{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:42:19Z","timestamp":1788910939330,"version":"build-2803163510"},"reference-count":87,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drug Deliv. and Transl. Res."],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco\u2009-2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone\/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (\u2248\u00a020\u201330%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s13346-021-00920-x","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T18:10:57Z","timestamp":1613067057000},"page":"524-545","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["A nanoemulsion\/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin"],"prefix":"10.1007","volume":"11","author":[{"given":"Irene","family":"Santalices","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"V\u00e1zquez-V\u00e1zquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel J.","family":"Santander-Ortega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Lozano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisca","family":"Ara\u00fajo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Sarmento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Shrestha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Pr\u00e9at","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Chenlo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara V.","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Benetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Cu\u00f1arro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulay","family":"Tovar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Torres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7187-9567","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"920_CR1","doi-asserted-by":"publisher","unstructured":"Usmani SS, Bedi\u00a0G, Samuel JS, Singh S, Kalra S, Kumar P, Ahuja AA, Sharma M, Gautam A, Raghava GPS. THPdb: Database of FDA-approved peptide and protein therapeutics, PLoS One. 2017;12 . https:\/\/doi.org\/10.1371\/journal.pone.0181748.","DOI":"10.1371\/journal.pone.0181748"},{"key":"920_CR2","doi-asserted-by":"publisher","first-page":"2700","DOI":"10.1016\/j.bmc.2017.06.052","volume":"26","author":"JL Lau","year":"2018","unstructured":"Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorganic Med Chem. 2018;26:2700\u20137. https:\/\/doi.org\/10.1016\/j.bmc.2017.06.052.","journal-title":"Bioorganic Med Chem"},{"key":"920_CR3","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/nrd.2018.183","volume":"18","author":"AC Anselmo","year":"2019","unstructured":"Anselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strategies for biologics. Nat Rev Drug Discov. 2019;18:19\u201340. https:\/\/doi.org\/10.1038\/nrd.2018.183.","journal-title":"Nat Rev Drug Discov"},{"key":"920_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/adma.201901935","volume":"1901935","author":"M Dur\u00e1n-Lobato","year":"2019","unstructured":"Dur\u00e1n-Lobato M, Niu Z, Alonso MJ. Oral delivery of biologics for precision medicine. Adv Mater. 2019;1901935:1\u201327. https:\/\/doi.org\/10.1002\/adma.201901935.","journal-title":"Adv Mater"},{"key":"920_CR5","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.addr.2016.02.004","volume":"106","author":"TAS Aguirre","year":"2016","unstructured":"Aguirre TAS, Teijeiro-Osorio D, Rosa M, Coulter IS, Alonso MJ, Brayden DJ. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv Drug Deliv Rev. 2016;106:223\u201341. https:\/\/doi.org\/10.1016\/j.addr.2016.02.004.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR6","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/s41573-019-0053-0","volume":"19","author":"DJ Drucker","year":"2020","unstructured":"Drucker DJ. Advances in oral peptide therapeutics. Nat Rev Drug Discov. 2020;19:277\u201389. https:\/\/doi.org\/10.1038\/s41573-019-0053-0.","journal-title":"Nat Rev Drug Discov"},{"key":"920_CR7","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.addr.2016.10.005","volume":"106","author":"DJ Brayden","year":"2016","unstructured":"Brayden DJ, Alonso MJ. Oral delivery of peptides: opportunities and issues for translation. Adv Drug Deliv Rev. 2016;106:193\u20135. https:\/\/doi.org\/10.1016\/j.addr.2016.10.005.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR8","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1002\/jbmr.1602","volume":"27","author":"N Binkley","year":"2012","unstructured":"Binkley N, Bolognese M, Sidorowicz-Bialynicka A, Vally T, Trout R, Miller C, Buben CE, Gilligan JP, Krause DS. A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial. J Bone Miner Res. 2012;27:1821\u20139. https:\/\/doi.org\/10.1002\/jbmr.1602.","journal-title":"J Bone Miner Res"},{"key":"920_CR9","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1210\/jc.2014-4113","volume":"100","author":"S Melmed","year":"2015","unstructured":"Melmed S, Popovic V, Bidlingmaier M, Mercado M, Van Der Lely AJ, Biermasz N, Bolanowski M, Coculescu M, Schopohl J, Racz K, Glaser B, Goth M, Greenman Y, Trainer P, Mezosi E, Shimon I, Giustina A, Korbonits M, Bronstein MD, Kleinberg D, Teichman S, Gliko-Kabir I, Mamluk R, Haviv A, Strasburger C. