(7097), 1126.
Huo, Q.; Margolese, D.I.; Ciesla, U.; Feng, P.; Gier, T.E.; Sieger, P.; Leon, R.; Petroff, P.M.; Schüth, F.; Stucky, G.D. Generalized synthesis of periodic surfactant/inorganic composite materials. Nature, 1994, 368(6469), 317-321.
Tian, Z.R.; Tong, W.; Wang, J.Y.; Duan, N.G.; Krishnan, V.V.; Suib, S.L. Manganese oxide mesoporous structures: Mixed-valent semiconducting catalysts. Science, 1997, 276(5314), 926-930.
Sun, T.; Ying, J.Y. Synthesis of microporous transition-metal-oxide molecular sieves by a supramolecular templating mechanism. Nature, 1997, 389(6652), 704.
Yang, P.; Zhao, D.; Margolese, D.I.; Chmelka, B.F.; Stucky, G.D. Generalized syntheses of large-pore mesoporous metal oxides with semicrystalline frameworks. Nature, 1998, 396(6707), 152.
Tian, B.; Liu, X.; Tu, B.; Yu, C.; Fan, J.; Wang, L.; Xie, S.; Stucky, G.D.; Zhao, D. Self-adjusted synthesis of ordered stable mesoporous minerals by acid-base pairs. Nat. Mater., 2003, 2(3), 159.
Grosso, D.; Boissière, C.; Smarsly, B.; Brezesinski, T.; Pinna, N.; Albouy, P.A.; Amenitsch, H.; Antonietti, M.; Sanchez, C. Periodically ordered nanoscale islands and mesoporous films composed of nanocrystallinemultimetallic oxides. Nat. Mater., 2004, 3(11), 787.
Corma, A.; Atienzar, P.; Garcia, H.; Chane-Ching, J.Y. Hierarchically mesostructured doped CeO2 with potential for solar-cell use. Nat. Mater., 2004, 3(6), 394.
Zou, X.; Conradsson, T.; Klingstedt, M.; Dadachov, M.S.; O’keeffe, M. A mesoporous germanium oxide with crystalline pore walls and its chiral derivative. Nature, 2005, 437(7059), 716.
Braun, P.V.; Osenar, P.; Stupp, S.I. Semiconducting superlattices templated by molecular assemblies. Nature, 1996, 380(6572), 325.
MacLachlan, M.J.; Coombs, N.; Ozin, G.A. Non-aqueous supramolecular assembly of mesostructured metal germanium sulphides from (Ge4S10) 4-clusters. Nature, 1999, 397(6721), 681.
Trikalitis, P.N.; Rangan, K.K.; Bakas, T.; Kanatzidis, M.G. Varied pore organization in mesostructured semiconductors based on the [SnSe4] 4-anion. Nature, 2001, 410(6829), 671.
Xu, Z.P.; Zeng, Q.H.; Lu, G.Q.; Yu, A.B. Inorganic nanoparticles as carriers for efficient cellular delivery. Chem. Eng. Sci., 2006, 61(3), 1027-1040.
Beck, J.S.; Vartuli, J.C.; Roth, W.J.; Leonowicz, M.E.; Kresge, C.T.; Schmitt, K.D.; Chu, C.T.W.; Olson, D.H.; Sheppard, E.W.; McCullen, S.B.; Higgins, J.B. A new family of mesoporous molecular sieves prepared with liquid crystal templates. . J. Am. Chem. Soc., 1992, 114(27), 10834-10843.
Hamidi, M.; Azadi, A.; Rafiei, P. Hydrogel nanoparticles in drug delivery. Adv. Drug Deliv. Rev., 2008, 60(15), 1638-1649.
Oh, J.K.; Siegwart, D.J.; Matyjaszewski, K. Synthesis and biodegradation of nanogels as delivery carriers for carbohydrate drugs. Biomacromolecules, 2007, 8(11), 3326-3331.
Bae, Y.; Jang, W.D.; Nishiyama, N.; Fukushima, S.; Kataoka, K. Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol. Bio. Syst., 2005, 1(3), 242-250.
