{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T19:06:42Z","timestamp":1791745602099,"version":"4.3.4"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"crossref","award":["2025A1515010639"],"award-info":[{"award-number":["2025A1515010639"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) is the seventh leading cause of death worldwide, posing a substantial global health burden. Although galantamine (GNT) is a first-line clinical drug for AD treatment, its therapeutic efficacy is constrained by inefficient brain delivery across the blood\u2013brain barrier (BBB). Nose-to-brain delivery represents a promising route to bypass the BBB. However, its efficiency remains limited by insufficient drug deposition in the anatomically restricted olfactory region. In this study, we developed a galantamine nasal spray (GNT-NS) with enhanced olfactory region deposition and evaluated its feasibility for nose-to-brain delivery in AD treatment. Methods: We optimized the formulation by systematically investigating the cascade relationship among formulation physicochemical properties, spray performance, and olfactory region deposition. Nasal deposition distribution was quantitatively evaluated using a physiologically realistic 3D-printed human nasal cavity model reconstructed from clinical magnetic resonance imaging (MRI) data. Further, the in vivo biodistribution and therapeutic efficacy of GNT-NS were evaluated in AD rats. Results: The optimized formulation P3 achieved an olfactory region fraction of 23.85%, markedly exceeding that of the unoptimized formulation P0. Subsequent in vivo biodistribution studies showed that P3 produced higher brain drug exposure than both intranasally administered P0 and the commercial oral formulation. Further pharmacodynamic studies demonstrated that GNT-NS significantly improved cognitive and behavioral deficits in AD rats, exhibiting superior therapeutic efficacy over commercially available oral galantamine tablets. Conclusions: Collectively, this study proposes a cascade regulation strategy linking formulation physicochemical properties, spray performance, and olfactory region deposition and demonstrates that optimizing nasal spray properties can enhance olfactory deposition, increase brain exposure and improve therapeutic efficacy. These findings provide a useful reference for the design of nose-to-brain delivery formulations for AD and other central nervous system diseases.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070885","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:00:17Z","timestamp":1784548817000},"page":"885","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Feasibility Study of Nose-to-Brain Delivery of Galantamine for Alzheimer\u2019s Disease: Enhancing Olfactory-Region Deposition to Improve Therapeutic Efficacy"],"prefix":"10.3390","volume":"18","author":[{"given":"Chuangxin","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunying","family":"Leung","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zizhao","family":"Zhai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanlin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6158-1094","authenticated-orcid":false,"given":"Qiuyi","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Yue","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongxuan","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3330-3537","authenticated-orcid":false,"given":"Xuejuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510006, China"},{"name":"College of Pharmacy, Jinan University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, X., Guo, T., Zhang, Y., Jiao, M., Ji, L., Dong, Z., Li, H., Chen, S., Zheng, W., and Jing, Q. (2024). Global burden of Alzheimer\u2019s disease and other dementias attributed to metabolic risks from 1990 to 2021: Results from the global burden of disease study 2021. BMC Psychiatry, 24.","DOI":"10.1186\/s12888-024-06375-x"},{"key":"ref_2","first-page":"1","article-title":"Recent advances in Alzheimer\u2019s disease: Mechanisms, clinical trials and new drug development strategies","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113409","DOI":"10.1016\/j.psychres.2020.113409","article-title":"Galantamine-Memantine combination in the treatment of Alzheimer\u2019s disease and beyond","volume":"293","author":"Koola","year":"2020","journal-title":"Psychiatry Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"114667","DOI":"10.1016\/j.jconrel.2026.114667","article-title":"Rationalizing nose-to-brain drug delivery: Machine learning-guided optimization and mechanistic elucidation of olfactory deposition for nasal sprays","volume":"39","author":"Zhai","year":"2026","journal-title":"J. Control. Release"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Liu, J., Ting, J.P., Al-Azzam, S., Ding, Y., and Afshar, S. (2021). Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062805"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41392-023-01481-w","article-title":"The blood\u2013brain barrier: Structure, regulation and drug delivery","volume":"8","author":"Wu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Costantino, H.R., Leonard, A.K., Brandt, G., Johnson, P.H., and Quay, S.C. (2008). Intranasal administration of acetylcholinesterase inhibitors. BMC Neurosci., 9.","DOI":"10.1186\/1471-2202-9-S3-S6"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"120482","DOI":"10.1016\/j.ijpharm.2021.120482","article-title":"QbD-steered development of mixed nanomicelles of galantamine: Demonstration of enhanced brain uptake, prolonged systemic retention and improved biopharmaceutical attributes","volume":"600","author":"Lohan","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bures, J., Tacheci, I., Kvetina, J., Radochova, V., Kohoutova, D., Valis, M., Rejchrt, S., Knoblochova, V., and Karasova, J.Z. (2021). Dextran sodium sulphate-induced gastrointestinal injury further aggravates the impact of galantamine on the gastric myoelectric activity in experimental pigs. Pharmaceuticals, 14.","DOI":"10.3390\/ph14060590"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"713","DOI":"10.4140\/TCP.n.2004.713","article-title":"Gastrointestinal adverse events in a general population sample of nursing home residents taking cholinesterase inhibitors","volume":"19","author":"Hughes","year":"2004","journal-title":"Consult. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.jconrel.2023.06.005","article-title":"Effective nose-to-brain drug delivery using a combination system targeting the olfactory region in monkeys","volume":"359","author":"Sasaki","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"124866","DOI":"10.1016\/j.ijpharm.2024.124866","article-title":"Advancement in the Nose-to-Brain Drug delivery of FDA-approved drugs for the better management of Depression and Psychiatric disorders","volume":"667","author":"Upadhyay","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jconrel.2021.06.007","article-title":"Usefulness of cell-penetrating peptides and penetration accelerating sequence for nose-to-brain delivery of glucagon-like peptide-2","volume":"335","author":"Akita","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Dighe, S., Jog, S., Momin, M., Sawarkar, S., and Omri, A. (2023). Intranasal Drug Delivery by Nanotechnology: Advances in and Challenges for Alzheimer\u2019s Disease Management. Pharmaceuticals, 16.","DOI":"10.3390\/pharmaceutics16010058"},{"key":"ref_16","first-page":"97","article-title":"A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer\u2019s disease","volume":"44","author":"Yue","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"115196","DOI":"10.1016\/j.addr.2024.115196","article-title":"Intranasal drug delivery: The interaction between nanoparticles and the nose-to-brain pathway","volume":"207","author":"Chen","year":"2024","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"123809","DOI":"10.1016\/j.ijpharm.2024.123809","article-title":"Rivastigmine nasal spray for the treatment of Alzheimer\u2019s Disease: Olfactory deposition and brain delivery","volume":"652","author":"Guo","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1080\/17425247.2022.2029845","article-title":"Nose-to-brain drug delivery for the treatment of Alzheimer\u2019s disease: Current advancements and challenges","volume":"19","author":"A","year":"2022","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_20","first-page":"53902","article-title":"Modeling and simulations of olfactory drug delivery with passive and active controls of nasally inhaled pharmaceutical aerosols","volume":"111","author":"Si","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ijpharm.2018.03.046","article-title":"Partitioning of dispersed nanoparticles in a realistic nasal passage for targeted drug delivery","volume":"543","author":"Dong","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"119341","DOI":"10.1016\/j.ijpharm.2020.119341","article-title":"In vitro assessment of an idealized nose for nasal spray testing: Comparison with regional deposition in realistic nasal replicas","volume":"582","author":"Chen","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"23684","DOI":"10.1021\/acsnano.4c08279","article-title":"Tailored Borneol-Modified Lipid Nanoparticles Nasal Spray for Enhanced Nose-to-Brain Delivery to Central Nervous System Diseases","volume":"18","author":"Wang","year":"2024","journal-title":"ACS Nano"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1021\/acs.molpharmaceut.7b00702","article-title":"Personalized Medicine in Nasal Delivery: The Use of Patient-Specific Administration Parameters To Improve Nasal Drug Targeting Using 3D-Printed Nasal Replica Casts","volume":"15","author":"Warnken","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41467-023-36519-8","article-title":"Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice","volume":"14","author":"Park","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41380-025-03143-5","article-title":"The NMDAR\/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer\u2019s disease","volume":"31","author":"Yan","year":"2026","journal-title":"Mol. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"28963","DOI":"10.1038\/s41598-025-13920-5","article-title":"Neuroprotective effect of Tozasertib in Streptozotocin-induced alzheimer\u2019s mice model","volume":"15","author":"Kaur","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2411426","DOI":"10.1002\/adfm.202411426","article-title":"Lyotropic Liquid Crystalline Based Nasal Spray for Improved Parkinson\u2019s Treatment: Enhanced Superior Nasal Tract Deposition and Antioxidation Strategy","volume":"35","author":"Xia","year":"2024","journal-title":"Adv. Funct. Mater."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sibinovska, N., \u017dakelj, S., Trontelj, J., and Kristan, K. (2022). Applicability of RPMI 2650 and Calu-3 Cell Models for Evaluation of Nasal Formulations. Pharmaceuticals, 14.","DOI":"10.3390\/pharmaceutics14020369"},{"key":"ref_30","unstructured":"U.S. Food and Drug Administration (2002). Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products\u2014Chemistry, Manufacturing, and Controls Documentation, FDA."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.4193\/RHINOL\/23.002","article-title":"Nasal cast deposition for xylo- and oxymetazoline formulations using two different nasal pumps","volume":"6","author":"Hagen","year":"2023","journal-title":"Rhinol. Online"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"053312","DOI":"10.1063\/5.0150890","article-title":"Primary spray breakup from a nasal spray atomizer using volume of fluid to discrete phase model","volume":"35","author":"Shrestha","year":"2023","journal-title":"Phys. Fluids"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1208\/s12249-018-1179-9","article-title":"Evaluation of Nasal Inlet Ports Having Simplified Geometry for the Pharmacopeial Assessment of Mass Fraction of Dose Likely to Penetrate Beyond the Nasopharynx: A Preliminary Investigation","volume":"19","author":"Williams","year":"2018","journal-title":"AAPS PharmSciTech"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"123341","DOI":"10.1016\/j.ijpharm.2023.123341","article-title":"Olfactory Drug Delivery with Intranasal Sprays after Nasal Midvault Reconstruction","volume":"644","author":"Chiang","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1208\/s12249-022-02278-w","article-title":"Spray Pattern and Plume Geometry Testing and Methodology: An IPAC-RS Working Group Overview","volume":"23","author":"Baxter","year":"2022","journal-title":"AAPS PharmSciTech"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.jconrel.2019.03.032","article-title":"Characterisation of nasal devices for delivery of insulin to the brain and evaluation in humans using functional magnetic resonance imaging","volume":"302","author":"Wingrove","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/S1808-8694(15)31386-0","article-title":"Nasal cavity geometry of healthy adults assessed using acoustic rhinometry","volume":"74","author":"Trindade","year":"2008","journal-title":"Braz. J. Otorhinolaryngol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.apsb.2023.06.007","article-title":"Visualization of nasal powder distribution using biomimetic human nasal cavity model","volume":"14","author":"Su","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jconrel.2023.12.054","article-title":"Nanotechnology for enhanced nose-to-brain drug delivery in treating neurological diseases","volume":"366","author":"Huang","year":"2024","journal-title":"J. Control. Release"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13195-020-00701-7","article-title":"Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers\u2014Results from the DELCODE study","volume":"12","author":"Sannemann","year":"2020","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s12974-023-02791-0","article-title":"The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice","volume":"20","author":"Li","year":"2023","journal-title":"J. Neuroinflammation"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/885\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:16:01Z","timestamp":1784693761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/885"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":41,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["pharmaceutics18070885"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18070885","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}