{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:34:41Z","timestamp":1782930881474,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development, and Innovation Office-NKFIH","award":["K146049"],"award-info":[{"award-number":["K146049"]}]},{"name":"National Research, Development, and Innovation Office-NKFIH","award":["TKP2021-EGA-32"],"award-info":[{"award-number":["TKP2021-EGA-32"]}]},{"name":"Ministry of Innovation and Technology (MIT) of Hungary from the National Research, Development and Innovation Fund (NRDIF)","award":["K146049"],"award-info":[{"award-number":["K146049"]}]},{"name":"Ministry of Innovation and Technology (MIT) of Hungary from the National Research, Development and Innovation Fund (NRDIF)","award":["TKP2021-EGA-32"],"award-info":[{"award-number":["TKP2021-EGA-32"]}]},{"name":"J\u00e1nos Bolyai Research Scholarship of the Hungarian Academy of Sciences","award":["K146049"],"award-info":[{"award-number":["K146049"]}]},{"name":"J\u00e1nos Bolyai Research Scholarship of the Hungarian Academy of Sciences","award":["TKP2021-EGA-32"],"award-info":[{"award-number":["TKP2021-EGA-32"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Encapsulation possibilities of an extensively investigated neuroprotective drug (kynurenic acid, KYNA) are studied via lipid-based nanocarriers to increase the blood\u2013brain barrier (BBB) specific permeability. The outcomes of various preparation conditions such as stirring and sonication time, concentration of the lipid carriers and the drug, and the drug-to-lipid ratio are examined. Considering the experimentally determined encapsulation efficiency, hydrodynamic diameter, and \u03b6-potential values, the initial lipid and drug concentration as well as the stirring and sonication time of the preparation were optimized. The average hydrodynamic diameter of the prepared asolectin-(LIP) and water-soluble lipopolymer (WSLP)-based liposomes was found to be ca. 25 and 60 nm under physiological conditions. The physicochemical characterization of the colloidal carriers proves that the preparation of the drug-loaded liposomes was a successful process, and secondary interactions were indicated between the drug molecule and the polymer residues around the WSLP membrane. Dissolution profiles of the active molecule under physiological conditions were registered, and the release of the unformulated and encapsulated drug is very similar. In addition to this outcome, the in vitro polar brain lipid extract (porcine)-based permeability test proved the achievement of two- or fourfold higher BBB specific penetration and lipid membrane retention for KYNA in the liposomal carriers relative to the unformatted drug.<\/jats:p>","DOI":"10.3390\/ijms241814251","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T02:26:17Z","timestamp":1695090377000},"page":"14251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Lipid-Based Nanocarriers for Delivery of Neuroprotective Kynurenic Acid: Preparation, Characterization, and BBB Transport"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0033-7968","authenticated-orcid":false,"given":"\u00c1d\u00e1m","family":"Juh\u00e1sz","sequence":"first","affiliation":[{"name":"Interdisciplinary Excellence Center, Department of Physical Chemistry and Materials Science, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary"},{"name":"MTA-SZTE Lend\u00fclet \u201cMomentum\u201d Noble Metal Nanostructures Research Group, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7659-0428","authenticated-orcid":false,"given":"Ditta","family":"Ungor","sequence":"additional","affiliation":[{"name":"MTA-SZTE Lend\u00fclet \u201cMomentum\u201d Noble Metal Nanostructures Research Group, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9667-6608","authenticated-orcid":false,"given":"Norbert","family":"Varga","sequence":"additional","affiliation":[{"name":"Interdisciplinary Excellence Center, Department of Physical Chemistry and Materials Science, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary"},{"name":"MTA-SZTE Lend\u00fclet \u201cMomentum\u201d Noble Metal Nanostructures Research Group, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-4813","authenticated-orcid":false,"given":"G\u00e1bor","family":"Katona","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, E\u00f6tv\u00f6s Str. 6, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy T.","family":"Balogh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Semmelweis University, H\u0151gyes Endre \u00fat 9, H-1092 Budapest, Hungary"},{"name":"Department of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics, M\u0171egyetem Rakpart 3, H-1111 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-9524","authenticated-orcid":false,"given":"Edit","family":"Csap\u00f3","sequence":"additional","affiliation":[{"name":"Interdisciplinary Excellence Center, Department of Physical Chemistry and Materials Science, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary"},{"name":"MTA-SZTE Lend\u00fclet \u201cMomentum\u201d Noble Metal Nanostructures Research Group, University of Szeged, Rerrich B. Sqr. 1, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1111\/cns.13768","article-title":"Kynurenic Acid in Neurodegenerative Disorders\u2014Unique Neuroprotection or Double-Edged Sword?","volume":"28","author":"Ostapiuk","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1474-4422(18)30456-3","article-title":"Statistics on the Burden of Dementia: Need for Stronger Data","volume":"18","author":"Launer","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.5535\/arm.22027","article-title":"Dementia Epidemiology Fact Sheet 2022","volume":"46","author":"Shin","year":"2022","journal-title":"Ann. Rehabil. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1586\/14737175.2015.1049999","article-title":"What Is the Tryptophan Kynurenine Pathway and Why Is It Important to Neurotherapeutics?","volume":"15","author":"Davis","year":"2015","journal-title":"Expert Rev. Neurother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/0006-8993(82)91048-4","article-title":"An Iontophoretic Investigation of the Actions of Convulsant Kynurenines and Their Interaction with the Endogenous Excitant Quinolinic Acid","volume":"247","author":"Perkins","year":"1982","journal-title":"Brain Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1111\/j.1471-4159.1991.tb03460.x","article-title":"Blood\u2013Brain Barrier Transport of Kynurenines: Implications for Brain Synthesis and Metabolism","volume":"56","author":"Fukui","year":"1991","journal-title":"J. Neurochem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jovanovic, F., Candido, K.D., and Knezevic, N.N. (2020). The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176045"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s10194-021-01239-1","article-title":"Clinical Relevance of Depressed Kynurenine Pathway in Episodic Migraine Patients: Potential Prognostic Markers in the Peripheral Plasma during the Interictal Period","volume":"22","author":"Tuka","year":"2021","journal-title":"J. Headache Pain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s00702-006-0545-z","article-title":"Kynurenine in Combination with Probenecid Mitigates the Stimulation-Induced Increase of c-Fos Immunoreactivity of the Rat Caudal Trigeminal Nucleus in an Experimental Migraine Model","volume":"114","author":"Toldi","year":"2007","journal-title":"J. Neural Transm."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sz\u0171cs, E., Stefanucci, A., Dimmito, M.P., Z\u00e1dor, F., Pieretti, S., Zengin, G., V\u00e9csei, L., Benyhe, S., Nalli, M., and Mollica, A. (2020). Discovery of Kynurenines Containing Oligopeptides as Potent Opioid Receptor Agonists. Biomolecules, 10.","DOI":"10.3390\/biom10020284"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00702-011-0755-x","article-title":"A Novel Kynurenic Acid Analog (SZR104) Inhibits Pentylenetetrazole-Induced Epileptiform Seizures. An Electrophysiological Study: Special Issue Related to Kynurenine","volume":"119","author":"Demeter","year":"2012","journal-title":"J. Neural Transm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41573-020-0090-8","article-title":"Engineering Precision Nanoparticles for Drug Delivery","volume":"20","author":"Mitchell","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Fam, S.Y., Chee, C.F., Yong, C.Y., Ho, K.L., Mariatulqabtiah, A.R., and Tan, W.S. (2020). Stealth Coating of Nanoparticles in Drug-Delivery Systems. Nanomaterials, 10.","DOI":"10.3390\/nano10040787"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"507178","DOI":"10.1155\/2014\/507178","article-title":"Preparation and Characterization