{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T18:40:34Z","timestamp":1764873634520,"version":"build-2065373602"},"reference-count":77,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T00:00:00Z","timestamp":1562889600000},"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>The current pharmacological treatments for Parkinson\u2019s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 \u00b1 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC\/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC\/D3 cells was also observed, and their permeation across Caco-2 and hCMEC\/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls.<\/jats:p>","DOI":"10.3390\/pharmaceutics11070331","type":"journal-article","created":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T11:49:38Z","timestamp":1562932178000},"page":"331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Boosting Drug Discovery for Parkinson\u2019s: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles"],"prefix":"10.3390","volume":"11","author":[{"given":"Miguel","family":"Pinto","sequence":"first","affiliation":[{"name":"CIQUP, Departmento de Qu\u00edmica e Bioqu\u00edmica, Centro de Investiga\u00e7\u00e3o em Qu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0102-0703","authenticated-orcid":false,"given":"Carlos","family":"Fernandes","sequence":"additional","affiliation":[{"name":"CIQUP, Departmento de Qu\u00edmica e Bioqu\u00edmica, Centro de Investiga\u00e7\u00e3o em Qu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-562X","authenticated-orcid":false,"given":"Eva","family":"Martins","sequence":"additional","affiliation":[{"name":"UCIBIO-REQUIMTE, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9962-7548","authenticated-orcid":false,"given":"Renata","family":"Silva","sequence":"additional","affiliation":[{"name":"UCIBIO-REQUIMTE, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Sofia","family":"Benfeito","sequence":"additional","affiliation":[{"name":"CIQUP, Departmento de Qu\u00edmica e Bioqu\u00edmica, Centro de Investiga\u00e7\u00e3o em Qu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9410-6874","authenticated-orcid":false,"given":"Fernando","family":"Cagide","sequence":"additional","affiliation":[{"name":"CIQUP, Departmento de Qu\u00edmica e Bioqu\u00edmica, Centro de Investiga\u00e7\u00e3o em Qu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8242-324X","authenticated-orcid":false,"given":"Ricardo F.","family":"Mendes","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, CICECO-Instituto de Materiais de Aveiro, Universidade de Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2051-5645","authenticated-orcid":false,"given":"Filipe A.","family":"Almeida Paz","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, CICECO-Instituto de Materiais de Aveiro, Universidade de Aveiro, 3810-193 Aveiro, Portugal"}]},{"given":"Jorge","family":"Garrido","sequence":"additional","affiliation":[{"name":"Departamento de Engenharia Qu\u00edmica, Instituto Superior de Engenharia do Porto (ISEP), Instituto Polit\u00e9cnico do Porto, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO-REQUIMTE, Laborat\u00f3rio de Toxicologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1050-2402","authenticated-orcid":false,"given":"Fernanda","family":"Borges","sequence":"additional","affiliation":[{"name":"CIQUP, Departmento de Qu\u00edmica e Bioqu\u00edmica, Centro de Investiga\u00e7\u00e3o em Qu\u00edmica, Faculdade de Ci\u00eancias, Universidade do Porto, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1126\/science.1067122","article-title":"Toxic Proteins in Neurodegenerative Disease","volume":"296","author":"Taylor","year":"2002","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/35040009","article-title":"Apoptosis in neurodegenerative disorders","volume":"1","author":"Mattson","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.ijpharm.2012.09.024","article-title":"Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson\u2019s disease","volume":"438","author":"Barcia","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"a008870","DOI":"10.1101\/cshperspect.a008870","article-title":"Clinical Approach to Parkinson\u2019s disease: Features, Diagnosis, and Principles of Management","volume":"2","author":"Massano","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5879","DOI":"10.1021\/acs.jmedchem.6b00527","article-title":"Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors","volume":"59","author":"Reis","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4960","DOI":"10.1021\/cr400265z","article-title":"Chromone: A Valid Scaffold in Medicinal Chemistry","volume":"114","author":"Gaspar","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7941","DOI":"10.1021\/acs.jmedchem.6b01720","article-title":"Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances","volume":"60","author":"Reis","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"39557","DOI":"10.1021\/acsami.8b17224","article-title":"PEGylated PLGA Nanoparticles As a Smart Carrier to Increase the Cellular Uptake of a Coumarin-Based Monoamine Oxidase B Inhibitor","volume":"10","author":"Fernandes","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_9","unstructured":"Molinspiration (2017, March 02). Molinspiration Cheminformatics. Available online: http:\/\/www.molinspiration.com."