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Spain","award":["B005830"],"award-info":[{"award-number":["B005830"]}]},{"name":"Instituto Salud Carlos III, Madrid, Spain","award":["FIS PI19\/00136"],"award-info":[{"award-number":["FIS PI19\/00136"]}]},{"name":"Instituto Salud Carlos III, Madrid, Spain","award":["PI20\/0077"],"award-info":[{"award-number":["PI20\/0077"]}]},{"name":"Instituto Salud Carlos III, Madrid, Spain","award":["FI19\/00007"],"award-info":[{"award-number":["FI19\/00007"]}]},{"name":"Instituto Salud Carlos III, Madrid, Spain","award":["FI21\/00146"],"award-info":[{"award-number":["FI21\/00146"]}]},{"name":"Instituto Salud Carlos III, Madrid, Spain","award":["CPII20\/00007"],"award-info":[{"award-number":["CPII20\/00007"]}]},{"name":"Instituto Salud Carlos III, Madrid, Spain","award":["B005830"],"award-info":[{"award-number":["B005830"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Lenvatinib, a tyrosine kinase inhibitor (TKI) approved for the treatment of progressive and radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), is associated with significant adverse effects that can be partially mitigated through the development of novel drug formulations. The utilization of nanoparticles presents a viable option, as it allows for targeted drug delivery, reducing certain side effects and enhancing the overall quality of life for patients. This study aimed to produce and assess, both in vitro and in vivo, the cytotoxicity, biodistribution, and therapeutic efficacy of lenvatinib-loaded PLGA nanoparticles (NPs), both with and without decoration using antibody conjugation (cetuximab), as a novel therapeutic approach for managing aggressive thyroid tumors. Methods: Poly(lactic-co-glycolic acid) nanoparticles (NPs), decorated with or without anti-EGFR, were employed as a lenvatinib delivery system. These NPs were characterized for size distribution, surface morphology, surface charge, and drug encapsulation efficiency. Cytotoxicity was evaluated through MTT assays using two cellular models, one representing normal thyroid cells (Nthy-ori 3-1) and the other representing anaplastic thyroid cells (CAL-62). Additionally, an in vivo xenograft mouse model was established to investigate biodistribution and therapeutic efficacy following intragastric administration. Results: The NPs demonstrated success in terms of particle size, polydispersity index (PDI), zeta potential, morphology, encapsulation efficiency, and cetuximab distribution across the surface. In vitro analysis revealed cytotoxicity in both cellular models with both formulations, but only the decorated NPs achieved an ID50 value in CAL-62 cells. Biodistribution analysis following intragastric administration in xenografted thyroid mice demonstrated good stability in terms of intestinal barrier function and tumor accumulation. Both formulations were generally well tolerated without inducing pathological effects in the examined organs. Importantly, both formulations increased tumor necrosis; however, decorated NPs exhibited enhanced parameters related to apoptotic\/karyolytic forms, mitotic index, and vascularization compared with NPs without decoration. Conclusions: These proof-of-concept findings suggest a promising strategy for administering TKIs in a more targeted and effective manner.<\/jats:p>","DOI":"10.3390\/biom13111647","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T02:20:37Z","timestamp":1699928437000},"page":"1647","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Lenvatinib-Loaded Poly(lactic-co-glycolic acid) Nanoparticles with Epidermal Growth Factor Receptor Antibody Conjugation as a Preclinical Approach to Therapeutically Improve Thyroid Cancer with Aggressive Behavior"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2971-5651","authenticated-orcid":false,"given":"Giovanna","family":"Revilla","sequence":"first","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"},{"name":"Departament of Biochemistry and Molecular Biology, Universitat Aut\u00f2noma de Barcelona, C\/Antoni M. Claret 167, 08025 Barcelona, Spain"},{"name":"Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5966-6155","authenticated-orcid":false,"given":"Nuseibah","family":"Al Qtaish","sequence":"additional","affiliation":[{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"},{"name":"Pharmacy Department, College of Pharmacy, Amman Arab University, P.O. Box 2234, Amman 11953, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0170-4355","authenticated-orcid":false,"given":"Pablo","family":"Caruana","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Sainz-Ramos","sequence":"additional","affiliation":[{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"},{"name":"Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Lopez-Mendez","sequence":"additional","affiliation":[{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"},{"name":"Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-3748","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"Paez-Espinosa","sequence":"additional","affiliation":[{"name":"Department