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J Clin Endocrinol Metab. 2015;100:1699\u2013708. https:\/\/doi.org\/10.1210\/jc.2014-4113.","journal-title":"J Clin Endocrinol Metab"},{"key":"920_CR10","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1089\/dia.2019.0185","volume":"22","author":"JD Bucheit","year":"2020","unstructured":"Bucheit JD, Pamulapati LG, Carter N, Malloy K, Dixon DL, Sisson EM. Oral semaglutide: a review of the first oral glucagon-like peptide 1 receptor agonist. Diabetes Technol Ther. 2020;22:10\u20138. https:\/\/doi.org\/10.1089\/dia.2019.0185.","journal-title":"Diabetes Technol Ther"},{"key":"920_CR11","unstructured":"RYBELSUS (semaglutide) tablets, for oral use. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2019\/213051s000lbl.pdf."},{"key":"920_CR12","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1089\/1520915041705929","volume":"6","author":"E Arbit","year":"2004","unstructured":"Arbit E. The physiological rationale for oral insulin administration. Diabetes Technol Ther. 2004;6:510\u20137. https:\/\/doi.org\/10.1089\/1520915041705929.","journal-title":"Diabetes Technol Ther"},{"key":"920_CR13","unstructured":"Berger M. Oral insulin 1922\u20131992: the history of continuous ambition and failure, in: B. M, G. FA (Eds.), Front. Insul. Pharmacol., Germany: Thieme Publishing Group. 1993;144\u2013148."},{"key":"920_CR14","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.addr.2020.05.007","volume":"157","author":"DJ Brayden","year":"2020","unstructured":"Brayden DJ, Hill TA, Fairlie DP, Maher S, Mrsny RJ. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches. Adv Drug Deliv Rev. 2020;157:2\u201336. https:\/\/doi.org\/10.1016\/j.addr.2020.05.007.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR15","unstructured":"Final Report Summary - TRANS-INT (New Oral Nanomedicines: Transporting Therapeutic Macromolecules across the Intestinal Barrier). https:\/\/cordis.europa.eu\/project\/id\/281035\/reporting."},{"key":"920_CR16","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.jddst.2017.06.018","volume":"42","author":"I Santalices","year":"2017","unstructured":"Santalices I, Gonella A, Torres D, Alonso MJ. Advances on the formulation of proteins using nanotechnologies. J Drug Deliv Sci Technol. 2017;42:155\u201380. https:\/\/doi.org\/10.1016\/j.jddst.2017.06.018.","journal-title":"J Drug Deliv Sci Technol"},{"key":"920_CR17","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.addr.2016.04.001","volume":"106","author":"Z Niu","year":"2016","unstructured":"Niu Z, Conejos-S\u00e1nchez I, Griffin BT, O\u2019Driscoll CM, Alonso MJ. Lipid-based nanocarriers for oral peptide delivery. Adv Drug Deliv Rev. 2016;106:337\u201354. https:\/\/doi.org\/10.1016\/j.addr.2016.04.001.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR18","doi-asserted-by":"publisher","first-page":"246","DOI":"10.2337\/diab.37.2.246","volume":"37","author":"C Damge","year":"1988","unstructured":"Damge C, Michel C, Aprahamian M, Couvreur P. New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier. Diabetes. 1988;37:246\u201351. https:\/\/doi.org\/10.2337\/diab.37.2.246.","journal-title":"Diabetes"},{"key":"920_CR19","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.ejps.2005.02.008","volume":"25","author":"M Garcia-Fuentes","year":"2005","unstructured":"Garcia-Fuentes M, Prego C, Torres D, Alonso MJ. A comparative study of the potential of solid triglyceride nanostructures coated with chitosan or poly(ethylene glycol) as carriers for oral calcitonin delivery. Eur J Pharm Sci. 2005;25:133\u201343. https:\/\/doi.org\/10.1016\/j.ejps.2005.02.008.","journal-title":"Eur J Pharm Sci"},{"key":"920_CR20","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.jconrel.2005.12.015","volume":"111","author":"C Prego","year":"2006","unstructured":"Prego C, Torres D, Fernandez-Megia E, Novoa-Carballal R, Qui\u00f1o\u00e1 E, Alonso MJ. Chitosan-PEG nanocapsules as new carriers for oral peptide delivery: effect of chitosan pegylation degree. J Control Release. 2006;111:299\u2013308. https:\/\/doi.org\/10.1016\/j.jconrel.2005.12.015.","journal-title":"J Control Release"},{"key":"920_CR21","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.jconrel.2017.02.024","volume":"263","author":"Z Niu","year":"2016","unstructured":"Niu Z, Tedesco E, Benetti F, Mabondzo A, Montagner IM, Marigo I, Gonzalez-Touceda D, Tovar S, Di\u00e9guez C, Santander-Ortega MJ, Alonso MJ. Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers. J Control Release. 2016;263:4\u201317. https:\/\/doi.org\/10.1016\/j.jconrel.2017.02.024.","journal-title":"J Control Release"},{"key":"920_CR22","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.ijpharm.2017.07.001","volume":"529","author":"A Gonzalez-Paredes","year":"2017","unstructured":"Gonzalez-Paredes A, Torres D, Alonso MJ. Polyarginine nanocapsules: a versatile nanocarrier with potential in transmucosal drug delivery. Int J Pharm. 