Rosen, M.J.; Kunjappu, J.T. surfactants and interfacial phenomena. In: ; chapter 8, emulsification by surfactants, 4th ed.. John wiley and sons: New Jersey, 2012; p. 336.
Mc Clements, D.J. Nanoemulsions versus microemulsions: Terminology, differences, and similarities. Soft Matter, 2012, 8(6), 1719-1729.
Fanun, M. Microemulsions properties and applications; Taylor and Francis: New York, 2009.
Fanun, M. Colloids in drug delivery; New York: Taylor and Francis, 2010.
Botterhuis, N.E.; Sun, Q.; Magusin, P.C.; Van Santen, R.A.; Sommerdijk, N.A. Hollow silica spheres with an ordered pore structure and their application in controlled release studies. Chem. Eur. J., 2006, 12(5), 1448-1456.
Lai, C.Y.; Trewyn, B.G.; Jeftinija, D.M.; Jeftinija, K.; Xu, S.; Jeftinija, S.; Lin, V.S.Y. A mesoporous silica nanosphere-based carrier system with chemically removable CdS nanoparticle caps for stimuli-responsive controlled release of neurotransmitters and drug molecules. . J. Am. Chem. Soc., 2003, 125(15), 4451-4459.
Lai, C.Y.; Trewyn, B.G.; Jeftinija, D.M.; Jeftinija, K.; Xu, S.; Jeftinija, S.; Lin, V.S.Y. A polyamidoaminedendrimer-capped mesoporous silica nanosphere-based gene transfection reagent. J. Am. Chem. Soc., 2004, 126(41), 13216-13217.
Giri, S.; Trewyn, B.G.; Stellmaker, M.P.; Lin, V.S.Y. Stimuli-responsive controlled-release delivery system based on mesoporous silica nanorods capped with magnetic nanoparticles. Angew. Chem. Int. Ed., 2005, 44(32), 5038-5044.
Martocchia, A.; Falaschi, P. Current strategies of therapy in Alzheimer’s disease. Open Neuropsychopharmacol. J., 2008, 1, 19-23.
Shah, R.S.; Lee, H.G.; Xiongwei, Z.; Perry, G.; Smith, M.A.; Castellani, R.J. Current approaches in the treatment of Alzheimer’s disease. Biomed. Pharmacother., 2008, 62(4), 199-207.
Mehta, M.; Adem, A.; Sabbagh, M. New acetylcholinesterase inhibitors for Alzheimer’s disease. Int. J. Alzheimers Dis., 2012, 2012 728983
Schneider, L.S. Treatment of Alzheimer’s disease with cholinesterase inhibitors. Clin. Ger. Med., 2001, 17(2), 337-358.
Sugimoto, H.; Ogura, H.; Arai, Y.; Iimura, Y.; Yamanishi, Y. Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor. Jpn. J. Pharmacol., 2002, 89(1), 7-20.
Sugimoto, H.; Ogura, H.; Arai, Y.; Iimura, Y.; Yamanishi, Y. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders II: Alzheimer’s disease. CNS Neurol. Disord. Drug Targets, 2011, 10(2), 251-270.
Prvulovic, D.; Schneider, B. Pharmacokinetic and pharmacodynamic evaluation of donepezil for the treatment of Alzheimer’s disease. Expert Opin. Drug Metab. Toxicol., 2014, 10(7), 1039-50.
Rogers, S.L.; Friedhoff, L.T. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses. Br. J. Clin. Pharmacol., 1998, 46(Suppl. 1), 1-6.
Raja Azalea, D.; Mohambed, M.; Joji, S.; Sankar, C. Design and evaluation of chitosan nanoparticles as novel drug carriers for the delivery of donepezil. Iran. J. Pharm. Sci, 2012, 8(3), 155-164.
Bhavna, Md. S.; Ali, M.; Baboota, S.; Sahni, J.K.; Bhatnagar, A.; Ali, J. Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting. Drug Dev. Ind. Pharm., 2014, 40(2), 278-287.
