{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T17:27:15Z","timestamp":1773941235831,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T00:00:00Z","timestamp":1603238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Tacrine (TAC) was the first FDA approved drug for the treatment of Alzheimer\u2019s disease, resulting in increased memory and enhanced cognitive symptoms in patients. However, long-term therapy presents poor patient compliance associated with undesired side effects such as nausea, vomiting and hepatoxicity. To improve its therapeutic efficacy and decrease toxicity, the use of nanoparticles could be applied as a possible solution to delivery TAC. In this context, a project has been designed to develop a new nanostructured lipid carrier (NLC) as a delivery system for TAC and conjugate TAC and model amphipathic peptide (MAP) to decrease TAC limitations. Different formulations loaded with TAC and TAC + MAP were prepared using a combination of Compritol 888 ATO as the solid lipid and Transcutol HP as the liquid lipid component. Physical characterization was evaluated in terms of particle size, surface charge, encapsulation efficiency and in vitro drug release studies. Particle size distributions within the nanometer range were obtained with encapsulation efficiencies of 72.4% for the TAC and 85.6% for the TAC + MAP conjugate. Furthermore, cytotoxicity of all NLC formulations was determined against neuroblastoma cell line SH-SY5Y. The optimized TAC delivery system revealed low toxicity suggesting this could be a potential carrier system to deliver TAC. However, TAC + MAP conjugated even encapsulated in the NLC system demonstrated toxicity against the SH-SY5Y cell line.<\/jats:p>","DOI":"10.3390\/nano10102089","type":"journal-article","created":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T10:27:58Z","timestamp":1603362478000},"page":"2089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Formulation, Characterization and Evaluation against SH-SY5Y Cells of New Tacrine and Tacrine-MAP Loaded with Lipid Nanoparticles"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8164-2504","authenticated-orcid":false,"given":"Sara","family":"Silva","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Pla\u0301cido da Costa, 4200-450 Porto, Portugal"},{"name":"Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5523-5622","authenticated-orcid":false,"given":"Joana","family":"Marto","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6799-2740","authenticated-orcid":false,"given":"L\u00eddia","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-4726","authenticated-orcid":false,"given":"Anto\u0301nio J.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, Avenida Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Pla\u0301cido da Costa, 4200-450 Porto, Portugal"},{"name":"Faculty of Medicine, University of Porto, Al. Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1021\/jm00128a024","article-title":"9-amino-l,2,3,4-tetrahydroacridin-l-ols: Synthesis and Evaluation As Potential Alzheimer\u2019S Disease Therapeutics","volume":"32","author":"Shutske","year":"1989","journal-title":"J. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1177\/106002809402800612","article-title":"Tacrine: First drug approved for alzheimer\u2019s disease","volume":"28","author":"Crismon","year":"1994","journal-title":"Ann. Pharmacother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1159\/000116478","article-title":"Tacrine in the Treatment of Alzheimer\u2019s Disease","volume":"29","author":"Summers","year":"1989","journal-title":"Eur. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.2174\/092986710791111206","article-title":"Tacrine Derivatives and Alzheimers Disease","volume":"17","author":"Tumiatti","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"439","DOI":"10.3233\/JAD-2006-9S350","article-title":"Tacrine, and Alzheimer\u2019s treatments","volume":"9","author":"Summers","year":"2006","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/ng1197-263","article-title":"Lack of apolipoprotein E dramatically reduces amyloid \u03b2-peptide deposition","volume":"17","author":"Bales","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00415-011-6145-3","article-title":"Progress in Alzheimer\u2019s disease","volume":"259","author":"Galimberti","year":"2012","journal-title":"J. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Briggs, R., Kennelly, S.P., and O\u2019Neill, D. (2016). Drug treatments in Alzheimer\u2019s disease. Clin. Med. J. R. Coll. Physicians Lond.","DOI":"10.7861\/clinmedicine.16-3-247"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s disease","volume":"25","author":"Lane","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/s41593-018-0325-8","article-title":"Astrocyte function from information processing to cognition and cognitive impairment","volume":"22","author":"Santello","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1056\/NEJM198611133152001","article-title":"Oral Tetrahydroaminoacridine in Long-Term Treatment of Senile Dementia, Alzheimer Type","volume":"315","author":"Summers","year":"1986","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/ageing\/18.4.223","article-title":"Clinical experience with and side-effects of tacrine hydrochloride in alzheimer\u2019s disease: A pilot study","volume":"18","author":"Forsyth","year":"1989","journal-title":"Age Ageing"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/clpt.1989.199","article-title":"Pharmacokinetics of tacrine hydrochloride in Alzheimer\u2019s disease","volume":"46","author":"Forsyth","year":"1989","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.5530\/jyp.2015.1.6","article-title":"Formulation and characterization of anti-alzheimer\u2019s drug loaded chitosan nanoparticles and its In vitro biological evaluation","volume":"7","author":"Tamilselvan","year":"2015","journal-title":"J. Young Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jconrel.2018.05.011","article-title":"Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs","volume":"281","author":"Agrawal","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.jconrel.2020.02.020","article-title":"Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting","volume":"321","author":"Agrawal","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1801702","DOI":"10.1002\/smll.201801702","article-title":"Elucidating the Influences of Size, Surface Chemistry, and Dynamic Flow on Cellular Association of Nanoparticles Made by Polymerization-Induced Self-Assembly","volume":"14","author":"Khor","year":"2018","journal-title":"Small"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2002861","DOI":"10.1002\/smll.202002861","article-title":"Cellular Interactions of Liposomes and PISA Nanoparticles during Human Blood Flow in a Microvascular Network","volume":"16","author":"Vu","year":"2020","journal-title":"Small"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.2174\/1385272820666161031161101","article-title":"Targeted Delivery of Lipid Nanoparticles by Means of Surface Chemical Modification","volume":"21","author":"Gaspar","year":"2017","journal-title":"Curr. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"84","DOI":"10.2174\/2405461504666190510121911","article-title":"Lipid Based Nanoparticles: Current Strategies for Brain Tumor Targeting","volume":"4","author":"Mohanta","year":"2019","journal-title":"Curr. Nanomater."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jconrel.2017.08.033","article-title":"Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases","volume":"264","author":"Tapeinos","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1517\/17425247.2014.935335","article-title":"Compritol 888 ATO: A multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals","volume":"11","author":"Aburahma","year":"2014","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.fct.2014.06.028","article-title":"A review of the nonclinical safety of Transcutol\u00ae, a highly purified form of diethylene glycol monoethyl ether (DEGEE) used as a pharmaceutical excipient","volume":"72","author":"Sullivan","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1023\/A:1022604120952","article-title":"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","volume":"20","author":"Kreuter","year":"2003","journal-title":"Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.tips.2017.01.003","article-title":"Cell-Penetrating Peptides: From Basic Research to Clinics","volume":"38","author":"Guidotti","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1021\/mp100223d","article-title":"The pharmacokinetics of cell-penetrating peptides","volume":"7","author":"Sarko","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4082","DOI":"10.1016\/j.biomaterials.2014.01.047","article-title":"Tumor targeting of a cell penetrating peptide by fusing with a pH-sensitive histidine-glutamate co-oligopeptide","volume":"35","author":"Fei","year":"2014","journal-title":"Biomaterials"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1021\/mp200481g","article-title":"Comparison of cationic and amphipathic cell penetrating peptides for siRNA delivery and efficacy","volume":"9","author":"Mo","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4542","DOI":"10.1021\/acs.molpharmaceut.9b00680","article-title":"\u03b1-Aminoisobutyric Acid-Containing Amphipathic Helical Peptide-Cyclic RGD Conjugation as a Potential Drug Delivery System for MicroRNA Replacement Therapy in Vitro","volume":"16","author":"Taniguchi","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0005-2736(98)00161-8","article-title":"Cellular uptake of an \u03b1-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically","volume":"1414","author":"Oehlke","year":"1998","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1007\/s43440-019-00032-x","article-title":"A new MAP-Rasagiline conjugate reduces \u03b1-synuclein inclusion formation in a cell model","volume":"72","author":"Vale","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s12264-013-1423-y","article-title":"Oxidative stress in Alzheimer\u2019s disease","volume":"30","author":"Chen","year":"2014","journal-title":"Neurosci. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1016\/S0047-6374(01)00309-8","article-title":"Acetylcholinesterase in Alzheimer\u2019s disease","volume":"122","author":"Talesa","year":"2001","journal-title":"Mech. Ageing Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ijpharm.2015.11.050","article-title":"Rifabutin-loaded solid lipid nanoparticles for inhaled antitubercular therapy: Physicochemical and in vitro studies","volume":"497","author":"Gaspar","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_36","first-page":"93","article-title":"Controlled release tacrine delivery system for the treatment of Alzheimer\u2019s disease","volume":"8","author":"Yang","year":"2001","journal-title":"Drug Deliv. J. Deliv. Target. Ther. Agents"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejpb.2008.03.009","article-title":"Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles","volume":"70","author":"Wilson","year":"2008","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.1039\/C6AN00357E","article-title":"Development of a biosensing system for tacrine based on nitrogen-doped graphene quantum dots and acetylcholinesterase","volume":"141","year":"2016","journal-title":"Analyst"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ejps.2015.11.014","article-title":"The compatibility of Tacrine molecule with poly(n-butylcyanoacrylate) and Chitosan as efficient carriers for drug delivery: A molecular dynamics study","volume":"82","author":"Eslami","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_40","first-page":"25","article-title":"Effect of Magnetic Tacrine-Loaded Chitosan Nanoparticles on Spatial Learning, Memory, Amyloid Precursor Protein and Seladin-1 Expression in the Hippocampus Of Streptozotocin-Exposed Rats","volume":"3","author":"Hassanzadeh","year":"2016","journal-title":"Int. Clin. Neurosci. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1166\/jbn.2007.049","article-title":"Lipid nanoparticles (SLN\u00ae, NLC\u00ae) for cutaneous drug delivery: Structure, protection and skin effects","volume":"3","author":"Souto","year":"2007","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8424","DOI":"10.1016\/j.biomaterials.2013.07.038","article-title":"Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy","volume":"34","author":"Chu","year":"2013","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16515","DOI":"10.1021\/ja804928q","article-title":"Using a sterically restrictive amino acid as a 19F NMR label to monitor and to control peptide aggregation in membranes","volume":"130","author":"Wadhwani","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1529\/biophysj.103.035964","article-title":"Infrared reflection absorption spectroscopy of amphipathic model peptides at the air\/water interface","volume":"86","author":"Kerth","year":"2004","journal-title":"Biophys. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00249-011-0771-7","article-title":"Antimicrobial and cell-penetrating peptides induce lipid vesicle fusion by folding and aggregation","volume":"41","author":"Wadhwani","year":"2012","journal-title":"Eur. Biophys. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e1984","DOI":"10.21769\/BioProtoc.1984","article-title":"Sulforhodamine B (SRB) Assay in Cell Culture to Investigate Cell Proliferation","volume":"6","author":"Orellana","year":"2016","journal-title":"Bio-Protocol"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/nprot.2006.179","article-title":"Sulforhodamine B colorimetric assay for cytotoxicity screening","volume":"1","author":"Vichai","year":"2006","journal-title":"Nat. Protoc."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/10\/10\/2089\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:25:40Z","timestamp":1760178340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/10\/10\/2089"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,21]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["nano10102089"],"URL":"https:\/\/doi.org\/10.3390\/nano10102089","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,21]]}}}