2017;529:474\u201385. https:\/\/doi.org\/10.1016\/j.ijpharm.2017.07.001.","journal-title":"Int J Pharm"},{"key":"920_CR23","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.jconrel.2018.10.022","volume":"291","author":"LN Thwala","year":"2018","unstructured":"Thwala LN, Delgado DP, Leone K, Marigo I, Benetti F, Chenlo M, Alvarez CV, Tovar S, Dieguez C, Csaba NS, Alonso MJ. Protamine nanocapsules as carriers for oral peptide delivery. J Control Release. 2018;291:157\u201368. https:\/\/doi.org\/10.1016\/j.jconrel.2018.10.022.","journal-title":"J Control Release"},{"key":"920_CR24","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.ejpb.2018.09.023","volume":"133","author":"I Santalices","year":"2018","unstructured":"Santalices I, Torres D, Lozano MV, Arroyo-Jim\u00e9nez MM, Alonso MJ, Santander-Ortega MJ. Influence of the surface properties of nanocapsules on their interaction with intestinal barriers. Eur J Pharm Biopharm. 2018;133:203\u201313. https:\/\/doi.org\/10.1016\/j.ejpb.2018.09.023.","journal-title":"Eur J Pharm Biopharm"},{"key":"920_CR25","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1007\/s003960050050","volume":"275","author":"P Calvo","year":"1997","unstructured":"Calvo P, Remu\u00f1\u00e1n-L\u00f3pez C, Vila-Jato JL, Alonso MJ. Development of positively charged colloidal drug carriers: chitosan-coated polyester nanocapsules and submicron-emulsions. Colloid Polym Sci. 1997;275:46\u201353. https:\/\/doi.org\/10.1007\/s003960050050.","journal-title":"Colloid Polym Sci"},{"key":"920_CR26","doi-asserted-by":"publisher","first-page":"6551","DOI":"10.1039\/c0cc01806f","volume":"46","author":"V Francisco","year":"2010","unstructured":"Francisco V, Basilio N, Garcia-Rio L, Leis JR, Marques EF, V\u00e1zquez-V\u00e1zquez C. Novel catanionic vesicles from calixarene and single-chain surfactant. Chem Commun. 2010;46:6551. https:\/\/doi.org\/10.1039\/c0cc01806f.","journal-title":"Chem Commun"},{"key":"920_CR27","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1039\/C6FD00015K","volume":"191","author":"YA Attia","year":"2016","unstructured":"Attia YA, V\u00e1zquez-V\u00e1zquez C, Blanco MC, Buceta D, L\u00f3pez-Quintela MA. Gold nanorod synthesis catalysed by Au clusters. Faraday Discuss. 2016;191:205\u201313. https:\/\/doi.org\/10.1039\/C6FD00015K.","journal-title":"Faraday Discuss"},{"key":"920_CR28","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1007\/s11095-008-9569-4","volume":"25","author":"E Jantratid","year":"2008","unstructured":"Jantratid E, Janssen N, Reppas C, Dressman JB. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update. Pharm Res. 2008;25:1663\u201376. https:\/\/doi.org\/10.1007\/s11095-008-9569-4.","journal-title":"Pharm Res"},{"key":"920_CR29","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.ijpharm.2009.05.069","volume":"379","author":"E Roger","year":"2009","unstructured":"Roger E, Lagarce F, Benoit JP. The gastrointestinal stability of lipid nanocapsules. Int J Pharm. 2009;379:260\u20135. https:\/\/doi.org\/10.1016\/j.ijpharm.2009.05.069.","journal-title":"Int J Pharm"},{"key":"920_CR30","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.jconrel.2016.10.002","volume":"243","author":"LN Thwala","year":"2016","unstructured":"Thwala LN, Beloqui A, Csaba NS, Gonz\u00e1lez-Touceda D, Tovar S, Dieguez C, Alonso MJ, Pr\u00e9at V. The interaction of protamine nanocapsules with the intestinal epithelium: a mechanistic approach. J Control Release. 2016;243:109\u201320. https:\/\/doi.org\/10.1016\/j.jconrel.2016.10.002.","journal-title":"J Control Release"},{"key":"920_CR31","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1211\/jpp.60.1.0008","volume":"60","author":"EL McConnell","year":"2008","unstructured":"McConnell EL, Basit AW, Murdan S. Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments. J Pharm Pharmacol. 2008;60:63\u201370. https:\/\/doi.org\/10.1211\/jpp.60.1.0008.","journal-title":"J Pharm Pharmacol"},{"key":"920_CR32","doi-asserted-by":"publisher","first-page":"913","DOI":"10.2217\/nnm.14.43","volume":"9","author":"E Zagato","year":"2014","unstructured":"Zagato E, Forier K, Martens T, Neyts K, Demeester J, De Smedt S, Remaut K, Braeckmans K. Single-particle tracking for studying nanomaterial dynamics: applications and fundamentals in drug delivery. Nanomedicine. 2014;9:913\u201327. https:\/\/doi.org\/10.2217\/nnm.14.43.","journal-title":"Nanomedicine"},{"key":"920_CR33","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.addr.2015.03.017","volume":"91","author":"BS Schuster","year":"2015","unstructured":"Schuster BS, Ensign LM, Allan DB, Suk JS, Hanes J. Particle tracking in drug and gene delivery research: state-of-the-art applications and methods. Adv Drug Deliv Rev. 2015;91:70\u201391. https:\/\/doi.org\/10.1016\/j.addr.2015.03.017.