{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T04:02:50Z","timestamp":1775620970162,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T00:00:00Z","timestamp":1621468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Nanoparticles may provide unique therapeutic opportunities when administered via the nasal cavity, yet the primary uptake and transfer pathways for these particles within the nasal mucosa are not well understood. The endocytic pathways involved in the uptake of fluorescently labeled, (Nile Red) solid lipid nanoparticles (SLNs) of different sizes (~30, 60, and 150 nm) were studied using excised bovine olfactory and nasal respiratory tissues. Endocytic activity contributing to nanoparticle uptake was investigated using a variety of pharmacological inhibitors, but none of the inhibitors were able to completely eliminate the uptake of the SLNs. The continued uptake of nanoparticles following exposure to individual inhibitors suggests that a number of endocytic pathways work in combination to transfer nanoparticles into the nasal mucosa. Following exposure to the general metabolic inhibitors, 2,4-DNP and sodium azide, additional, non-energy-dependent pathways for nanoparticle uptake were also observed. While the smallest nanoparticles (30 nm) were the most resistant to the effects of pharmacologic inhibitors, the largest (150 nm) were still able to transfer significant amounts of the particles into the tissues. The rapid nanoparticle uptake observed demonstrates that these lipid particles are promising vehicles to accomplish both local and systemic drug delivery following nasal administration.<\/jats:p>","DOI":"10.3390\/pharmaceutics13050761","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T11:45:57Z","timestamp":1621511157000},"page":"761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Endocytic Uptake of Solid Lipid Nanoparticles by the Nasal Mucosa"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1366-4271","authenticated-orcid":false,"given":"Ammar S.","family":"Al Khafaji","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Science and Experimental Therapeutics, College of Pharmacy, University of Iowa, 115 S. Grand Avenue, Pharmacy Building, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen D.","family":"Donovan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science and Experimental Therapeutics, College of Pharmacy, University of Iowa, 115 S. Grand Avenue, Pharmacy Building, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1615\/CritRevTherDrugCarrierSyst.2017018693","article-title":"Lipid Nanoparticles for Nasal\/intranasal Drug Delivery","volume":"34","author":"Cunha","year":"2017","journal-title":"Crit. Rev.\u2122 Ther. Drug Carr. Syst."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0027-5107(97)00126-7","article-title":"Metabolic Capacity of Nasal Tissue: Interspecies Comparisons of Xenobiotic-metabolizing Enzymes","volume":"380","author":"Dahl","year":"1997","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3109\/10408449109019571","article-title":"Nasal Cavity Enzymes Involved in Xenobiotic Metabolism: Effects on the Toxicity of Inhalants","volume":"21","author":"Dahl","year":"1991","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"767","DOI":"10.3109\/08958378.2015.1066903","article-title":"Gene Expression and Immunochemical Localization of Major Cytochrome P450 Drug-metabolizing Enzymes in Bovine Nasal Olfactory and Respiratory Mucosa","volume":"27","author":"Dhamankar","year":"2015","journal-title":"Inhal. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6459","DOI":"10.2174\/0929867326666190827151741","article-title":"Intranasal Nanoparticulate Systems As Alternative Route of Drug Delivery","volume":"26","author":"Alshweiat","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.jconrel.2017.09.001","article-title":"Progress in Brain Targeting Drug Delivery System by Nasal Route","volume":"268","author":"Khan","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.ejpb.2014.05.004","article-title":"Solid Lipid Nanoparticles as Vehicles of Drugs to the Brain: Current State of the Art","volume":"87","author":"Gastaldi","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_8","first-page":"298","article-title":"Microsphere Transport Pathways in the Rabbit Nasal Mucosa","volume":"1","author":"Huang","year":"1996","journal-title":"Int. J. Pharm. Adv"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nnano.2012.3","article-title":"Oral Exposure to Polystyrene Nanoparticles Affects Iron Absorption","volume":"7","author":"Mahler","year":"2012","journal-title":"Nat. Nanotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.addr.2020.06.002","article-title":"Lipid Nanoparticles for Nucleic Acid Delivery: Current Perspectives","volume":"154\u2013155","author":"Samaridou","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1021\/mp4006968","article-title":"Solid Lipid Nanoparticle Formulations of Docetaxel Prepared with High Melting Point Triglycerides: In Vitro and In Vivo Evaluation","volume":"11","author":"Naguib","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_12","first-page":"e53102","article-title":"Solid Lipid Nanoparticles (SLNs) for Intracellular Targeting Applications","volume":"105","author":"Raimondi","year":"2015","journal-title":"JoVE (J. Vis. Exp.)"