{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:53:15Z","timestamp":1791247995795,"version":"4.1.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":99,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Nano"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Proton boron capture therapy (PBCT), based on proton-boron fusion reactions (\n                    <jats:sup>11<\/jats:sup>\n                    B\u2009+\u2009p \u21923\u03b1\u2009+\u20098.7\u00a0MeV), has the potential to enhance the biological effectiveness of proton therapy. To achieve this potential, the efficient delivery of enough\n                    <jats:sup>11<\/jats:sup>\n                    B to cancer cells will be paramount. This study demonstrates a newly developed method of poor solvent\u2013mediated spontaneous assembly of polymeric micelles with entrapped\n                    <jats:italic>o<\/jats:italic>\n                    -carborane, in which ethanol is a good solvent for the payload\n                    <jats:italic>o<\/jats:italic>\n                    -carborane but a poor solvent for the hydrophobic segment poly(\u03b5-caprolactone) in this amphiphilic block copolymer. This method provided smaller polymeric micelles compared to use of tetrahydrofuran, a good solvent for the amphiphilic block copolymer, as the sole solvent for both payload and copolymer. The prepared nanoscale formulation enabled the boron-rich cage compound\n                    <jats:italic>o<\/jats:italic>\n                    -carborane to be effectively delivered to tumor cells, and its enhancement of the biological effectiveness of proton therapy was preliminarily validated in a pancreatic ductal adenocarcinoma cell line, MiaPaCa-2, by survival assays and DNA damage assessment. The\n                    <jats:sup>111<\/jats:sup>\n                    In-labeled congener was also successfully prepared and used in biodistribution assays in normal mice, opening the way to further studies on image-guided PBCT in preclinical animal models.\n                  <\/jats:p>","DOI":"10.1186\/s12645-026-00400-2","type":"journal-article","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T03:44:31Z","timestamp":1782618271000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["o-carborane encapsulated into polymeric micelles for proton boron capture therapy"],"prefix":"10.1186","volume":"17","author":[{"given":"Guodong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu-Xu","family":"Teng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9lia","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipa","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayan","family":"Sahoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lurdes","family":"Gano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f3nio","family":"Paulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"issue":"6","key":"400_CR1","doi-asserted-by":"publisher","first-page":"e245","DOI":"10.1016\/S1470-2045(23)00184-5","volume":"24","author":"S Yan","year":"2023","unstructured":"Yan S, Ngoma TA, Ngwa W, Bortfeld TR (2023) Global democratisation of proton radiotherapy. Lancet Oncol 24(6):e245\u2013e254","journal-title":"Lancet Oncol"},{"key":"400_CR2","first-page":"35","volume":"9","author":"A Luhr","year":"2018","unstructured":"Luhr A, von Neubeck C, Krause M, Troost EGC (2018) Relative biological effectiveness in proton beam therapy - Current knowledge and future challenges. Clin Transl Radiat Oncol 9:35\u201341","journal-title":"Clin Transl Radiat Oncol"},{"key":"400_CR3","doi-asserted-by":"crossref","unstructured":"Yoon DK, Jung JY, Suh TS (2014) Application of proton boron fusion reaction to radiation therapy: A Monte Carlo simulation study. Appl Phys Lett 105(22)","DOI":"10.1063\/1.4903345"},{"issue":"1","key":"400_CR4","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1038\/s41598-018-19258-5","volume":"8","author":"GAP Cirrone","year":"2018","unstructured":"Cirrone GAP, Manti L, Margarone D, Petringa G, Giuffrida L, Minopoli A, Picciotto A, Russo G, Cammarata F, Pisciotta P, Perozziello FM, Romano F, Marchese V, Milluzzo G, Scuderi V, Cuttone G, Korn G (2018) First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness. Sci