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR34","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.addr.2004.06.001","volume":"57","author":"J Suh","year":"2005","unstructured":"Suh J, Dawson M, Hanes J. Real-time multiple-particle tracking: applications to drug and gene delivery. Adv Drug Deliv Rev. 2005;57:63\u201378. https:\/\/doi.org\/10.1016\/j.addr.2004.06.001.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0370-1573(00)00070-3","volume":"339","author":"R Metzler","year":"2000","unstructured":"Metzler R, Klafter J. The random walk\u2019s guide to anomalous diffusion: a fractional dynamics approach. Phys Rep. 2000;339:1\u201377. https:\/\/doi.org\/10.1016\/S0370-1573(00)00070-3.","journal-title":"Phys Rep"},{"key":"920_CR36","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.ejpb.2012.10.003","volume":"83","author":"F Antunes","year":"2013","unstructured":"Antunes F, Andrade F, Ara\u00fajo F, Ferreira D, Sarmento B. Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide drugs. Eur J Pharm Biopharm. 2013;83:427\u201335. https:\/\/doi.org\/10.1016\/j.ejpb.2012.10.003.","journal-title":"Eur J Pharm Biopharm"},{"key":"920_CR37","doi-asserted-by":"publisher","unstructured":"des Rieux A, Fievez V, Th\u00e9ate I, Mast J, Pr\u00e9at V, Schneider YJ.\u00a0An improved in vitro model of human intestinal follicle-associated epithelium to study nanoparticle transport by M cells. Eur J Pharm Sci. 2007;30:380\u2013391.\u00a0https:\/\/doi.org\/10.1016\/j.ejps.2006.12.006.","DOI":"10.1016\/j.ejps.2006.12.006"},{"key":"920_CR38","unstructured":"The human protein atlas. https:\/\/www.proteinatlas.org\/ENSG00000171105-INSR\/cell."},{"key":"920_CR39","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1074\/jbc.273.3.1349","volume":"273","author":"KA Dooley","year":"1998","unstructured":"Dooley KA, Millinder S, Osborne TF. Sterol regulation of 3-hydroxy-3-methylglutaryl-coenzyme A synthase gene through a direct interaction between sterol regulatory element binding protein and the trimeric CCAAT-binding factor\/nuclear factor Y. J Biol Chem. 1998;273:1349\u201356. https:\/\/doi.org\/10.1074\/jbc.273.3.1349.","journal-title":"J Biol Chem"},{"key":"920_CR40","doi-asserted-by":"publisher","first-page":"18480","DOI":"10.1016\/S0021-9258(19)81383-2","volume":"263","author":"JR Smith","year":"1988","unstructured":"Smith JR, Osborne TF, Brown MS, Goldstein JL, Gil G. Multiple sterol regulatory elements in promoter for hamster 3-hydroxy-3-methylglutaryl-coenzyme A synthase. J Biol Chem. 1988;263:18480\u20137.","journal-title":"J Biol Chem"},{"key":"920_CR41","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1046\/j.1523-1747.2000.00822.x","volume":"114","author":"IR Harris","year":"2000","unstructured":"Harris IR, H\u00f6ppner H, Siefken W, Farrell AM, Wittern KP. Regulation of HMG-CoA synthase and HMG-CoA reductase by insulin and epidermal growth factor in HaCaT keratinocytes. J Invest Dermatol. 2000;114:83\u20137. https:\/\/doi.org\/10.1046\/j.1523-1747.2000.00822.x.","journal-title":"J Invest Dermatol"},{"key":"920_CR42","doi-asserted-by":"publisher","unstructured":"Bravo SB, Garcia-Rendueles MER, Perez-Romero S, Cameselle Teijeiro J, Rodrigues JS, Barreiro F, Alvarez CV.\u00a0Expression of exogenous proteins and short hairpin RNAs in human primary thyrocytes. Anal Biochem. 2010;400:219\u2013228. https:\/\/doi.org\/10.1016\/j.ab.2010.01.034.","DOI":"10.1016\/j.ab.2010.01.034"},{"key":"920_CR43","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1016\/j.idairyj.2006.06.015","volume":"16","author":"B Marten","year":"2006","unstructured":"Marten B, Pfeuffer M, Schrezenmeir J. Medium-chain triglycerides. Int Dairy J. 2006;16:1374\u201382. https:\/\/doi.org\/10.1016\/j.idairyj.2006.06.015.","journal-title":"Int Dairy J"},{"key":"920_CR44","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.addr.2007.10.010","volume":"60","author":"CW Pouton","year":"2008","unstructured":"Pouton CW, Porter CJH. Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev. 2008;60:625\u201337. https:\/\/doi.org\/10.1016\/j.addr.2007.10.010.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR45","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1023\/A:1011922819926","volume":"15","author":"M Tob\u00edo","year":"1998","unstructured":"Tob\u00edo M, Gref R, Sanchez A, Langer R, Alonso MJ. Stealth PLA-PEG nanoparticles as protein carriers for nasal administration. Pharm Res. 1998;15:270\u20135. https:\/\/doi.org\/10.1023\/A:1011922819926.","journal-title":"Pharm Res"},{"key":"920_CR46","doi-asserted-by":"publisher","unstructured":"Tob\u0131\u0301o M, S\u00e1nchez A, Vila A, Soriano I, Evora C, Vila-Jato JL, Alonso MJ.\u00a0The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration. Colloids Surf B Biointerfaces. 2000;18:315\u2013323.\u00a0https:\/\/doi.org\/10.1016\/S0927-7765(99)00157-5.","DOI":"10.1016\/S0927-7765(99)00157-5"},{"key":"920_CR47","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.ijpharm.2011.12.025","volume":"423","author":"M Wulff-P\u00e9rez","year":"2012","unstructured":"Wulff-P\u00e9rez M, de Vicente J, Mart\u00edn-Rodr\u00edguez A, G\u00e1lvez-Ruiz MJ. Controlling lipolysis through steric surfactants: new insights on the controlled degradation of submicron emulsions after oral and intravenous administration. Int J Pharm. 