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1093\/toxsci\/kfp087","article-title":"Mechanisms of Quantum Dot Nanoparticle Cellular Uptake","volume":"110","author":"Zhang","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1083\/jcb.200908086","article-title":"Amiloride Inhibits Macropinocytosis by Lowering Submembranous pH and Preventing Rac1 and Cdc42 Signaling","volume":"188","author":"Koivusalo","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3716","DOI":"10.1021\/mp5004674","article-title":"Transport Pathways of Solid Lipid Nanoparticles Across Madin\u2013Darby Canine Kidney Epithelial Cell Monolayer","volume":"11","author":"Chai","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1039\/C7PY01603D","article-title":"Entry of Nanoparticles into Cells: The Importance of Nanoparticle Properties","volume":"9","author":"Zhao","year":"2018","journal-title":"Polym. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1080\/03639045.2019.1593434","article-title":"Fabrication of Solid Lipid Nanoparticles of Lurasidone HCl for Oral Delivery: Optimization, In Vitro Characterization, Cell Line Studies and In Vivo Efficacy in Schizophrenia","volume":"45","author":"Patel","year":"2019","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jcis.2015.10.057","article-title":"Cellular Uptake and Transcytosis of Lipid-based Nanoparticles Across the Intestinal Barrier: Relevance for Oral Drug Delivery","volume":"463","author":"Neves","year":"2016","journal-title":"J. Colloid Interface Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jconrel.2013.03.033","article-title":"Just Getting into Cells is Not Enough: Mechanisms Underlying 4-(N)-stearoyl Gemcitabine Solid Lipid Nanoparticle\u2019s Ability to Overcome Gemcitabine Resistance Caused by RRM1 Overexpression","volume":"169","author":"Wonganan","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"877","DOI":"10.3109\/10837450.2014.938857","article-title":"Elucidation of Intestinal Absorption Mechanism of Carvedilol-loaded Solid Lipid Nanoparticles Using Caco-2 Cell Line As an In-vitro Model","volume":"20","author":"Shah","year":"2015","journal-title":"Pharm. Dev. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1042\/bj20031253","article-title":"Size-dependent Internalization of Particles Via the Pathways of Clathrin-and Caveolae-mediated Endocytosis","volume":"377","author":"Rejman","year":"2004","journal-title":"Biochem. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5929","DOI":"10.1021\/acsami.6b00821","article-title":"Transport Mechanisms of Solid Lipid Nanoparticles Across Caco-2 Cell Monolayers and their Related Cytotoxicology","volume":"8","author":"Chai","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.ijpharm.2015.10.011","article-title":"Enhanced Bioavailability of Tripterine Through Lipid Nanoparticles Using Broccoli-derived Lipids As a Carrier Material","volume":"495","author":"Li","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ijpharm.2010.04.039","article-title":"The Characteristics and Mechanism of Simvastatin Loaded Lipid Nanoparticles to Increase Oral Bioavailability in Rats","volume":"394","author":"Zhang","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.nano.2011.08.016","article-title":"Solid Lipid Nanoparticles Loading Candesartan Cilexetil Enhance Oral Bioavailability: In Vitro Characteristics and Absorption Mechanism in Rats","volume":"8","author":"Zhang","year":"2012","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_26","unstructured":"Albarki, M.A.H. (2019). Evaluation of Poly D,L lactic-co-glycolic Acid (PLGA) Nanoparticle Uptake Pathways across the Nasal Mucosa. [Ph.D. Thesis, University of Iowa]."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/5\/761\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:04:57Z","timestamp":1760162697000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/5\/761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,20]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["pharmaceutics13050761"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13050761","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,20]]}}}