{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T10:49:00Z","timestamp":1775558940083,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04501\/2020, POCI-01-0145-FEDER-007628, UID\/IC\/00051\/2019, UIDB\/50006\/2020, CENTRO-01-0145-FEDER-03075, UID\/QUI\/00313\/2020, IF\/00286\/2015, SFRH\/BD\/149138\/2019 and SFRH\/BD\/133996\/2017"],"award-info":[{"award-number":["UIDB\/04501\/2020, POCI-01-0145-FEDER-007628, UID\/IC\/00051\/2019, UIDB\/50006\/2020, CENTRO-01-0145-FEDER-03075, UID\/QUI\/00313\/2020, IF\/00286\/2015, SFRH\/BD\/149138\/2019 and SFRH\/BD\/133996\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>A properly designed nanosystem aims to deliver an optimized concentration of the active pharmaceutical ingredient (API) at the site of action, resulting in a therapeutic response with reduced adverse effects. Due to the vast availability of lipids and surfactants, producing stable lipid dispersions is a double-edged sword: on the one hand, the versatility of composition allows for a refined design and tuning of properties; on the other hand, the complexity of the materials and their physical interactions often result in laborious and time-consuming pre-formulation studies. However, how can they be tailored, and which premises are required for a \u201cright at first time\u201d development? Here, a stepwise framework encompassing the sequential stages of nanoparticle production for disulfiram delivery is presented. Drug in lipid solubility analysis leads to the selection of the most suitable liquid lipids. As for the solid lipid, drug partitioning studies point out the lipids with increased capacity for solubilizing and entrapping disulfiram. The microscopical evaluation of the physical compatibility between liquid and solid lipids further indicates the most promising core compositions. The impact of the outer surfactant layer on the colloidal properties of the nanosystems is evaluated recurring to machine learning algorithms, in particular, hierarchical clustering, principal component analysis, and partial least squares regression. Overall, this work represents a comprehensive systematic approach to nanoparticle formulation studies that serves as a basis for selecting the most suitable excipients that comprise solid lipid nanoparticles and nanostructured lipid carriers.<\/jats:p>","DOI":"10.3390\/biom12020223","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T21:59:55Z","timestamp":1643320795000},"page":"223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["A Stepwise Framework for the Systematic Development of Lipid Nanoparticles"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3212-7324","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Basso","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-4517","authenticated-orcid":false,"given":"Maria","family":"Mendes","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2840-6091","authenticated-orcid":false,"given":"T\u00e2nia","family":"Cova","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"given":"Jo\u00e3o","family":"Sousa","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"given":"Alberto","family":"Pais","sequence":"additional","affiliation":[{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"given":"Ana","family":"Fortuna","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-5805","authenticated-orcid":false,"given":"Rui","family":"Vitorino","sequence":"additional","affiliation":[{"name":"iBiMED\u2014Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal"},{"name":"UnIC, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"QOPNA & LAQV-REQUIMTE, Chemistry Department, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-548X","authenticated-orcid":false,"given":"Carla","family":"Vitorino","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Chemistry Centre, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"ref_1","unstructured":"Brunton, L.L., Hilal-Dandan, R., and Knollmann, B.C. (2018). Chapter 23: Ethanol. Goodman & Gilman\u2019s: The Pharmacological Basis of Therapeutics, McGraw-Hill Education. [13th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Basso, J., Mendes, M., Fortuna, A., Vitorino, R., Sousa, J., Pais, A., and Vitorino, C. (2020). Nanotechnological approaches in cancer: The role of celecoxib and disulfiram. Drug Repurposing in Cancer Therapy, Elsevier.","DOI":"10.1016\/B978-0-12-819668-7.00014-2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"182","DOI":"10.4103\/2230-973X.167661","article-title":"Nanostructured lipid carriers: An emerging platform for improving oral bioavailability of lipophilic drugs","volume":"5","author":"Khan","year":"2015","journal-title":"Int. J. Pharm. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"207","DOI":"10.2174\/157016311796799062","article-title":"20 years of lipid nanoparticles (SLN & NLC): Present state of development & industrial applications","volume":"8","author":"Muller","year":"2011","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Souto, E.B., and M\u00fcller, R.H. (2007). Lipid nanoparticles (solid lipid nanoparticles and nanostructured lipid carriers) for cosmetic, dermal, and transdermal applications. Nanoparticulate Drug Delivery Systems, CRC Press.","DOI":"10.1201\/9781420008449-14"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.addr.2012.09.021","article-title":"Solid lipid nanoparticles: Production, characterization and applications","volume":"64","author":"Mehnert","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ijpharm.2008.10.003","article-title":"Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products","volume":"366","author":"Pardeike","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"M\u00fcller, R.H., Alexiev, U., Sinambela, P., and Keck, C.M. (2016). Nanostructured lipid carriers (NLC): The second generation of solid lipid nanoparticles. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement, Springer.","DOI":"10.1007\/978-3-662-47862-2_11"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jconrel.2007.12.018","article-title":"Potential of solid lipid nanoparticles in brain targeting","volume":"127","author":"Kaur","year":"2008","journal-title":"J. Control. Release"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.addr.2011.04.006","article-title":"Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor","volume":"64","author":"Li","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Valenzuela, R., and Valenzuela, A. (2013). Overview about lipid structure. Lipid Metabolism, IntechOpen.","DOI":"10.5772\/52306"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ejpb.2016.08.001","article-title":"Preclinical safety of solid lipid nanoparticles and nanostructured lipid carriers: Current evidence from in vitro and in vivo evaluation","volume":"108","author":"Doktorovova","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"506","DOI":"10.3389\/fphar.2020.00506","article-title":"Composition and functionality of lipid emulsions in parenteral nutrition: Examining evidence in clinical applications","volume":"11","author":"Narayanan","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.colsurfb.2010.12.024","article-title":"The size of solid lipid nanoparticles: An interpretation from experimental design","volume":"84","author":"Vitorino","year":"2011","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.jconrel.2013.02.011","article-title":"Co-encapsulating nanostructured lipid carriers for transdermal application: From experimental design to the molecular detail","volume":"167","author":"Vitorino","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ijpharm.2016.09.065","article-title":"Can lipid nanoparticles improve intestinal absorption?","volume":"515","author":"Mendes","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"119661","DOI":"10.1016\/j.ijpharm.2020.119661","article-title":"Biomimeting ultra-small lipid nanoconstructs for glioblastoma treatment: A computationally guided experimental approach","volume":"587","author":"Mendes","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1021\/la4029035","article-title":"On the role of specific interactions in the diffusion of nanoparticles in aqueous polymer solutions","volume":"30","author":"Mun","year":"2014","journal-title":"Langmuir"},{"key":"ref_19","first-page":"4439","article-title":"High-concentration zeta potential measurements using light-scattering techniques","volume":"368","author":"Kaszuba","year":"2010","journal-title":"Philos. Trans. R. Soc. Math. Phys. Eng. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Basso, J., Ramos, M.L., Pais, A., Vitorino, R., Fortuna, A., and Vitorino, C. (2021). Expediting Disulfiram Assays through a Systematic Analytical Quality by Design Approach. Chemosensors, 9.","DOI":"10.3390\/chemosensors9070172"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1208\/s12249-018-1078-0","article-title":"Unstructured formulation data analysis for the optimization of lipid nanoparticle drug delivery vehicles","volume":"19","author":"Silva","year":"2018","journal-title":"AAPS Pharm. Sci. Tech."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"120095","DOI":"10.1016\/j.ijpharm.2020.120095","article-title":"Sorting hidden patterns in nanoparticle performance for glioblastoma using machine learning algorithms","volume":"592","author":"Basso","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0169-7439(01)00155-1","article-title":"PLS-regression: A basic tool of chemometrics","volume":"58","author":"Wold","year":"2001","journal-title":"Chemom. Intell. Lab. Syst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0378-5173(02)00180-1","article-title":"Nanostructured lipid matrices for improved microencapsulation of drugs","volume":"242","author":"Radtke","year":"2002","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Doktorovova, S., Shegokar, R., and Souto, E.B. (2017). Role of excipients in formulation development and biocompatibility of lipid nanoparticles (SLNs\/NLCs). Nanostructures for Novel Therapy, Elsevier.","DOI":"10.1016\/B978-0-323-46142-9.00030-X"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jcis.2009.06.033","article-title":"Influence of hydrophilic surfactants on the properties of multiple W\/O\/W emulsions","volume":"338","author":"Schmidts","year":"2009","journal-title":"J. Colloid Interface Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.mencom.2015.09.026","article-title":"Properties of nanocapsules obtained from oil-in-water nanoemulsions","volume":"5","author":"Koroleva","year":"2015","journal-title":"Mendeleev Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ijpharm.2008.12.030","article-title":"Production and characterization of Hesperetin nanosuspensions for dermal delivery","volume":"371","author":"Mishra","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ijpharm.2011.05.008","article-title":"Lipid nanocarriers for dermal delivery of lutein: Preparation, characterization, stability and performance","volume":"414","author":"Mitri","year":"2011","journal-title":"Int. J. Pharm."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/223\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:08:55Z","timestamp":1760134135000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/223"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["biom12020223"],"URL":"https:\/\/doi.org\/10.3390\/biom12020223","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,27]]}}}