2012;423:161\u20136. https:\/\/doi.org\/10.1016\/j.ijpharm.2011.12.025.","journal-title":"Int J Pharm"},{"key":"920_CR48","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/s13346-019-00678-3","volume":"10","author":"E Samaridou","year":"2020","unstructured":"Samaridou E, Kalamidas N, Santalices I, Crecente-Campo J, Alonso MJ. Tuning the PEG surface density of the PEG-PGA enveloped Octaarginine-peptide Nanocomplexes. Drug Deliv Transl Res. 2020;10:241\u201358. https:\/\/doi.org\/10.1007\/s13346-019-00678-3.","journal-title":"Drug Deliv Transl Res"},{"key":"920_CR49","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.addr.2011.12.009","volume":"64","author":"LM Ensign","year":"2012","unstructured":"Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv Drug Deliv Rev. 2012;64:557\u201370. https:\/\/doi.org\/10.1016\/j.addr.2011.12.009.","journal-title":"Adv Drug Deliv Rev"},{"key":"920_CR50","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.jconrel.2004.04.026","volume":"98","author":"A Vila","year":"2004","unstructured":"Vila A, Gill H, McCallion O, Alonso MJ. Transport of PLA-PEG particles across the nasal mucosa: effect of particle size and PEG coating density. J Control Release. 2004;98:231\u201344. https:\/\/doi.org\/10.1016\/j.jconrel.2004.04.026.","journal-title":"J Control Release"},{"key":"920_CR51","doi-asserted-by":"publisher","first-page":"9217","DOI":"10.1021\/acsnano.5b03876","volume":"9","author":"Q Xu","year":"2015","unstructured":"Xu Q, Ensign LM, Boylan NJ, Sch\u00f6n A, Gong X, Yang JC, Lamb NW, Cai S, Yu T, Freire E, Hanes J. Impact of surface polyethylene glycol (PEG) density on biodegradable nanoparticle transport in mucus ex vivo and distribution in vivo. ACS Nano. 2015;9:9217\u201327. https:\/\/doi.org\/10.1021\/acsnano.5b03876.","journal-title":"ACS Nano"},{"key":"920_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijpharm.2013.04.002","volume":"449","author":"D Chen","year":"2013","unstructured":"Chen D, Xia D, Li X, Zhu Q, Yu H, Zhu C, Gan Y. Comparative study of Pluronic\u00ae F127-modified liposomes and chitosan-modified liposomes for mucus penetration and oral absorption of cyclosporine A in rats. Int J Pharm. 2013;449:1\u20139. https:\/\/doi.org\/10.1016\/j.ijpharm.2013.04.002.","journal-title":"Int J Pharm"},{"key":"920_CR53","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.ijpharm.2013.11.028","volume":"460","author":"M Niu","year":"2014","unstructured":"Niu M, Tan Y, Guan P, Hovgaard L, Lu Y, Qi J, Lian R, Li X, Wu W. Enhanced oral absorption of insulin-loaded liposomes containing bile salts: a mechanistic study. Int J Pharm. 2014;460:119\u201330. https:\/\/doi.org\/10.1016\/j.ijpharm.2013.11.028.","journal-title":"Int J Pharm"},{"key":"920_CR54","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.ejpb.2012.02.009","volume":"81","author":"M Niu","year":"2012","unstructured":"Niu M, Lu Y, Hovgaard L, Guan P, Tan Y, Lian R, Qi J, Wu W. Hypoglycemic activity and oral bioavailability of insulin-loaded liposomes containing bile salts in rats: the effect of cholate type, particle size and administered dose. Eur J Pharm Biopharm. 2012;81:265\u201372. https:\/\/doi.org\/10.1016\/j.ejpb.2012.02.009.","journal-title":"Eur J Pharm Biopharm"},{"key":"920_CR55","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.2217\/nnm.12.141","volume":"8","author":"C Chen","year":"2013","unstructured":"Chen C, Fan T, Jin Y, Zhou Z, Yang Y, Zhu X, Zhang Z, Zhang Q, Huang Y. Orally delivered salmon calcitonin-loaded solid lipid nanoparticles prepared by micelle\u2013double emulsion method via the combined use of different solid lipids. Nanomedicine. 2013;8:1085\u2013100. https:\/\/doi.org\/10.2217\/nnm.12.141.","journal-title":"Nanomedicine"},{"key":"920_CR56","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.ijpharm.2007.03.009","volume":"340","author":"J Liu","year":"2007","unstructured":"Liu J, Gong T, Wang C, Zhong Z, Zhang Z. Solid lipid nanoparticles loaded with insulin by sodium cholate-phosphatidylcholine-based mixed micelles: preparation and characterization. Int J Pharm. 2007;340:153\u201362. https:\/\/doi.org\/10.1016\/j.ijpharm.2007.03.009.","journal-title":"Int J Pharm"},{"key":"920_CR57","doi-asserted-by":"publisher","unstructured":"Sun S, Liang N, Piao H, Yamamoto H, Kawashima Y, Cui F. Insulin-S.O (sodium oleate) complex-loaded PLGA nanoparticles: Formulation, characterization and in vivo evaluation. J Microencapsul. 2010;27:471\u2013478. https:\/\/doi.org\/10.3109\/02652040903515490.","DOI":"10.3109\/02652040903515490"},{"key":"920_CR58","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.ijpharm.2012.10.025","volume":"441","author":"S Hu","year":"2013","unstructured":"Hu S, Niu M, Hu F, Lu Y, Qi J, Yin Z, Wu W. Integrity and stability of oral liposomes containing bile salts studied in simulated and ex vivo gastrointestinal media. Int J Pharm. 