Baysal, I.; Ucar, G.; Gultekinoglu, M.; Ulubayram, K.; Yabanoglu-Ciftci, S. Donepezil loaded PLGA-b-PEG nanoparticles: their ability to induce destabilization of amyloid fibrils and to cross blood brain barrier in vitro. J. Neural Transm., 2017, 124(1), 33-45.
Al Asmari, A.K.; Ullah, Z.; Tariq, M.; Fatani, A. Preparation, characterization, and in vivo evaluation of intranasally administered liposomal formulation of donepezil. Drug Des. Dev. Ther., 2016, 10, 205-215.
Jakki, S.L.; Ramesh, Y.V.; Gowthamarajan, K.; Senthil, V.; Jain, K.; Sood, S.; Pathak, D. Novel anionic polymer as a carrier for CNS delivery of anti-Alzheimer drug. Drug Deliv., 2016, 23(9), 3471-3479.
Kalaiarasi, S.; Arjun, P.; Nandhagopal, S.; Brijitta, J.; Iniyan, A.M.; Vincent, S.G.P.; Kannan, R.R. Development of biocompatible nanogel for sustained drug release by overcoming the blood brain barrier in zebrafish model. J. Appl. Biomed., 2016, 14(2), 157-169.
AnjiReddy, K.; Karpagam, S. Chitosan nanofilm and electrospun nanofiber for quick drug release in the treatment of Alzheimer’s disease: In vitro and in vivo evaluation. Int. J. Biol. Macromol., 2017, 105, 131-142.
Takeuchi, I.; Takeshita, T.; Suzuki, T.; Makino, K. Iontophoretic transdermal delivery using chitosan-coated PLGA nanoparticles for positively charged drugs. Colloids Surf. B., 2017, 160, 520-526.
Spencer, C.M.; Noble, S. Rivastigmine. Drugs Aging, 1998, 13(5), 391-411.
Tanaka, K.; Mizukawa, K.; Ogawa, N.; Mori, A. Post-ischemic administration of the acetylcholinesterase inhibitor ENA-713 prevents delayed neuronal death in the gerbil hippocampus. Neurochem. Res., 1995, 20(6), 663-667.
Chen, Y.; Shohami, E.; Bass, R.; Weinstock, M. Cerebro-protective effects of ENA713, a novel acetylcholinesterase inhibitor, in closed head injury in the rat. Brain Res., 1998, 784(1), 18-24.
Tanaka, K.; Ogawa, N.; Asanuma, M.; Hirata, H.; Kondo, Y.; Nakayama, N.; Mori, A. Effects of the acetylcholinesterase inhibitor ENA-713 on ischemia-induced changes in acetylcholine and aromatic amine levels in the gerbil brain. Arch. Int. Pharmacodyn. Ther., 1992, 323, 85-96.
Polinsky, R.J. Clinical pharmacology of rivastigmine: A new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin. Ther., 1998, 20(4), 634-647.
Anand, R.; Gharabawi, G. Clinical development of Exelon (TM)(ENA-713): The ADENa (R) programme. J. Drug Dev. Clin. Pract., 1996, 8(2), 117-122.
Anand, R.; Gharabawi, G.; Enz, A. Efficacy and safety results of the early phase studies with Exelon (TM)(ENA-713) in Alzheimer’s disease: An overview. J. Drug Dev. Clin. Pract., 1996, 8(2), 109-116.
Enz, A.; Meier, D.; Spiegel, R. Alzheimer Disease: Therapeutic strategies. In: Effects of novel cholinesterase inhibitors based on the mechanism of enzyme inhibition; Boston: Birkhäuser, 1994; pp. 125-130.
Enz, A.; Amstutz, R.; Boddeke, H.; Gmelin, G.; Malanowski, J. Brain selective inhibition of acetylcholinesterase: A novel approach to therapy for Alzheimer’s disease. Prog. Brain Res., 1993, 98, 431-438.
Couvreur, P.; Kante, B.; Roland, M.; Guiot, P.; Bauduin, P.; Speiser, P. Polycyanoacrylatenanocapsules as potential lysosomotropic carriers: Preparation, morphological and sorptive properties. J. Pharm. Pharmacol., 1979, 31(1), 331-332.