Rep 8(1):1141","journal-title":"Sci Rep"},{"issue":"1","key":"400_CR5","doi-asserted-by":"publisher","first-page":"19264","DOI":"10.1038\/s41598-024-69370-y","volume":"14","author":"A Jel\u00ednek Michaelidesov\u00e1","year":"2024","unstructured":"Jel\u00ednek Michaelidesov\u00e1 A, Kundr\u00e1t P, Zahradn\u00ed\u010dek O, Danilov\u00e1 I, Pachnerov\u00e1 Brabcov\u00e1 K, Vachelov\u00e1 J, Vilimovsk\u00fd J, David M, Vondr\u00e1\u010dek V, Dav\u00eddkov\u00e1 M (2024) First independent validation of the proton-boron capture therapy concept. Sci Rep 14(1):19264","journal-title":"Sci Rep"},{"issue":"1","key":"400_CR6","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/s42003-023-04770-w","volume":"6","author":"FP Cammarata","year":"2023","unstructured":"Cammarata FP, Torrisi F, Vicario N, Bravata V, Stefano A, Salvatorelli L, D\u2019Aprile S, Giustetto P, Forte GI, Minafra L, Calvaruso M, Richiusa S, Cirrone GAP, Petringa G, Broggi G, Cosentino S, Scopelliti F, Magro G, Porro D, Libra M, Ippolito M, Russo G, Parenti R, Cuttone G (2023) Proton boron capture therapy (PBCT) induces cell death and mitophagy in a heterotopic glioblastoma model. Commun Biol 6(1):388","journal-title":"Commun Biol"},{"key":"400_CR7","doi-asserted-by":"crossref","unstructured":"Hosobuchi M, Kataoka J, Yokokawa H, Okazaki Y, Hirayama R, Inaniwa T, Ueda M, Kimura M (2023) Experimental verification of efficacy of pBCT in terms of physical and biological aspects, Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 1045:167537","DOI":"10.1016\/j.nima.2022.167537"},{"issue":"9","key":"400_CR8","doi-asserted-by":"publisher","first-page":"6098","DOI":"10.1002\/mp.15824","volume":"49","author":"M Manandhar","year":"2022","unstructured":"Manandhar M, Bright SJ, Flint DB, Martinus DKJ, Kolachina RV, Ben Kacem M, Titt U, Martin TJ, Lee CL, Morrison K, Shaitelman SF, Sawakuchi GO (2022) Effect of boron compounds on the biological effectiveness of proton therapy. Med Phys 49(9):6098\u20136109","journal-title":"Med Phys"},{"key":"400_CR9","doi-asserted-by":"crossref","unstructured":"Tran NH, Shtam T, Marchenko YY, Konevega AL, Lebedev D (2023) Current State and Prospectives for Proton Boron Capture Therapy. Biomedicines 11(6)","DOI":"10.3390\/biomedicines11061727"},{"issue":"1","key":"400_CR10","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1038\/s41598-023-28428-z","volume":"13","author":"T Shtam","year":"2023","unstructured":"Shtam T, Burdakov V, Garina A, Garaeva L, Tran NH, Volnitskiy A, Kuus E, Amerkanov D, Pack F, Andreev G, Lubinskiy A, Shabalin K, Verlov N, Ivanov E, Ezhov V, Lebedev D, Konevega AL (2023) Experimental validation of proton boron capture therapy for glioma cells. Sci Rep 13(1):1341","journal-title":"Sci Rep"},{"key":"400_CR11","doi-asserted-by":"crossref","unstructured":"Sato M, Hirose K, Takeno S, Aihara T, Nihei K, Takai Y, Hayashi T, Bando K, Kimura H, Tsurumi K, Ono K (2024) Safety of Boron Neutron Capture Therapy with Borofalan((10)B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance. Cancers (Basel) 16(5)","DOI":"10.3390\/cancers16050869"},{"key":"400_CR12","doi-asserted-by":"publisher","first-page":"122605","DOI":"10.1016\/j.biomaterials.2024.122605","volume":"309","author":"T Fujimoto","year":"2024","unstructured":"Fujimoto T, Teraishi F, Kanehira N, Tajima T, Sakurai Y, Kondo N, Yamagami M, Kuwada A, Morihara A, Kitamatsu M, Fujimura A, Suzuki M, Takaguchi Y, Shigeyasu K, Fujiwara T, Michiue H (2024) BNCT pancreatic cancer treatment strategy with glucose-conjugated boron drug. Biomaterials 309:122605","journal-title":"Biomaterials"},{"key":"400_CR13","doi-asserted-by":"publisher","first-page":"111826","DOI":"10.1016\/j.colsurfb.2021.111826","volume":"204","author":"H Quan","year":"2021","unstructured":"Quan H, Fan L, Huang Y, Xia X, He Y, Liu S, Yu J (2021) Hyaluronic acid-decorated carborane-TAT conjugation nanomicelles: A potential boron agent with enhanced selectivity of tumor cellular uptake. Colloids Surf B: Biointerfaces 204:111826","journal-title":"Colloids Surf B: Biointerfaces"},{"key":"400_CR14","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.biomaterials.2015.03.061","volume":"56","author":"Y Iguchi","year":"2015","unstructured":"Iguchi