2013;441:693\u2013700. https:\/\/doi.org\/10.1016\/j.ijpharm.2012.10.025.","journal-title":"Int J Pharm"},{"key":"920_CR59","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.jconrel.2019.05.011","volume":"304","author":"TNQ Phan","year":"2019","unstructured":"Phan TNQ, Shahzadi I, Bernkop-Schn\u00fcrch A. Hydrophobic ion-pairs and lipid-based nanocarrier systems: the perfect match for delivery of BCS class 3 drugs. J Control Release. 2019;304:146\u201355. https:\/\/doi.org\/10.1016\/j.jconrel.2019.05.011.","journal-title":"J Control Release"},{"key":"920_CR60","doi-asserted-by":"publisher","unstructured":"Ristroph KD, Prud\u2019homme RK.\u00a0Hydrophobic ion pairing: Encapsulating small molecules, peptides, and proteins into nanocarriers, Nanoscale Adv. 2019;1:4207\u20134237. https:\/\/doi.org\/10.1039\/c9na00308h.","DOI":"10.1039\/c9na00308h"},{"key":"920_CR61","doi-asserted-by":"publisher","first-page":"7279","DOI":"10.1021\/la900310k","volume":"25","author":"M Kastantin","year":"2009","unstructured":"Kastantin M, Ananthanarayanan B, Karmali P, Ruoslahti E, Tirrell M. Effect of the lipid chain melting transition on the stability of DSPE- PEG(2000) micelles. Langmuir. 2009;25:7279\u201386. https:\/\/doi.org\/10.1021\/la900310k.","journal-title":"Langmuir"},{"key":"920_CR62","doi-asserted-by":"publisher","unstructured":"Plaza-Oliver M, Fern\u00e1ndez Sainz de Baranda J, Rodr\u00edguez Robledo V, Castro-V\u00e1zquez L, Gonzalez-Fuentes J, Marcos P, Lozano MV, Santander-Ortega MJ, Arroyo-Jimenez MM.\u00a0Design of the interface of edible nanoemulsions to modulate the bioaccessibility of neuroprotective antioxidants. Int J Pharm. 2015;490:209\u2013218. https:\/\/doi.org\/10.1016\/j.ijpharm.2015.05.031.","DOI":"10.1016\/j.ijpharm.2015.05.031"},{"key":"920_CR63","doi-asserted-by":"publisher","first-page":"6195","DOI":"10.1021\/nl503371p","volume":"14","author":"E Van Der Pol","year":"2014","unstructured":"Van Der Pol E, Coumans FAW, Sturk A, Nieuwland R, Van Leeuwen TG. Refractive index determination of nanoparticles in suspension using nanoparticle tracking analysis. Nano Lett. 2014;14:6195\u2013201. https:\/\/doi.org\/10.1021\/nl503371p.","journal-title":"Nano Lett"},{"key":"920_CR64","doi-asserted-by":"publisher","first-page":"13481","DOI":"10.1021\/ja204043b","volume":"133","author":"L Vukovic","year":"2011","unstructured":"Vukovic L, Khatib FA, Drake SP, Madriaga A, Brandenburg KS, Kr\u00e1l P, Onyuksel H. Structure and dynamics of highly PEG-ylated sterically stabilized micelles in aqueous media Petr Kr. J Am Chem Soc. 2011;133:13481\u20138. https:\/\/doi.org\/10.1021\/ja204043b.","journal-title":"J Am Chem Soc"},{"key":"920_CR65","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.foodhyd.2010.09.007","volume":"25","author":"A Torcello-G\u00f3mez","year":"2011","unstructured":"Torcello-G\u00f3mez A, Maldonado-Valderrama J, de Vicente J, Cabrerizo-V\u00edlchez MA, G\u00e1lvez-Ruiz MJ, Mart\u00edn-Rodr\u00edguez A. Investigating the effect of surfactants on lipase interfacial behaviour in the presence of bile salts. Food Hydrocoll. 2011;25:809\u201316. https:\/\/doi.org\/10.1016\/j.foodhyd.2010.09.007.","journal-title":"Food Hydrocoll"},{"key":"920_CR66","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1016\/j.drudis.2014.01.011","volume":"19","author":"AC Groo","year":"2014","unstructured":"Groo AC, Lagarce F. Mucus models to evaluate nanomedicines for diffusion. Drug Discov Today. 2014;19:1097\u2013108. https:\/\/doi.org\/10.1016\/j.drudis.2014.01.011.","journal-title":"Drug Discov Today"},{"key":"920_CR67","doi-asserted-by":"publisher","first-page":"4269","DOI":"10.1021\/acs.langmuir.7b00351","volume":"33","author":"MJ Santander-Ortega","year":"2017","unstructured":"Santander-Ortega MJ, Plaza-Oliver M, Rodr\u00edguez-Robledo V, Castro-V\u00e1zquez L, Villaseca-Gonz\u00e1lez N, Gonz\u00e1lez-Fuentes J, Cano EL, Marcos P, Lozano MV, Arroyo-Jim\u00e9nez MM. PEGylated nanoemulsions for oral delivery: role of the inner core on the final fate of the formulation. Langmuir. 2017;33:4269\u201379. https:\/\/doi.org\/10.1021\/acs.langmuir.7b00351.","journal-title":"Langmuir"},{"key":"920_CR68","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.ijpharm.2013.10.003","volume":"458","author":"F Ara\u00fajo","year":"2013","unstructured":"Ara\u00fajo F, Sarmento B. Towards the characterization of an in vitro triple co-culture intestine cell model for permeability studies. Int J Pharm. 2013;458:128\u201334. https:\/\/doi.org\/10.1016\/j.ijpharm.2013.10.003.","journal-title":"Int J Pharm"},{"key":"920_CR69","doi-asserted-by":"publisher","unstructured":"Ara\u00fajo F, Pereira C, Costa J, Barrias C, Granja PL, Sarmento B.\u00a0In vitro M-like cells genesis through a tissue-engineered triple-culture intestinal model. J Biomed Mater Res B Appl Biomater. 2016;104:782\u2013788. https:\/\/doi.org\/10.1002\/jbm.b.33508.","DOI":"10.1002\/jbm.b.33508"},{"key":"920_CR70","doi-asserted-by":"publisher","unstructured":"Yang D, Liu D, Qin M, Chen B, Song S, Dai W, Zhang H, Wang X, Wang Y, He B, Tang X, Zhang Q.