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.yexmp.2008.12.004","article-title":"Nanoparticle-based targeted drug delivery","volume":"86","author":"Singh","year":"2009","journal-title":"Exp. Mol. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ekladious, I., Colson, Y.L., and Grinstaff, M.W. (2018). Polymer\u2013drug conjugate therapeutics: Advances, insights and prospects. Nat. Rev. Drug Discov.","DOI":"10.1038\/s41573-018-0005-0"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1016\/j.actbio.2011.07.025","article-title":"Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: In vitro and in vivo studies","volume":"7","author":"Seju","year":"2011","journal-title":"Acta Biomater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1007\/s11671-009-9431-6","article-title":"A Novel Docetaxel-Loaded Poly (\u03b5-Caprolactone)\/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment","volume":"4","author":"Mei","year":"2009","journal-title":"Nanoscale Res. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1126\/scitranslmed.3003594","article-title":"A Dense Poly (Ethylene Glycol) Coating Improves Penetration of Large Polymeric Nanoparticles Within Brain Tissue","volume":"4","author":"Nance","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1023\/A:1010931127745","article-title":"Long-Circulating PEGylated Polycyanoacrylate Nanoparticles as New Drug Carrier for Brain Delivery","volume":"18","author":"Calvo","year":"2001","journal-title":"Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jsps.2017.10.012","article-title":"Applications of nanoparticle systems in drug delivery technology","volume":"26","author":"Rizvi","year":"2018","journal-title":"Saudi Pharm. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.addr.2015.09.012","article-title":"PEGylation as a strategy for improving nanoparticle-based drug and gene delivery","volume":"99","author":"Suk","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.brainres.2008.01.039","article-title":"Poly(n-butylcyanoacrylate) nanoparticles coated with polysorbate 80 for the targeted delivery of rivastigmine into the brain to treat Alzheimer\u2019s disease","volume":"1200","author":"Wilson","year":"2008","journal-title":"Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ejpb.2008.03.009","article-title":"Targeted delivery of tacrine into the brain with polysorbate 80-coated poly(n-butylcyanoacrylate) nanoparticles","volume":"70","author":"Wilson","year":"2008","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_20","first-page":"2679","article-title":"Novel docetaxel-loaded nanoparticles based on PCL-Tween 80 copolymer for cancer treatment","volume":"6","author":"Ma","year":"2011","journal-title":"Int. J. Nanomed."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1080\/10611860903112842","article-title":"Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles","volume":"17","author":"Kurakhmaeva","year":"2009","journal-title":"J. Drug Target."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2012.05.015","article-title":"Polysorbate 80 coated poly (\u025b-caprolactone)\u2013poly (ethylene glycol)\u2013poly (\u025b-caprolactone) micelles for paclitaxel delivery","volume":"434","author":"Wang","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jconrel.2016.05.044","article-title":"Nanoparticle-mediated brain drug delivery: Overcoming blood\u2013brain barrier to treat neurodegenerative diseases","volume":"235","author":"Saraiva","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.ijpharm.2011.01.015","article-title":"Selegiline-functionalized, PEGylated poly(alkyl cyanoacrylate) nanoparticles: Investigation of interaction with amyloid-\u03b2 peptide and surface reorganization","volume":"416","author":"Souguir","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s11481-016-9685-6","article-title":"Tailoring Lipid and Polymeric Nanoparticles as siRNA Carriers towards the Blood-Brain Barrier\u2014From Targeting to Safe