Clinical Biochemistry, School of Medicine, Pontificia Universidad Cat\u00f3lica del Ecuador (PUCE), Av. 12 de Octubre 1076 y Roca, Quito 17012184, Pichincha, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2847-3737","authenticated-orcid":false,"given":"Changda","family":"Li","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"},{"name":"Departament of Biochemistry and Molecular Biology, Universitat Aut\u00f2noma de Barcelona, C\/Antoni M. Claret 167, 08025 Barcelona, Spain"},{"name":"Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00faria Fucui","family":"Vallverd\u00fa","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Edwards","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5551-0145","authenticated-orcid":false,"given":"Antonio","family":"Moral","sequence":"additional","affiliation":[{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"Department of General Surgery, Hospital de la Santa Creu i Sant Pau, C\/Sant Quint\u00ed 89, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Ignacio","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Hospital de la Santa Creu i Sant Pau, C\/Sant Quint\u00ed 89, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9021-2485","authenticated-orcid":false,"given":"Juan Carlos","family":"Escol\u00e0-Gil","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"},{"name":"Departament of Biochemistry and Molecular Biology, Universitat Aut\u00f2noma de Barcelona, C\/Antoni M. Claret 167, 08025 Barcelona, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3938-2267","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Pedraz","sequence":"additional","affiliation":[{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"},{"name":"Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9312-8147","authenticated-orcid":false,"given":"Idoia","family":"Gallego","sequence":"additional","affiliation":[{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"},{"name":"Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5055-6814","authenticated-orcid":false,"given":"Rosa","family":"Corcoy","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"},{"name":"Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"CIBER de Diabetes y Enfermedades Metab\u00f3licas Asociadas (CIBERDEM), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2956-5833","authenticated-orcid":false,"given":"Mar\u00eda Virtudes","family":"C\u00e9spedes","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1536-7601","authenticated-orcid":false,"given":"Gustavo","family":"Puras","sequence":"additional","affiliation":[{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country (UPV\/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain"},{"name":"Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eug\u00e8nia","family":"Mato","sequence":"additional","affiliation":[{"name":"Research Biomedical Institute (IIB) Sant Pau, C\/Sant Quint\u00ed 77, 08041 Barcelona, Spain"},{"name":"Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), C\/Monforte de Lemos 3-5, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1177\/1758834014548188","article-title":"Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer","volume":"6","author":"Worden","year":"2014","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aashiq, M., Silverman, D.A., Na\u2019ara, S., Takahashi, H., and Amit, M. (2019). Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies. Cancers, 11.","DOI":"10.3390\/cancers11091382"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1089\/thy.2011.0535","article-title":"The Impact of Distant Metastases at Presentation on Prognosis in Patients with Differentiated Carcinoma of the Thyroid Gland","volume":"22","author":"Nixon","year":"2012","journal-title":"Thyroid"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6467","DOI":"10.2147\/OTT.S84625","article-title":"Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer","volume":"9","author":"Lorusso","year":"2016","journal-title":"OncoTargets Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ejca.2019.05.031","article-title":"Real-world efficacy and safety of lenvatinib: Data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy","volume":"118","author":"Locati","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.21037\/gs.2019.10.18","article-title":"Novel treatments for anaplastic thyroid carcinoma","volume":"9","author":"Ferrari","year":"2020","journal-title":"Gland Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1099280","DOI":"10.3389\/fonc.2022.1099280","article-title":"Molecular features of aggressive thyroid cancer","volume":"12","author":"Elia","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/nrclinonc.2015.30","article-title":"SELECT\u2014Lenvatinib in thyroid cancer","volume":"12","author":"Killock","year":"2015","journal-title":"Nat. Rev. Clin. 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