\u00a0Intestinal mucin induces more endocytosis but less transcytosis of nanoparticles across enterocytes by triggering nano-clustering and strengthening the retrograde pathway. ACS Appl Mater Interfaces. 2018;acsami.7b19153.\u00a0https:\/\/doi.org\/10.1021\/acsami.7b19153.","DOI":"10.1021\/acsami.7b19153"},{"key":"920_CR71","first-page":"6334","volume":"50","author":"T Lesuffleur","year":"1990","unstructured":"Lesuffleur T, Barbat A, Dussaulx E, Zweibaum A. Growth adaptation to methotrexate of HT-29 human colon carcinoma cells is associated with their ability to differentiate into columnar absorptive and mucus-secreting cells. Cancer Res. 1990;50:6334\u201343.","journal-title":"Cancer Res"},{"key":"920_CR72","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1023\/A:1010974909998","volume":"18","author":"I Behrens","year":"2001","unstructured":"Behrens I, Stenberg P, Artursson P, Kissel T. Transport of lipophilic drug molecules in a new mucus secreting cell culture model based on Ht-29 MTX cells. Pharm Res. 2001;18:1138\u201345.","journal-title":"Pharm Res"},{"key":"920_CR73","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1002\/(SICI)1520-6017(200001)89:1<63::AID-JPS7>3.0.CO;2-6","volume":"89","author":"C Hilgendorf","year":"2000","unstructured":"Hilgendorf C, Spahn-langguth H, Reg\u00e5rdh CG, Lipka E. Caco-2 versus Caco-2\/HT29-MTX co-cultured cell lines: permeabilities via diffusion, inside- and outside-directed carrier-mediated transport. J Pharm Sci. 2000;89:63\u201375.","journal-title":"J Pharm Sci"},{"key":"920_CR74","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1113\/expphysiol.1993.sp003717","volume":"78","author":"RA Goodlad","year":"1993","unstructured":"Goodlad RA, Lee CY, Gilbey SG, Ghatei MA, Bloom SR. Insulin and intestinal epithelial cell proliferation. Exp Physiol. 1993;78:697\u2013705.","journal-title":"Exp Physiol"},{"key":"920_CR75","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1136\/gut.40.1.57","volume":"40","author":"EE Wheeler","year":"1997","unstructured":"Wheeler EE, Challacombe DN. The trophic action of growth hormone, insulin- like growth factor-I, and insulin on human duodenal mucosa cultured in vitro. Transplantation. 1997;40:57\u201360. https:\/\/doi.org\/10.1136\/gut.40.1.57.","journal-title":"Transplantation"},{"key":"920_CR76","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.clnu.2010.03.002","volume":"30","author":"WH Hartl","year":"2011","unstructured":"Hartl WH, Alpers DH. The trophic effects of substrate, insulin, and the route of administration on protein synthesis and the preservation of small bowel mucosal mass in large mammals. Clin Nutr. 2011;30:20\u20137. https:\/\/doi.org\/10.1016\/j.clnu.2010.03.002.","journal-title":"Clin Nutr"},{"key":"920_CR77","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jconrel.2004.07.030","volume":"101","author":"C Prego","year":"2005","unstructured":"Prego C, Garc\u00eda M, Torres D, Alonso MJ. Transmucosal macromolecular drug delivery. J Control Release. 2005;101:151\u201362. https:\/\/doi.org\/10.1016\/j.jconrel.2004.07.030.","journal-title":"J Control Release"},{"key":"920_CR78","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/S0278-6915(99)00106-4","volume":"38","author":"KA Traul","year":"2000","unstructured":"Traul KA, Driedger A, Ingle DL, Nakhasi D. Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol. 2000;38:79\u201398. https:\/\/doi.org\/10.1016\/S0278-6915(99)00106-4.","journal-title":"Food Chem Toxicol"},{"key":"920_CR79","doi-asserted-by":"publisher","unstructured":"Holm R, Mul\u0308lertz A, Mu H.\u00a0Bile salts and their importance for drug absorption. Int J Pharm. 2013;453:44\u201355. https:\/\/doi.org\/10.1016\/j.ijpharm.2013.04.003.","DOI":"10.1016\/j.ijpharm.2013.04.003"},{"key":"920_CR80","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1016\/j.ejpb.2014.10.008","volume":"88","author":"DJ Brayden","year":"2014","unstructured":"Brayden DJ, Gleeson J, Walsh EG. A head-to-head multi-parametric high content analysis of a series of medium chain fatty acid intestinal permeation enhancers in Caco-2 cells. Eur J Pharm Biopharm. 2014;88:830\u20139. https:\/\/doi.org\/10.1016\/j.ejpb.2014.10.008.","journal-title":"Eur J Pharm Biopharm"},{"key":"920_CR81","doi-asserted-by":"publisher","unstructured":"Manning MC, Evans GJ, Payne RW.\u00a0Protein stability during bioprocessing, in: F. Jameel, S. Hershenson (Eds.), Formul. Process Dev. Strateg. Manuf. Biopharm., John Wiley & Sons, Inc., 2010:605\u2013624. https:\/\/doi.org\/10.1002\/9780470595886.","DOI":"10.1002\/9780470595886"},{"key":"920_CR82","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.ijpharm.2012.08.024","volume":"437","author":"N Reix","year":"2012","unstructured":"Reix N, Parat A, Seyfritz E, Van Der Werf R, Epure V, Ebel N, Danicher L, Marchioni E, Jeandidier N, Pinget M, Fr\u00e8re Y, Sigrist S. In vitro uptake evaluation in Caco-2 cells and in vivo results in diabetic rats of insulin-loaded PLGA nanoparticles. Int J Pharm. 