Wilson, B.; Samanta, M.K.; Santhi, K.; Kumar, K.P.S.; Paramakrishnan, N.; Suresh, B. Poly (n-butylcyanoacrylate) nanoparticles coated with polysorbate 80 for the targeted delivery of rivastigmine into the brain to treat Alzheimer’s disease. Brain Res., 2008, 1200, 159-168.
Arumugam, K.; Subramanian, G.; Mallayasamy, S.; Averineni, R.; Reddy, M.; Udupa, N. A study of rivastigmine liposomes for delivery into the brain through intranasal route. Acta Pharm., 2008, 58(3), 287-297.
Craparo, E.F.; Pitarresi, G.; Bondì, M.L.; Casaletto, M.P.; Licciardi, M.; Giammona, G. A nanoparticulate drug-delivery system for rivastigmine: Physico-chemical and in vitro biological characterization. Macromol. Biosci., 2008, 8(3), 247-259.
Joshi, S.A.; Chavhan, S.S.; Sawant, K.K. Rivastigmine-loaded PLGA and PBCA nanoparticles: preparation, optimization, characterization, in vitro and pharmacodynamic studies. Eur. J. Pharm. Biopharm., 2010, 76(2), 189-199.
Garberg, P.; Ball, M.; Borg, N.; Cecchelli, R.; Fenart, L.; Hurst, R.D.; Lindmark, T.; Mabondzo, A.; Nilsson, J.E.; Raub, T.J.; Stanimirovic, D. In vitro models for the blood-brain barrier. Toxicol. In Vitro, 2005, 19(3), 299-334.
Wang, Q.; Rager, J.D.; Weinstein, K.; Kardos, P.S.; Dobson, G.L.; Li, J.; Hidalgo, I.J. Evaluation of the MDR-MDCK cell line as a permeability screen for the blood–brain barrier. Int. J. Pharm., 2005, 288(2), 349-359.
Mutlu, N.B.; Değim, Z.; Yılmaz, Ş.; Eşsiz, D.; Nacar, A. New perspective for the treatment of Alzheimer diseases: Liposomal rivastigmine formulations. Drug Dev. Ind. Pharm., 2011, 37(7), 775-789.
preet Kaur, S.; Rao, R.; Hussain, A.; Khatkar, S. Preparation and characterization of rivastigmine loaded chitosan nanoparticles. J. Pharm. Sci. Res, 2011, 3(5), 1227-1232.
Wilson, B.; Samanta, M.K.; Muthu, M.S.; Vinothapooshan, G. Design and evaluation of chitosan nanoparticles as novel drug carrier for the delivery of rivastigmine to treat Alzheimer’s disease. Ther. Deliv., 2011, 2(5), 599-609.
Fazil, M.; Md, S.; Haque, S.; Kumar, M.; Baboota, S. kaur Sahni, J.; Ali, J. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur. J. Pharm. Sci., 2012, 47(1), 6-15.
Ognibene, M.C.; Rocco, F.; Craparo, E.F.; Picone, P.; Ceruti, M.; Giammona, G. Biocompatible micelles based on squalene portions linked to pegylated polyaspartamide as potential colloidal drug carriers. Curr. Nanosci., 2011, 7(5), 747-756.
Scialabba, C.; Rocco, F.; Licciardi, M.; Pitarresi, G.; Ceruti, M.; Giammona, G. Amphiphilicpolyaspartamide copolymer-based micelles for rivastigmine delivery to neuronal cells. Drug Deliv., 2012, 19(6), 307-316.
Ismail, M.F.; ElMeshad, A.N.; Salem, NAH. Potential therapeutic effect of nanobased formulation of rivastigmine on rat model of Alzheimer’s disease. Int. J. Nanomedicine, 2013, 8, 393-406.
Pagar, K.; Vavia, P. Rivastigmine-loaded L-lactide-depsipeptide polymeric nanoparticles: Decisive formulation variable optimization. Sci. Pharm., 2013, 81(3), 865-888.