Y, Michiue H, Kitamatsu M, Hayashi Y, Takenaka F, Nishiki T, Matsui H (2015) Tumor-specific delivery of BSH-3R for boron neutron capture therapy and positron emission tomography imaging in a mouse brain tumor model. Biomaterials 56:10\u201317","journal-title":"Biomaterials"},{"key":"400_CR15","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.jconrel.2021.02.021","volume":"332","author":"T Nomoto","year":"2021","unstructured":"Nomoto T, Yao Y, Inoue Y, Suzuki M, Kanamori K, Takemoto H, Matsui M, Tomoda K, Nishiyama N (2021) Fructose-functionalized polymers to enhance therapeutic potential of p-boronophenylalanine for neutron capture therapy. J Control Rel 332:184\u2013193","journal-title":"J Control Rel"},{"issue":"4","key":"400_CR16","doi-asserted-by":"publisher","first-page":"eaaz1722","DOI":"10.1126\/sciadv.aaz1722","volume":"6","author":"T Nomoto","year":"2020","unstructured":"Nomoto T, Inoue Y, Yao Y, Suzuki M, Kanamori K, Takemoto H, Matsui M, Tomoda K, Nishiyama N (2020) Poly(vinyl alcohol) boosting therapeutic potential of p-boronophenylalanine in neutron capture therapy by modulating metabolism. Sci Adv 6(4):eaaz1722","journal-title":"Sci Adv"},{"issue":"1","key":"400_CR17","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.1038\/s41467-022-29780-w","volume":"13","author":"J Li","year":"2022","unstructured":"Li J, Sun Q, Lu C, Xiao H, Guo Z, Duan D, Zhang Z, Liu T, Liu Z (2022) Boron encapsulated in a liposome can be used for combinational neutron capture therapy. Nat Commun 13(1):2143","journal-title":"Nat Commun"},{"issue":"14","key":"400_CR18","doi-asserted-by":"publisher","first-page":"6844","DOI":"10.1021\/acs.chemrev.8b00199","volume":"118","author":"H Cabral","year":"2018","unstructured":"Cabral H, Miyata K, Osada K, Kataoka K (2018) Block copolymer micelles in nanomedicine applications. Chem Rev 118(14):6844\u20136892","journal-title":"Chem Rev"},{"key":"400_CR19","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.biomaterials.2016.06.002","volume":"101","author":"Z He","year":"2016","unstructured":"He Z, Wan X, Schulz A, Bludau H, Dobrovolskaia MA, Stern ST, Montgomery SA, Yuan H, Li Z, Alakhova D, Sokolsky M, Darr DB, Perou CM, Jordan R, Luxenhofer R, Kabanov AV (2016) A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials 101:296\u2013309","journal-title":"Biomaterials"},{"key":"400_CR20","doi-asserted-by":"crossref","unstructured":"Serras A, Faustino C, Pinheiro L (2024) Functionalized Polymeric Micelles for Targeted Cancer Therapy: Steps from Conceptualization to Clinical Trials. Pharmaceutics 16(8)","DOI":"10.3390\/pharmaceutics16081047"},{"issue":"1","key":"400_CR21","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jconrel.2012.04.024","volume":"163","author":"HC Shin","year":"2012","unstructured":"Shin HC, Cho H, Lai TC, Kozak KR, Kolesar JM, Kwon GS (2012) Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D, L-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin. J Control Rel 163(1):93\u201399","journal-title":"J Control Rel"},{"key":"400_CR22","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.biomaterials.2018.01.014","volume":"159","author":"J Zhao","year":"2018","unstructured":"Zhao J, Wang H, Hsiao CH, Chow DS, Koay EJ, Kang Y, Wen X, Huang Q, Ma Y, Bankson JA, Ullrich SE, Overwijk W, Maitra A, Piwnica-Worms D, Fleming JB, Li C (2018) Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy. Biomaterials 159:215\u2013228","journal-title":"Biomaterials"},{"key":"400_CR23","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.jconrel.2021.02.031","volume":"332","author":"M Ghezzi","year":"2021","unstructured":"Ghezzi M, Pescina S, Padula C, Santi P, Del Favero E, Cant\u00f9 L, Nicoli S (2021) Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions. J Controlled Rel 332:312\u2013336","journal-title":"J Controlled Rel"},{"issue":"10","key":"400_CR24","doi-asserted-by":"publisher","first-page":"9881","DOI":"10.1021\/acsnano.8b02481","volume":"12","author":"J Zhao","year":"2018","unstructured":"Zhao J, Xiao Z, Li T, Chen H, Yuan Y, Wang YA, Hsiao CH, Chow DS, Overwijk WW, Li C (2018) Stromal modulation reverses primary resistance to immune checkpoint blockade in pancreatic cancer. ACS Nano 