Administration","volume":"12","author":"Gomes","year":"2017","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1021\/bm901371p","article-title":"Synthesis, Self-Assembly, and Drug-Loading Capacity of Well-Defined Cyclodextrin-Centered Drug-Conjugated Amphiphilic A14B7 Miktoarm Star Copolymers Based on Poly(\u03b5-caprolactone) and Poly(ethylene glycol)","volume":"11","author":"Gou","year":"2010","journal-title":"Biomacromolecules"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8867","DOI":"10.1038\/srep08867","article-title":"Cascade exciton-pumping engines with manipulated speed and efficiency in light-harvesting porous \u03c0-network films","volume":"5","author":"Gu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6842","DOI":"10.1038\/s41598-017-07272-y","article-title":"Development of hydroxybenzoic-based platforms as a solution to deliver dietary antioxidants to mitochondria","volume":"7","author":"Teixeira","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.tiv.2013.12.006","article-title":"Inhibition of monoamine oxidase (MAO) by \u03b2-carbolines and their interactions in live neuronal (PC12) and liver (HuH-7 and MH1C1) cells","volume":"28","author":"Santillo","year":"2014","journal-title":"Toxicol. In Vitro"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1517\/17425255.1.2.175","article-title":"Caco-2 cell permeability assays to measure drug absorption","volume":"1","author":"Li","year":"2005","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jouan, E., Le V\u00e9e, M., Mayati, A., Denizot, C., Parmentier, Y., and Fardel, O. (2016). Evaluation of P-Glycoprotein Inhibitory Potential Using a Rhodamine 123 Accumulation Assay. Pharmaceutics, 8.","DOI":"10.3390\/pharmaceutics8020012"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"971","DOI":"10.2147\/IJN.S39532","article-title":"Preparation, characterization and application of star-shaped PCL\/PEG micelles for the delivery of doxorubicin in the treatment of colon cancer","volume":"8","author":"Gao","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1021\/bm400161g","article-title":"Y-Shaped mPEG-PLA Cabazitaxel Conjugates: Well-Controlled Synthesis by Organocatalytic Approach and Self-Assembly into Interface Drug-Loaded Core-Corona Nanoparticles","volume":"14","author":"Bensaid","year":"2013","journal-title":"Biomacromolecules"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0378-5173(98)00381-0","article-title":"Flurbiprofen-loaded nanospheres: Analysis of the matrix structure by thermal methods","volume":"179","author":"Gamisans","year":"1999","journal-title":"Int. J. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1021\/js950474+","article-title":"Comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules, and nanoemulsions, as ocular drug carriers","volume":"85","author":"Calvo","year":"1996","journal-title":"J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"22877","DOI":"10.1038\/srep22877","article-title":"Characterization of organic matter of plants from lakes by thermal analysis in a N2 atmosphere","volume":"6","author":"Guo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1016\/j.actbio.2009.11.035","article-title":"A novel paclitaxel-loaded poly (\u03b5-caprolactone)\/Poloxamer 188 blend nanoparticle overcoming multidrug resistance for cancer treatment","volume":"6","author":"Zhang","year":"2010","journal-title":"Acta Biomater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.colsurfb.2016.04.054","article-title":"PEGylated PLGA nanospheres optimized by design of experiments for ocular administration of dexibuprofen-in vitro, ex vivo and in vivo characterization","volume":"145","author":"Egea","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1002\/jps.20094","article-title":"Solid-state solubility influences encapsulation and release of hydrophobic drugs from PLGA\/PLA nanoparticles","volume":"93","author":"Panyam","year":"2004","journal-title":"J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0168-3659(99)00253-9","article-title":"The preparation and evaluation of poly (\u03f5-caprolactone) microparticles containing both a lipophilic and a hydrophilic drug","volume":"65","author":"Zinutti","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.msec.2015.08.062","article-title":"Synthesis and characterization of the antitubercular phenazine lapazine and development of PLGA and PCL nanoparticles for its entrapment","volume":"58","author":"Silveira","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.msec.2013.12.024","article-title":"Aceclofenac microspheres: Quality by design approach","volume":"36","author":"Deshmukh","year":"2014","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1021\/mp300452g","article-title":"Formation of Stable Nanocarriers by in Situ Ion Pairing during Block-Copolymer-Directed Rapid Precipitation","volume":"10","author":"Pinkerton","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1007\/s11095-013-1025-4","article-title":"Brain Delivery of NAP with PEG-PLGA Nanoparticles Modified with Phage Display Peptides","volume":"30","author":"Li","year":"2013","journal-title":"Pharm. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1039\/C3NR04878K","article-title":"Transport of nanoparticles through the blood-brain barrier for imaging and therapeutic applications","volume":"6","author":"Shilo","year":"2014","journal-title":"Nanoscale"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Massella, D., Celasco, E., Sala\u00fcn, F., Ferri, A., and Barresi, A. (2018). Overcoming the Limits of Flash Nanoprecipitation: Effective Loading of Hydrophilic Drug into Polymeric Nanoparticles with Controlled Structure. Polymers, 10.","DOI":"10.3390\/polym10101092"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jconrel.2015.06.002","article-title":"PLGA nanoparticles prepared by nano-emulsion templating using low-energy methods as efficient nanocarriers for drug delivery across the blood\u2013brain barrier","volume":"211","author":"Fornaguera","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Pfeiffer, C., Rehbock, C., H\u00fchn, D., Carrillo-Carrion, C., de Aberasturi, D.J., Merk, V., Barcikowski, S., and Parak, W.J. (2014). Interaction of colloidal nanoparticles with their local environment: The (ionic) nanoenvironment around nanoparticles is different from bulk and determines the physico-chemical properties of the nanoparticles. J. R. Soc. Interface, 11.","DOI":"10.1098\/rsif.2013.0931"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3871","DOI":"10.1021\/mp400342f","article-title":"Resveratrol-Loaded Nanoparticles Based on Poly(epsilon-caprolactone) and Poly(d,l-lactic-co-glycolic acid)\u2013Poly(ethylene glycol) Blend for Prostate Cancer Treatment","volume":"10","author":"Sanna","year":"2013","journal-title":"Mol. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1021\/acs.chemrev.5b00346","article-title":"Degradable Controlled-Release Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release","volume":"116","author":"Kamaly","year":"2016","journal-title":"Chem. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejpb.2006.12.014","article-title":"Swelling and erosion of pectin matrix tablets and their impact on drug release behavior","volume":"67","author":"Sriamornsak","year":"2007","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5607\/en.2011.20.1.1","article-title":"MAO-inhibitors in Parkinson\u2019s disease","volume":"20","author":"Riederer","year":"2011","journal-title":"Exp. Neurobiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1016\/j.freeradbiomed.2011.08.030","article-title":"Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress","volume":"51","author":"Schneider","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.brainres.2010.03.102","article-title":"Comparison between proliferative and neuron-like SH-SY5Y cells as an in vitro model for Parkinson disease studies","volume":"1337","author":"Lopes","year":"2010","journal-title":"Brain Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10899","DOI":"10.1021\/acs.jafc.7b03627","article-title":"Release Properties and Cellular Uptake in Caco-2 Cells of Size-Controlled Chitosan Nanoparticles","volume":"65","author":"Je","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s10534-017-0030-1","article-title":"Iron modulates the activity of monoamine oxidase B in SH-SY5Y cells","volume":"30","author":"Lu","year":"2017","journal-title":"BioMetals"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1021\/mp200129p","article-title":"Transcriptomic and Quantitative Proteomic Analysis of Transporters and Drug Metabolizing Enzymes in Freshly Isolated Human Brain Microvessels","volume":"8","author":"Shawahna","year":"2011","journal-title":"Mol. Pharm."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3109\/1061186X.2011.589435","article-title":"Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers","volume":"19","author":"Geldenhuys","year":"2011","journal-title":"J. Drug Target."