Pagar, K.P.; Sardar, S.M.; Vavia, P.R. Novel L-Lactide-depsipeptide polymeric carrier for enhanced brain uptake of rivastigmine in treatment of Alzheimer’s disease. J. Biomed. Nanotechnol., 2014, 10(3), 415-426.
Wavikar, P.R.; Vavia, P.R. Rivastigmine-loaded in situ gelling nanostructured lipid carriers for nose to brain delivery. J. Liposome Res., 2015, 25(2), 141-149.
Nonaka, N.; Farr, S.A.; Kageyama, H.; Shioda, S.; Banks, W.A. Delivery of galanin-like peptide to the brain: Targeting with intranasal delivery and cyclodextrins. J. Pharmacol. Exp. Ther., 2008, 325(2), 513-519.
Westin, U.E.; Boström, E.; Gråsjö, J.; Hammarlund-Udenaes, M.; Björk, E. Direct nose-to-brain transfer of morphine after nasal administration to rats. Pharm. Res., 2006, 23(3), 565-572.
Illum, L. Transport of drugs from the nasal cavity to the central nervous system. Eur. J. Pharm. Sci., 2000, 11(1), 1-18.
Kissel, T.; Werner, U. Nasal delivery of peptides: An in vitro cell culture model for the investigation of transport and metabolism in human nasal epithelium. J. Control. Release, 1998, 53(1-3), 195-203.
O’Flynn, P.; Blattman, A.; Ponchel, G.; D, Duchêne. The effect of posture on nasal clearance of bioadhesive starch microspheres. STP. Pharma. Sci., 1995, 5(6), 442-446.
Illum, L. Drug delivery systems for nasal application. STP Pharma, 1987, 3(7), 594-598.
Brime, B.; Ballesteros, M.P.; Frutos, P. Preparation and in vitro characterization of gelatin microspheres containing Levodopa for nasal administration. J. Microencapsul., 2000, 17(6), 777-784.
Türker, S.; Onur, E.; Ózer, Y. Nasal route and drug delivery systems. Pharm. World Sci., 2004, 26(3), 137-142.
Yang, Z.Z.; Zhang, Y.Q.; Wang, Z.Z.; Wu, K.; Lou, J.N.; Qi, X.R. Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration. Int. J. Pharm., 2013, 452(1), 344-354.
Nagpal, K.; Singh, S.K.; Mishra, D.N. Optimization of brain targeted chitosan nanoparticles of Rivastigmine for improved efficacy and safety. Int. J. Biol. Macromol., 2013, 59, 72-83.
Shah, B.M.; Misra, M.; Shishoo, C.J.; Padh, H. Nose to brain microemulsion-based drug delivery system of rivastigmine: Formulation and ex-vivo characterization. Drug Deliv., 2013, 22(7), 918-930.
Shah, B.; Khunt, D.; Bhatt, H.; Misra, M.; Padh, H. Application of quality by design approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles: Effect on formulation and characterization parameters. Eur. J. Pharm. Sci., 2015, 78, 54-66.
Hemmati, K.; Sahraei, R.; Ghaemy, M. Synthesis and characterization of a novel magnetic molecularly imprinted polymer with incorporated graphene oxide for drug delivery. Polymer., 2016, 101, 257-268.
Salatin, S.; Barar, J.; Barzegar-Jalali, M.; Adibkia, K.; Jelvehgari, M. Thermosensitive in situ nanocomposite of rivastigmine hydrogen tartrate as an intranasal delivery system: Development, characterization, ex vivo permeation and cellular studies. ‎. Colloids Surf. B., 2017, 159, 629-638.
Malekpour-Galogahi, F.; Hatamian-Zarmi, A.; Ganji, F.; Ebrahimi-Hosseinzadeh, B.; Nojoki, F.; Sahraeian, R.; Mokhtari-Hosseini, Z.B. Preparation and optimization of rivastigmine-loaded tocopherol succinate-based solid lipid nanoparticles. J. Liposome Res., 2017, 1, 1-10.
