{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:38:47Z","timestamp":1790908727907,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"School of Pharmacy, Rutgers, the State University of New Jersey"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a \u201ctriple-drug therapy\u201d in treating Alzheimer\u2019s disease (AD). Female APP\/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP\/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (A\u03b2) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer\u2019s disease treatment and nose-to-brain delivery.<\/jats:p>","DOI":"10.3390\/ijms251910357","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T06:55:52Z","timestamp":1727333752000},"page":"10357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer\u2019s Disease Therapy"],"prefix":"10.3390","volume":"25","author":[{"given":"David","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milin","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga B.","family":"Garbuzenko","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1633-4705","authenticated-orcid":false,"given":"Tamara","family":"Minko","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA"},{"name":"Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA"},{"name":"Environmental and Occupational Health Science Institute, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.7150\/ijbs.57078","article-title":"Interaction between A\u03b2 and Tau in the Pathogenesis of Alzheimer\u2019s Disease","volume":"17","author":"Zhang","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13195-017-0307-1","article-title":"Gene suppression approaches to neurodegeneration","volume":"9","author":"Ghosh","year":"2017","journal-title":"Alzheimers Res. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"119129","DOI":"10.1016\/j.lfs.2021.119129","article-title":"A review on advances of treatment modalities for Alzheimer\u2019s disease","volume":"276","author":"Fauzi","year":"2021","journal-title":"Life Sci."},{"key":"ref_5","unstructured":"Kuns, B., Rosani, A., Patel, P., and Varghese, D. (2024). Memantine. StatPearls, StatPearls Publishing."},{"key":"ref_6","unstructured":"Kumar, A., Gupta, V., and Sharma, S. (2024). Donepezil. StatPearls, StatPearls Publishing."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.tibtech.2018.01.006","article-title":"Nanotechnology-Based Strategies for siRNA Brain Delivery for Disease Therapy","volume":"36","author":"Zheng","year":"2018","journal-title":"Trends Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jconrel.2018.04.034","article-title":"Systemic delivery of BACE1 siRNA through neuron-targeted nanocomplexes for treatment of Alzheimer\u2019s disease","volume":"279","author":"Wang","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"123727","DOI":"10.1016\/j.ijpharm.2023.123727","article-title":"Knockdown of BACE1 by a multistage brain-targeting polyion complex improved memory and learning behaviors in APP\/PS1 transgenic mouse model","volume":"650","author":"Jia","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1021\/bc8000722","article-title":"Surface-modified and internally cationic polyamidoamine dendrimers for efficient siRNA delivery","volume":"19","author":"Patil","year":"2008","journal-title":"Bioconjug. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1021\/nn102711d","article-title":"Multifunctional triblock Nanocarrier (PAMAM-PEG-PLL) for the efficient intracellular siRNA delivery and gene silencing","volume":"5","author":"Patil","year":"2011","journal-title":"ACS Nano"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jconrel.2009.06.019","article-title":"Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery","volume":"140","author":"Taratula","year":"2009","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sajid, M.I., Moazzam, M., Kato, S., Yeseom Cho, K., and Tiwari, R.K. (2020). Overcoming Barriers for siRNA Therapeutics: From Bench to Bedside. Pharmaceuticals, 13.","DOI":"10.3390\/ph13100294"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wong, A.D., Ye, M., Levy, A.F., Rothstein, J.D., Bergles, D.E., and Searson, P.C. (2013). The blood-brain barrier: An engineering perspective. Front. Neuroeng., 6.","DOI":"10.3389\/fneng.2013.00007"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1007\/s11095-007-9374-5","article-title":"Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development","volume":"24","author":"Ohtsuki","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pulgar, V.M. (2018). Transcytosis to Cross the Blood Brain Barrier, New Advancements and Challenges. Front. Neurosci., 12.","DOI":"10.3389\/fnins.2018.01019"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"288","DOI":"10.18433\/J3NC79","article-title":"Intranasal drug delivery: How, why and what for?","volume":"12","author":"Pires","year":"2009","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sonvico, F., Clementino, A., Buttini, F., Colombo, G., Pescina, S., Stanis\u00e7uaski Guterres, S., Raffin Pohlmann, A., and Nicoli, S. (2018). Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting. Pharmaceutics, 10.","DOI":"10.20944\/preprints201802.0077.v1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12989-019-0290-8","article-title":"Correlation of regional deposition dosage for inhaled nanoparticles in human and rat olfactory","volume":"16","author":"Tian","year":"2019","journal-title":"Part. Fibre Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lee, D., and Minko, T. (2021). Nanotherapeutics for Nose-to-Brain Drug Delivery: An Approach to Bypass the Blood Brain Barrier. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122049"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate, C., Yen, F.T., and Arab-Tehrany, E. (2022). Alzheimer\u2019s Disease: Treatment Strategies and Their Limitations. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213954"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hong, S.S., Oh, K.T., Choi, H.G., and Lim, S.J. (2019). Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11100540"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3632","DOI":"10.1073\/pnas.0205689101","article-title":"Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer\u2019s disease patients","volume":"101","author":"Li","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s43856-024-00527-6","article-title":"Combined use of Donepezil and Memantine increases the probability of five-year survival of Alzheimer\u2019s disease patients","volume":"4","author":"Yaghmaei","year":"2024","journal-title":"Commun. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2311670","DOI":"10.1002\/smll.202311670","article-title":"Multifunctional Liposomes Targeting Amyloid-beta Oligomers for Early Diagnosis and Therapy of Alzheimer\u2019s Disease","volume":"20","author":"Senapati","year":"2024","journal-title":"Small"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jconrel.2024.06.005","article-title":"PEG length effect of peptide-functional liposome for blood brain barrier (BBB) penetration and brain targeting","volume":"372","author":"Du","year":"2024","journal-title":"J. Control. Release"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3109\/10717544.2013.838713","article-title":"Insights into direct nose to brain delivery: Current status and future perspective","volume":"21","author":"Mittal","year":"2014","journal-title":"Drug Deliv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1166\/jbn.2019.2724","article-title":"The Trigeminal Pathway Dominates the Nose-to-Brain Transportation of Intact Polymeric Nanoparticles: Evidence from Aggregation-Caused Quenching Probes","volume":"15","author":"Li","year":"2019","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.ijpharm.2017.07.077","article-title":"Enhancement of nose-to-brain delivery of hydrophilic macromolecules with stearate- or polyethylene glycol-modified arginine-rich peptide","volume":"530","author":"Kanazawa","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.jconrel.2022.03.017","article-title":"Nose-to-brain\/spinal cord delivery kinetics of liposomes with different surface properties","volume":"344","author":"Kurano","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1007\/s11095-013-1280-4","article-title":"Development of 2D and 3D mucus models and their interactions with mucus-penetrating paclitaxel-loaded lipid nanocapsules","volume":"31","author":"Groo","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"De Martini, L.B., Sulmona, C., Brambilla, L., and Rossi, D. (2023). Cell-Penetrating Peptides as Valuable Tools for Nose-to-Brain Delivery of Biological Drugs. Cells, 12.","DOI":"10.3390\/cells12121643"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jconrel.2020.03.009","article-title":"Clearance of two organic nanoparticles from the brain via the paravascular pathway","volume":"322","author":"Gu","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Bacyinski, A., Xu, M., Wang, W., and Hu, J. (2017). The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy. Front. Neuroanat., 11.","DOI":"10.3389\/fnana.2017.00101"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.neuroscience.2015.01.058","article-title":"Donepezil improves learning and memory deficits in APP\/PS1 mice by inhibition of microglial activation","volume":"290","author":"Guo","year":"2015","journal-title":"Neuroscience"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/jnr.22172","article-title":"Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP\/PS1 transgenic mice","volume":"88","author":"Alley","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"eabc7031","DOI":"10.1126\/sciadv.abc7031","article-title":"Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer\u2019s disease therapy","volume":"6","author":"Zhou","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"773","DOI":"10.3233\/JAD-170786","article-title":"Medical Comorbidity in Alzheimer\u2019s Disease: A Nested Case-Control Study","volume":"63","author":"Wang","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Maigler, F., Ladel, S., Flamm, J., G\u00e4nger, S., Kurpiers, B., Kiderlen, S., V\u00f6lk, R., Hamp, C., Hartung, S., and Spiegel, S. (2021). Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111904"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1208\/s12248-024-00967-x","article-title":"Liposomal Formulations of Anti-Alzheimer Drugs and siRNA for Nose-to-Brain Delivery: Design, Safety and Efficacy In Vitro","volume":"26","author":"Lee","year":"2024","journal-title":"AAPS J."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Prieur, E.A.K., and Jadavji, N.M. (2019). Assessing Spatial Working Memory Using the Spontaneous Alternation Y-maze Test in Aged Male Mice. Bio-Protoc., 9.","DOI":"10.21769\/BioProtoc.3162"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Kim, H.Y., Kim, H.V., Lee, D.K., Yang, S.-H., and Kim, Y. (2016). Rapid and sustained cognitive recovery in APP\/PS1 transgenic mice by co-administration of EPPS and donepezil. Sci. Rep., 6.","DOI":"10.1038\/srep34165"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13041-019-0495-7","article-title":"Minor ginsenoside F1 improves memory in APP\/PS1 mice","volume":"12","author":"Han","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_44","first-page":"e55523","article-title":"Assessment of Spontaneous Alternation, Novel Object Recognition and Limb Clasping in Transgenic Mouse Models of Amyloid-\u03b2 and Tau Neuropathology","volume":"123","author":"Miedel","year":"2017","journal-title":"J. Vis. Exp."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10357\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:03:36Z","timestamp":1760112216000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,26]]},"references-count":44,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910357"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910357","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,26]]}}}