{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T10:35:02Z","timestamp":1760524502001,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T00:00:00Z","timestamp":1685664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS114723"],"award-info":[{"award-number":["NS114723"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Herman A. \u201cDusty\u201d Rhodes Eminent Scholar Chair in Engineering","award":["NS114723"],"award-info":[{"award-number":["NS114723"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The blood\u2013brain barrier (BBB) is an obstacle to the permeation of most therapeutic drugs into the brain, limiting treatments for neurological disorders. Drugs loaded within nanocarriers that pass through the BBB can overcome this limitation. Halloysite consists of naturally occurring biocompatible clay nanotubes of 50 nm diameter and 15 nm lumen, allowing the loading and sustained release of loaded drugs. These have demonstrated the ability to transport loaded molecules into cells and organs. We propose to use halloysite nanotubes as a \u201cnano-torpedo\u201d for drug delivery through the BBB due to their needle-like shape. To determine if they can cross the BBB using a non-invasive, clinically translatable route of administration, we loaded halloysite with either diazepam or xylazine and delivered these intranasally to mice daily over six days. The sedative effects of these drugs were observed in vestibulomotor tests conducted at two, five, and seven days after the initial administration. Behavioral tests were conducted 3.5 h after administration to show that the effects were from halloysite\/delivered drugs and not from the drug alone. As expected, the treated mice performed more poorly than the sham, drug alone, and halloysite-vehicle-treated mice. These results confirm that halloysite permeates the BBB to deliver drugs when administered intranasally.<\/jats:p>","DOI":"10.3390\/ijms24119648","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T02:41:35Z","timestamp":1685673695000},"page":"9648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Clay Nanotubes Loaded with Diazepam or Xylazine Permeate the Brain through Intranasal Administration in Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Yaswanthi","family":"Yanamadala","sequence":"first","affiliation":[{"name":"Center for Biomedical Engineering and Rehabilitation Sciences, Louisiana Tech University, Rustom, LA 71270, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahdi Y.","family":"Saleh","sequence":"additional","affiliation":[{"name":"Institute for Micromanufacturing, Louisiana Tech University, Rustom, LA 71270, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afrika A.","family":"Williams","sequence":"additional","affiliation":[{"name":"Center for Biomedical Engineering and Rehabilitation Sciences, Louisiana Tech University, Rustom, LA 71270, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0722-5643","authenticated-orcid":false,"given":"Yuri","family":"Lvov","sequence":"additional","affiliation":[{"name":"Institute for Micromanufacturing, Louisiana Tech University, Rustom, LA 71270, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8857-154X","authenticated-orcid":false,"given":"Teresa A.","family":"Murray","sequence":"additional","affiliation":[{"name":"Center for Biomedical Engineering and Rehabilitation Sciences, Louisiana Tech University, Rustom, LA 71270, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101631","DOI":"10.1016\/j.apmt.2022.101631","article-title":"On a highway to the brain: A review on nose-to-brain drug delivery using nanoparticles","volume":"29","author":"Formica","year":"2022","journal-title":"Appl. Mater. Today"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3389\/fbioe.2021.629832","article-title":"The Application of Nanotechnology for the Diagnosis and Treatment of Brain Diseases and Disorders","volume":"9","author":"Ngowi","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_3","unstructured":"(2023, May 24). Neurodegenerative Diseases, Available online: https:\/\/www.niehs.nih.gov\/research\/supported\/health\/neurodegenerative\/index.cfm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.1039\/D0TB02957B","article-title":"Recent advances in the design of inorganic and nano-clay particles for the treatment of brain disorders","volume":"9","author":"Persano","year":"2021","journal-title":"J. Mater. Chem. B"},{"key":"ref_5","first-page":"367","article-title":"Noninvasive Routes of Proteins and Peptides Drug Delivery","volume":"73","author":"Sharma","year":"2011","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_6","first-page":"600","article-title":"Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider","volume":"50","author":"Turner","year":"2011","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.brainresbull.2018.10.009","article-title":"Evaluation of intranasal delivery route of drug administration for brain targeting","volume":"143","author":"Bors","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/jps.21924","article-title":"Intranasal delivery to the central nervous system: Mechanisms and experimental considerations","volume":"99","author":"Dhuria","year":"2010","journal-title":"J. Pharm. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1517\/17425247.3.4.529","article-title":"Intravail: Highly effective intranasal delivery of peptide and protein drugs","volume":"3","author":"Maggio","year":"2006","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/jps.20718","article-title":"Nanoparticulate systems for nasal delivery of drugs: A real improvement over simple systems?","volume":"96","author":"Illum","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_11","first-page":"991","article-title":"Overview of intranasally delivered peptides: Key considerations for pharmaceutical development. Expert Opin","volume":"15","author":"Donovan","year":"2018","journal-title":"Drug Deliv."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Massaro, M., Ciani, R., Cin\u00e0, G., Colletti, C.G., Leone, F., and Riela, S. (2022). Antimicrobial Nanomaterials Based on Halloysite Clay Mineral: Research Advances and Outlook. Antibiotics, 11.","DOI":"10.3390\/antibiotics11121761"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1016\/j.progpolymsci.2014.04.004","article-title":"Recent advance in research on halloysite nanotubes-polymer nanocomposite","volume":"39","author":"Liu","year":"2014","journal-title":"Prog. Polym. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/adma.201502341","article-title":"Halloysite Clay Nanotubes for Loading and Sustained Release of Functional Compounds","volume":"28","author":"Lvov","year":"2016","journal-title":"Adv. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Biddeci, G., Spinelli, G., Colomba, P., and Di Blasi, F. (2022). Nanomaterials: A Review about Halloysite Nanotubes, Properties, and Application in the Biological Field. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911518"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1080\/17425247.2019.1665020","article-title":"Biomedical potential of clay nanotube formulations and their toxicity assessment","volume":"16","author":"Santos","year":"2019","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1800419","DOI":"10.1002\/mabi.201800419","article-title":"Tubule Nanoclay-Organic Heterostructures for Biomedical Applications","volume":"19","author":"Liu","year":"2019","journal-title":"Macromol. Biosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1021\/bm9014446","article-title":"Cytocompatibility and uptake of halloysite clay nanotubes","volume":"11","author":"Vergaro","year":"2010","journal-title":"Biomacromolecules"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1007\/s12274-015-0759-1","article-title":"Cell surface engineering with polyelectrolyte-stabilized magnetic nanoparticles: A facile approach for fabrication of artificial multicellular tissue-mimicking clusters","volume":"8","author":"Dzamukova","year":"2015","journal-title":"Nano Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1080\/17435390.2020.1780642","article-title":"Evaluation of toxicity of halloysite nanotubes and multi-walled carbon nanotubes to endothelial cells in vitro and blood vessels in vivo","volume":"14","author":"Wu","year":"2020","journal-title":"Nanotoxicology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/tox.22543","article-title":"Halloysite nanotubes-induced Al accumulation and oxidative damage in liver of mice after 30-day repeated oral administration","volume":"33","author":"Wang","year":"2018","journal-title":"Environ. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.nanoso.2018.03.009","article-title":"Uptake of halloysite clay nanotubes by human cells: Colourimetric viability tests and microscopy study","volume":"15","author":"Kamalieva","year":"2018","journal-title":"Nano Struct. Nano Objects"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.colsurfb.2018.06.042","article-title":"Preparation of multifunctional PEG-graft-Halloysite Nanotubes for Controlled Drug Release, Tumor Cell Targeting, and Bio-imaging","volume":"170","author":"Mehdia","year":"2018","journal-title":"Coll. Surfaces B Biointerf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23050","DOI":"10.1021\/acsami.9b07499","article-title":"Selective antimicrobial effects of curcumin @ halloysite nanoformulation: A Caenorhabditis elegans study","volume":"11","author":"Fakhrullina","year":"2019","journal-title":"ACS Appl. Mater. Interf."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18965","DOI":"10.1021\/acssuschemeng.9b04365","article-title":"Toxicity Evaluation of One-Dimensional Nanoparticles Using Caenorhabditis elegans: A Comparative Study of Halloysite Nanotubes and Chitin Nanocrystals","volume":"7","author":"Zhao","year":"2019","journal-title":"ACS Sustain. Chem. Eng."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3389\/fbioe.2020.00451","article-title":"Tagged Halloysite Nanotubes as a Carrier for Intercellular Delivery in Brain Microvascular Endothelium","volume":"8","author":"Saleh","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1080\/08869634.1990.11678317","article-title":"A Review of Oral Skeletal Muscle Relaxants for the Craniomandibular Disorder (CMD) Practitioner","volume":"8","author":"Stanko","year":"1990","journal-title":"CRANIO"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1161\/STROKEAHA.119.026652","article-title":"Validity and Reliability of Neurological Scores in Mice Exposed to Middle Cerebral Artery Occlusion","volume":"50","author":"Bieber","year":"2019","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep31286","article-title":"MATSAP: An automated analysis of stretch-Attend posture in rodent behavioral experiments","volume":"6","author":"Holly","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26578","DOI":"10.1021\/acsami.6b09074","article-title":"Enhanced Therapeutic Efficacy of Doxorubicin for Breast Cancer Using Chitosan Oligosaccharide-Modified Halloysite Nanotubes","volume":"8","author":"Yang","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_31","first-page":"629","article-title":"Evaluation of Recent Intranasal Drug Delivery Systems to the Central Nervous System","volume":"14","author":"Wen","year":"2022","journal-title":"Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.actbio.2016.10.042","article-title":"Microfluidic assembly of a nano-in-micro dual drug delivery platform composed of halloysite nanotubes and a pH-responsive polymer for colon cancer therapy","volume":"48","author":"Li","year":"2017","journal-title":"Acta Biomater."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1177\/0885328215593837","article-title":"Poly(l-lactide)\/halloysite nanotube electrospun mats as dual-drug delivery systems and their therapeutic efficacy in infected full-thickness burns","volume":"30","author":"Zhang","year":"2015","journal-title":"J. Biomater. Appl."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9335","DOI":"10.1038\/s41598-021-88599-5","article-title":"Diazepam causes sedative rather than anxiolytic effects in C57BL\/6J mice","volume":"11","author":"Tort","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7815","DOI":"10.1038\/s41598-020-64783-x","article-title":"Longitudinal in vivo imaging of progressive axonal damage and resolution with minocycline treatment after diffuse brain injury in a murine model","volume":"10","author":"Pernici","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7946","DOI":"10.1038\/s41598-019-44174-7","article-title":"Time Course Images of Cellular Injury and Recovery in Murine Brain with High-Resolution GRIN Lens System","volume":"9","author":"Pernici","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lee, S.A., Holly, K.S., Voziyanov, V., Villalba, S.L., Tong, R., Grigsby, H.E., Glasscock, E., Szele, F.G., Vlachos, I., and Murray, T.A. (2016). Gradient index microlens implanted in prefrontal cortex of mouse does not affect behavioral test performance over time. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0146533"},{"key":"ref_38","unstructured":"(2023, May 24). Diazepam: 7 Things You Should Know\u2014Drugs.com. Available online: https:\/\/www.drugs.com\/tips\/diazepam-patient-tips."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9648\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:47:33Z","timestamp":1760125653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/11\/9648"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,2]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24119648"],"URL":"https:\/\/doi.org\/10.3390\/ijms24119648","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,6,2]]}}}