Salatin, S.; Barar, J.; Barzegar-Jalali, M.; Adibkia, K.; Kiafar, F.; Jelvehgari, M. Development of a nanoprecipitation method for the entrapment of a very water-soluble drug into Eudragit RL nanoparticles. Res. Pharm. Sci., 2017, 12(1), 1-14.
Karimzadeh, M.; Rashidi, L.; Ganji, F. Mesoporous silica nanoparticles for efficient rivastigmine hydrogen tartrate delivery into SY5Y cells. Drug Dev. Ind. Pharm., 2017, 43(4), 628-636.
Gauri, B. Development and evaluation of an intranasal nanoparticulate formulation for enhanced transport of rivastigmine into the brain, Diss. Curtin. University. 2017.
Proskurnina, N.F.; Yakovleva, A.P. Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid [Russian]. Zh. Obschchei. Khim. (J Gen Chem)., 1952, 22, 1899-1902.
Cronin, J.R. The plant alkaloid galantamine: Approved as a drug: Sold as a supplement. Altern. Complementary. Ther., 2001, 7(6), 380-383.
Harvey, A.L. The pharmacology of galanthamine and its analogues. Pharmacol. Ther., 1995, 68(1), 113-128.
Pacheco, G.; Palacios-Esquivel, R.; Moss, D.E. Cholinesterase inhibitors proposed for treating dementia in Alzheimer’s disease: Selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase. J. Pharmacol. Exp. Ther., 1995, 274(2), 767-770.
Thomsen, T.; Bickel, U.; Fischer, J.P.; Kewitz, H. Stereoselectivity of cholinesterase inhibition by galantamine and tolerance in humans. Eur. J. Clin. Pharm., 1990, 39, 603-605.
Thomsen, T.; Kewitz, H. Selective inhibition of human acetylcholinesterase by galantamine in vitro and in vivo. Life Sci., 1990, 46, 1553-1558.
Thomsen, T.; Zendeh, B.; Fischer, J.P.; Kewitz, H. In vitro effects of various cholinesterase inhibitors on acetyl- and butyryl-cholinesterases of healthy volunteers. Biochemical. Pharmacol., 1991, 41, 139-141.
Thomsen, T.; Kaden, B.; Fischer, J.P.; Bickel, U.; Barz, H.; Gusztony, G.; Cervos-Navarro, J.; Kewitz, H. Inhibition of acetylcholinesterase activity in human brain tissue and erythrocytes by galantamine, physostigmine and tacrine. Eur. J. Clin. Chem. Clin. Biochem., 1991, 29, 487-492.
Johansson, I.M.; Nordberg, A. Pharmacokinetic studies of cholinesterase inhibitors. Acta Neurol. Scand., 1993, 149, 22-25.
Bickel, U.; Thomsen, T.; Weber, W.; Fischer, J.P.; Bachus, R.; Nitz, M.; Kewitz, H. Pharmacokinetics of galantamine in humans and corresponding cholinesterase inhibition. Clin. Pharmacol. Ther., 1991, 50, 420-428.
Janssen Pharmaceutica. Reminyl (galantamine HBr): Prescribing information. Titusville (NJ): Janssen Pharmaceut., 2001.
Li, W.; Zhou, Y.; Zhao, N.; Hao, B.; Wang, X.; Kong, P. Pharmacokinetic behavior and efficiency of acetylcholinesterase inhibition in rat brain after intranasal administration of galanthamine hydrobromide loaded flexible liposomes. Environ. Toxicol. Pharmacol., 2012, 34(2), 272-279.
Suzuki, R.; Takizawa, T.; Negishi, Y.; Hagisawa, K.; Tanaka, K.; Sawamura, K.; Utoguchi, N.; Nishioka, T.; Maruyama, K. Gene delivery by combination of novel liposomal bubbles with perfluoropropane and ultrasound. J. Control. Release, 2007, 117(1), 130-136.
Mufamadi, M.S.; Choonara, Y.E.; Kumar, P.; Modi, G.; Naidoo, D.; van Vuuren, S.; Ndesendo, V.M.; du Toit, L.C.; Iyuke, S.E.; Pillay, V. Ligand-functionalized nanoliposomes for targeted delivery of galantamine. Int. J. Pharm., 2013, 448(1), 267-281.