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1517\/17460441.2015.974545","article-title":"Blood\u2013brain barrier models: In vitro to in vivo translation in preclinical development of CNS-targeting biotherapeutics","volume":"10","author":"Stanimirovic","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3389\/fnmol.2018.00166","article-title":"Comparison of a Rat Primary Cell-Based Blood-Brain Barrier Model with Epithelial and Brain Endothelial Cell Lines: Gene Expression and Drug Transport","volume":"11","author":"Veszelka","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0169-409X(00)00128-9","article-title":"Caco-2 monolayers in experimental and theoretical predictions of drug transport1PII of original article: S0169-409X(96)00415-2. The article was originally published in Advanced Drug Delivery Reviews 22 (1996) 67\u201384.1","volume":"46","author":"Artursson","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2045-8118-10-16","article-title":"The hCMEC\/D3 cell line as a model of the human blood brain barrier","volume":"10","author":"Weksler","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1021\/acs.bioconjchem.8b00151","article-title":"Development of a PEGylated-Based Platform for Efficient Delivery of Dietary Antioxidants Across the Blood\u2013Brain Barrier","volume":"29","author":"Fernandes","year":"2018","journal-title":"Bioconj. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrd3187","article-title":"Coexistence of passive and carrier-mediated processes in drug transport","volume":"9","author":"Sugano","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1016\/j.biomaterials.2004.07.050","article-title":"Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs","volume":"26","author":"Win","year":"2005","journal-title":"Biomaterials"},{"key":"ref_66","first-page":"2191","article-title":"Parameters and characteristics governing cellular internalization and trans-barrier trafficking of nanostructures","volume":"10","author":"Murugan","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.bbamem.2008.09.016","article-title":"Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery","volume":"1788","author":"Deli","year":"2009","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3109\/03639045.2012.758130","article-title":"Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting","volume":"40","author":"Ali","year":"2014","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"8508","DOI":"10.1039\/C5TB01425E","article-title":"A poly-l-glutamic acid functionalized nanocomplex for improved oral drug absorption","volume":"3","author":"Zhu","year":"2015","journal-title":"J. Mater. Chem. B"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1111\/j.1471-4159.2008.05730.x","article-title":"The human brain endothelial cell line hCMEC\/D3 as a human blood-brain barrier model for drug transport studies","volume":"107","author":"Poller","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4137\/DTI.S12519","article-title":"P-glycoprotein Inhibition for Optimal Drug Delivery","volume":"7","author":"Amin","year":"2013","journal-title":"Drug Target Insights"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1007\/s11095-007-9347-8","article-title":"Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps","volume":"25","author":"Werle","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ijpharm.2006.01.020","article-title":"Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies","volume":"313","author":"Shen","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_74","first-page":"297","article-title":"The solvents Cremophor EL and Tween 80 modulate daunorubicin resistance in the multidrug resistant Ehrlich ascites tumor","volume":"2","author":"Friche","year":"1990","journal-title":"Cancer Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1002\/jps.10175","article-title":"Effects of Poly(ethylene glycol) on Efflux Transporter Activity in Caco-2 Cell Monolayers","volume":"91","author":"Hugger","year":"2002","journal-title":"J. Pharm. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejpb.2015.11.019","article-title":"Novel in vitro transport method for screening the reversibility of P-glycoprotein inhibitors","volume":"100","author":"Netsomboon","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_77","first-page":"445","article-title":"Enhanced brain targeting of temozolomide in polysorbate-80 coated polybutylcyanoacrylate nanoparticles","volume":"6","author":"Tian","year":"2011","journal-title":"Int. J. Nanomed."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/7\/331\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:05:02Z","timestamp":1760187902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/7\/331"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,12]]},"references-count":77,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["pharmaceutics11070331"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11070331","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2019,7,12]]}}}