2012;437:213\u201320. https:\/\/doi.org\/10.1016\/j.ijpharm.2012.08.024.","journal-title":"Int J Pharm"},{"key":"920_CR83","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.jconrel.2018.03.004","volume":"276","author":"Z Niu","year":"2018","unstructured":"Niu Z, Samaridou E, Jaumain E, Co\u00ebne J, Ullio G, Shrestha N, Garcia J, Dur\u00e1n-Lobato M, Tovar S, Santander-Ortega MJ, Lozano MV, Arroyo-Jimenez MM, Ramos-Membrive R, Pe\u00f1uelas I, Mabondzo A, Pr\u00e9at V, Teixid\u00f3 M, Giralt E, Alonso MJ. PEG-PGA enveloped octaarginine-peptide nanocomplexes: an oral peptide delivery strategy. J Control Release. 2018;276:125\u201339. https:\/\/doi.org\/10.1016\/j.jconrel.2018.03.004.","journal-title":"J Control Release"},{"key":"920_CR84","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/0168-3659(90)90013-J","volume":"13","author":"C Damge","year":"1990","unstructured":"Damge C, Michel C, Aprahamian M, Couvreur P, Devissaguet JP. Nanocapsules as carriers for oral peptide delivery. J Control Release. 1990;13:233\u20139. https:\/\/doi.org\/10.1016\/0168-3659(90)90013-J.","journal-title":"J Control Release"},{"key":"920_CR85","doi-asserted-by":"publisher","first-page":"5691","DOI":"10.1016\/j.biomaterials.2009.06.055","volume":"30","author":"L Yin","year":"2009","unstructured":"Yin L, Ding J, He C, Cui L, Tang C, Yin C. Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials. 2009;30:5691\u2013700. https:\/\/doi.org\/10.1016\/j.biomaterials.2009.06.055.","journal-title":"Biomaterials"},{"key":"920_CR86","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.2042-7158.1991.tb05437.x","volume":"43","author":"C Michel","year":"1991","unstructured":"Michel C, Aprahamian M, Defontaine L, Couvreur P, Damg\u00e9 C. The effect of site of administration in the gastrointestinal tract on the absorption of insulin from nanocapsules in diabetic rats. J Pharm Pharmacol. 1991;43:1\u20135. https:\/\/doi.org\/10.1111\/j.2042-7158.1991.tb05437.x.","journal-title":"J Pharm Pharmacol"},{"key":"920_CR87","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.jconrel.2005.10.029","volume":"110","author":"M Morishita","year":"2006","unstructured":"Morishita M, Goto T, Nakamura K, Lowman AM, Takayama K, Peppas NA. Novel oral insulin delivery systems based on complexation polymer hydrogels: single and multiple administration studies in type 1 and 2 diabetic rats. J Control Release. 2006;110:587\u201394. https:\/\/doi.org\/10.1016\/j.jconrel.2005.10.029.","journal-title":"J Control Release"}],"updated-by":[{"DOI":"10.1007\/s13346-021-00957-y","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000}}],"container-title":["Drug Delivery and Translational Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-021-00920-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13346-021-00920-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-021-00920-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T11:36:03Z","timestamp":1627644963000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13346-021-00920-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,11]]},"references-count":87,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["920"],"URL":"https:\/\/doi.org\/10.1007\/s13346-021-00920-x","relation":{"correction":[{"id-type":"doi","id":"10.1007\/s13346-021-00957-y","asserted-by":"object"}]},"ISSN":["2190-393X","2190-3948"],"issn-type":[{"value":"2190-393X","type":"print"},{"value":"2190-3948","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,11]]},"assertion":[{"value":"19 January 2021","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2021","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 March 2021","order":3,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":4,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":5,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s13346-021-00957-y","URL":"https:\/\/doi.org\/10.1007\/s13346-021-00957-y","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments were reviewed and approved by the ethics committee at the University of Santiago de Compostela ID: 1500AE\/12\/FUN01\/FIS02\/CDG3 (Spanish Royal Decree 1201\/2005, of October 10th) and ID: 15010\/17\/17002 (Spanish Royal Decree 53\/2013, of February 1st) and were executed in accordance with governing Spanish law and European Directives and Guidelines for the use of animals in animal studies; performed therefore in compliance with the Directive 2010\/63\/EU of the European Parliament and Council of 22nd September 2010 on the protection of animals used for scientific purposes and under the Spanish Royal Decree 53\/2013 February 1st on the protection of animals used for experimental and other scientific purposes, including teaching.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All authors agreed with the content, and all gave explicit consent to submit this work. They obtained consent from the responsible authorities at the institute\/organization where the work has been carried out, before the work is submitted.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that there are no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}