Fornaguera, C.; Feiner-Gracia, N.; Calderó, G.; García-Celma, M.J.; Solans, C. Galantamine-loaded PLGA nanoparticles, from nanoemulsion templating, as novel advanced drug delivery systems to treat neurodegenerative diseases. Nanoscale, 2015, 7(28), 12076-12084.
Hanafy, A.S.; Farid, R.M.; ElGamal, S.S. 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., 2015, 41(12), 2055-2068.
Raza, K.; Katare, O.P.; Setia, A.; Bhatia, A.; Singh, B. Improved therapeutic performance of dithranol against psoriasis employing systematically optimized nanoemulsomes. J. Microencapsul., 2013, 30(3), 225-236.
Misra, S.; Chopra, K.; Sinha, V.R.; Medhi, B. Galantamine-loaded solid–lipid nanoparticles for enhanced brain delivery: preparation, characterization, in vitro and in vivo evaluations. Drug Deliv., 2016, 23(4), 1434-1443.
Calvo, P.; Remuñan-López, C.; Vila-Jato, J.L.; Alonso, M.J. Chitosan and chitosan/ethylene oxide-propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines. Pharm. Res., 1997, 14, 1431-1436.
Hanafy, A.S.; Farid, R.M.; Helmy, M.W.; ElGamal, S.S. Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: Future potential contribution in Alzheimer’s disease management. Drug Deliv., 2016, 23(8), 3111-3122.
Piccirillo, C.; Pullar, R.C.; Costa, E.; Santos-Silva, A.; Pintado, M.M.E.; Castro, P.M. Hydroxyapatite-based materials of marine origin: A bioactivity and sintering study. Mater. Sci. Eng. C, 2015, 51, 309-315.
Stanić, V.; Dimitrijević, S.; Antić-Stanković, J.; Mitrić, M.; Jokić, B.; Plećaš, I.B.; Raičević, S. Synthesis, characterization and antimicrobial activity of copper and zinc-doped hydroxyapatite nanopowders. Appl. Surf. Sci., 2010, 256(20), 6083-6089.
Wahba, S.M.; Darwish, A.S.; Kamal, S.M. Ceria-containing uncoated and coated hydroxyapatite-based galantamine nanocomposites for formidable treatment of Alzheimer’s disease in ovariectomized albino-rat model. ‎. Mater. Sci. Eng. C, 2016, 65, 151-163.
Gajbhiye, K.R.; Gajbhiye, V.; Siddiqui, I.A.; Pilla, S.; Soni, V. Ascorbic acid tethered polymeric nanoparticles enable efficient brain delivery of galantamine: An in vitro-in vivo study. Sci. Rep., 2017, 7(1), 11086.
Xia, L.W.; Xie, R.; Ju, X.J.; Wang, W.; Chen, Q.; Chu, L.Y. Nanostructured smart hydrogels with rapid response and high elasticity. Nat. Commun., 2013, 4, 2226.
Licciardi, M.; Campisi, M.; Cavallaro, G.; Cervello, M.; Azzolina, A.; Giammona, G. Synthesis and characterization of polyaminoacidic polycations for gene delivery. Biomaterials, 2006, 27(9), 2066-2075.
Piccirillo, C.; Pullar, R.C.; Costa, E.; Santos-Silva, A.; Pintado, M.M.E.; Castro, P.M. Hydroxyapatite-based materials of marine origin: A bioactivity and sintering study. Mater. Sci. Eng. C, 2015, 51, 309-315.
Stanić, V.; Dimitrijević, S.; Antić-Stanković, J.; Mitrić, M.; Jokić, B.; Plećaš, I.B.; Raičević, S. Synthesis, characterization and antimicrobial activity of copper and zinc-doped hydroxyapatite nanopowders. Appl. Surf. Sci., 2010, 256(20), 6083-6089.

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Year: 2020
Page: [228 - 247]
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DOI: 10.2174/2210681209666190228143636
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