of Kynurenic Acid Occluded in Sol-Gel Silica and Sba-15 Silica as Release Reservoirs","volume":"2014","author":"Ortiz","year":"2014","journal-title":"J. Nanomater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.clay.2018.01.024","article-title":"Anti-Ulcerant Kynurenic Acid Molecules Intercalated Mg\/Al-Layered Double Hydroxide and Its Release Study","volume":"156","year":"2018","journal-title":"Appl. Clay Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ejps.2016.02.012","article-title":"Targeting of the Kynurenic Acid across the Blood-Brain Barrier by Core-Shell Nanoparticles","volume":"86","author":"Varga","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"117047","DOI":"10.1016\/j.carbpol.2020.117047","article-title":"Serum Protein-Hyaluronic Acid Complex Nanocarriers: Structural Characterisation and Encapsulation Possibilities","volume":"251","author":"Varga","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.bioorg.2019.01.019","article-title":"Innovative Nano-Carriers in Anticancer Drug Delivery-a Comprehensive Review","volume":"85","author":"Dong","year":"2019","journal-title":"Bioorganic Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hsu, J.F., Chu, S.M., Liao, C.C., Wang, C.J., Wang, Y.S., Lai, M.Y., Wang, H.C., Huang, H.R., and Tsai, M.H. (2021). Nanotechnology and Nanocarrier-Based Drug Delivery as the Potential Therapeutic Strategy for Glioblastoma Multiforme: An Update. Cancers, 13.","DOI":"10.3390\/cancers13020195"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Alshawwa, S.Z., Kassem, A.A., Farid, R.M., Mostafa, S.K., and Labib, G.S. (2022). Nanocarrier Drug Delivery Systems: Characterization, Limitations, Future Perspectives and Implementation of Artificial Intelligence. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040883"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"975","DOI":"10.2147\/IJN.S68861","article-title":"Liposomes as Nanomedical Devices","volume":"10","author":"Bozzuto","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lombardo, D., and Kiselev, M.A. (2022). Methods of Liposomes Preparation: Formation and Control Factors of Versatile Nanocarriers for Biomedical and Nanomedicine Application. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030543"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Obuchi, H., and Toyota, T. (2023). A Practical Guide to Preparation and Applications of Giant Unilamellar Vesicles Formed via Centrifugation of Water-in-Oil Emulsion Droplets. Membranes, 13.","DOI":"10.3390\/membranes13040440"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1038\/s41467-022-29272-x","article-title":"Membrane Thickness, Lipid Phase and Sterol Type Are Determining Factors in the Permeability of Membranes to Small Solutes","volume":"13","author":"Frallicciardi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, P., Chen, G., and Zhang, J. (2022). A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives. Molecules, 27.","DOI":"10.3390\/molecules27041372"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6261","DOI":"10.2174\/0929867325666180530114534","article-title":"The Therapeutic Impact of New Migraine Discoveries","volume":"26","author":"Tajti","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Abd Elhameed, H.A.H., Ungor, D., Igaz, N., Gopisetty, M.K., Kiricsi, M., Csap\u00f3, E., and Gyurcsik, B. (2020). High Molecular Weight Poly(Ethylenimine)-Based Water-Soluble Lipopolymer for Transfection of Cancer Cells. Macromol. Biosci., 20.","DOI":"10.1002\/mabi.202000040"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.jcis.2022.07.025","article-title":"Transport of Cationic Liposomes in a Human Blood Brain Barrier Model: Role of the Stereochemistry of the Gemini Amphiphile on Liposome Biological Features","volume":"627","author":"Simonis","year":"2022","journal-title":"J. Colloid Interface Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jphotochem.2018.07.029","article-title":"Acid-Alkaline Properties of Triplet State and Radical of Kynurenic Acid","volume":"365","author":"Zhuravleva","year":"2018","journal-title":"J. Photochem. Photobiol. A Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pereira-Leite, C., Figueiredo, M., Burdach, K., Nunes, C., and Reis, S. (2020). Unraveling the Role of Drug-Lipid Interactions in NSAIDs-Induced Cardiotoxicity. Membranes, 11.","DOI":"10.3390\/membranes11010024"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12615","DOI":"10.1021\/jp206013z","article-title":"Lipid-Drug Interaction: Biophysical Effects of Tolmetin on Membrane Mimetic Systems of Different Dimensionality","volume":"115","author":"Nunes","year":"2011","journal-title":"J. Phys. Chem. B"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10529-020-03054-1","article-title":"Surfactants: Physicochemical Interactions with Biological Macromolecules","volume":"43","author":"Banat","year":"2021","journal-title":"Biotechnol. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.tibs.2012.11.005","article-title":"Detergent Solubilization of Lipid Bilayers: A Balance of Driving Forces","volume":"38","author":"Lichtenberg","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Corsaro, C., Neri, G., Mezzasalma, A.M., and Fazio, E. (2021). Weibull Modeling of Controlled Drug Release from Ag-PMA Nanosystems. Polymers, 13.","DOI":"10.3390\/polym13172897"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105026","DOI":"10.1016\/j.ejps.2019.105026","article-title":"Interpreting Non-Linear Drug Diffusion Data: Utilizing Korsmeyer-Peppas Model to Study Drug Release from Liposomes","volume":"138","author":"Wu","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ijpharm.2011.03.051","article-title":"Higuchi Equation: Derivation, Applications, Use and Misuse","volume":"418","author":"Siepmann","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhu, W., Long, J., and Shi, M. (2023). Release Kinetics Model Fitting of Drugs with Different Structures from Viscose Fabric. Materials, 16.","DOI":"10.3390\/ma16083282"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/1010-6030(93)85084-L","article-title":"Comparative Photophysical Study of Rose Bengal, Eosin Y and Their Monomethyl and Dimethyl Derivatives","volume":"72","year":"1993","journal-title":"J. Photochem. Photobiol. A Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/sj.gt.3301938","article-title":"Water-Soluble Lipopolymer as an Efficient Carrier for Gene Delivery to Myocardium","volume":"10","author":"Lee","year":"2003","journal-title":"Gene Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"115405","DOI":"10.1016\/j.molliq.2021.115405","article-title":"Spreadsheet-Based Nonlinear Analysis of in Vitro Release Properties of a Model Drug from Colloidal Carriers","volume":"328","author":"Ungor","year":"2021","journal-title":"J. Mol. Liq."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"118614","DOI":"10.1016\/j.molliq.2022.118614","article-title":"Albumin-Hyaluronic Acid Colloidal Nanocarriers: Effect of Human and Bovine Serum Albumin for Intestinal Ibuprofen Release Enhancement","volume":"351","author":"Katona","year":"2022","journal-title":"J. Mol. Liq."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/marc.200900630","article-title":"Cross-Linked Multilayers of Poly(Vinyl Amine) as a Single Component and Their Interaction with Proteins","volume":"31","author":"Dragan","year":"2010","journal-title":"Macromol. Rapid Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1007\/s002160100897","article-title":"Determination of Electrokinetic Charge with a Particle-Charge Detector, and Its Relationship to the Total Charge","volume":"371","author":"Fischer","year":"2001","journal-title":"Fresenius\u2019 J. Anal. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s10973-012-2310-x","article-title":"A Microcalorimetric Titration Study on the Micelle Formation of Alkanediyl-\u03b1,\u03c9-Bis(Dimethylalkylammonium Bromide) Surfactants at a 283.15\u2013343.15 K Temperature Range","volume":"110","author":"Piekarski","year":"2012","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15628","DOI":"10.1002\/chem.201704205","article-title":"Palladium-Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis of a Trifluoro Analogue of Sildenafil","volume":"23","author":"Zwillinger","year":"2017","journal-title":"Chem.-A Eur. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:53:16Z","timestamp":1760129596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,18]]},"references-count":45,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241814251"],"URL":"https:\/\/doi.org\/10.3390\/ijms241814251","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,18]]}}}