12(10):9881\u20139893","journal-title":"ACS Nano"},{"issue":"4","key":"400_CR25","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.jiec.2008.01.019","volume":"14","author":"Y-M Lim","year":"2008","unstructured":"Lim Y-M, Gwon H-J, Shin J, Jeun JP, Nho YC (2008) Preparation of porous poly(\u025b-caprolactone) scaffolds by gas foaming process and in vitro\/in vivo degradation behavior using \u03b3-ray irradiation. J Ind Eng Chem 14(4):436\u2013441","journal-title":"J Ind Eng Chem"},{"issue":"46","key":"400_CR26","doi-asserted-by":"publisher","first-page":"54739","DOI":"10.1021\/acsami.1c16383","volume":"13","author":"N Meher","year":"2021","unstructured":"Meher N, Seo K, Wang S, Bidkar AP, Fogarty M, Dhrona S, Huang X, Tang R, Blaha C, Evans MJ, Raleigh DR, Jun YW, VanBrocklin HF, Desai TA, Wilson DM, Ozawa T, Flavell RR (2021) Synthesis and preliminary biological assessment of carborane-loaded theranostic nanoparticles to target prostate-specific membrane antigen. ACS Appl Mater Interfaces 13(46):54739\u201354752","journal-title":"ACS Appl Mater Interfaces"},{"key":"400_CR27","doi-asserted-by":"publisher","first-page":"102915","DOI":"10.1016\/j.dnarep.2020.102915","volume":"93","author":"A Shibata","year":"2020","unstructured":"Shibata A, Jeggo PA (2020) Roles for 53BP1 in the repair of radiation-induced DNA double strand breaks. DNA Repair (Amst) 93:102915","journal-title":"DNA Repair (Amst)"},{"issue":"1","key":"400_CR28","first-page":"5","volume":"750","author":"R Scully","year":"2013","unstructured":"Scully R, Xie A (2013) Double strand break repair functions of histone H2AX. Mutat Research\/Fundamental Mol Mech Mutagen 750(1):5\u201314","journal-title":"Mutat Research\/Fundamental Mol Mech Mutagen"},{"issue":"1","key":"400_CR29","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13550-016-0167-x","volume":"6","author":"AC Laan","year":"2016","unstructured":"Laan AC, Santini C, Jennings L, de Jong M, Bernsen MR, Denkova AG (2016) Radiolabeling polymeric micelles for in vivo evaluation: a novel, fast, and facile method. EJNMMI Res 6(1):12","journal-title":"EJNMMI Res"},{"issue":"1","key":"400_CR30","first-page":"67","volume":"9","author":"A de la Fuente","year":"2019","unstructured":"de la Fuente A, Kramer S, Mohr N, Pektor S, Klasen B, Bausbacher N, Miederer M, Zentel R, Rosch F (2019) (68)Ga[Ga]-, (111)In[In]-oxine: a novel strategy of in situ radiolabeling of HPMA-based micelles. Am J Nucl Med Mol Imaging 9(1):67\u201383","journal-title":"Am J Nucl Med Mol Imaging"},{"issue":"3","key":"400_CR31","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1158\/0008-5472.CAN-07-5714","volume":"68","author":"RF Hwang","year":"2008","unstructured":"Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, Ji B, Evans DB, Logsdon CD (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68(3):918\u2013926","journal-title":"Cancer Res"},{"key":"400_CR32","unstructured":"Berger MJ, Coursey JS, Zucker MA, Chang J (2005) ESTAR, PSTAR, and ASTAR: Computer programs for calculating stopping-power and range tables for electrons, protons, and helium ions (version 1.2.3), National Institute of Standards and Technology, Gaithersburg, MD Originally published as: M.J. Berger, NISTIR 4999, National Institute of Standards and Technology, Gaithersburg, MD (1993)"},{"issue":"1","key":"400_CR33","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.ijrobp.2016.04.007","volume":"96","author":"CH McFadden","year":"2016","unstructured":"McFadden CH, Hallacy TM, Flint DB, Granville DA, Asaithamby A, Sahoo N, Akselrod MS, Sawakuchi GO (2016) Time-lapse monitoring of DNA damage colocalized with particle tracks in single living cells. Int J Radiat Oncol Biol Phys 96(1):221\u2013227","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"400_CR34","unstructured":"Andreo DTBP, Hohlfield K et al (2006) Absorbed dose determination in external beam radiotherapy: An international code of practice for dosimetry based on standards of absorbed dose to water, IAEA TRS-398 V12 International Atomic Energy Agency"},{"issue":"1","key":"400_CR35","doi-asserted-by":"publisher","first-page":"01TR01","DOI":"10.1088\/1361-6560\/aaf26a","volume":"64","author":"SJ McMahon","year":"2018","unstructured":"McMahon SJ (2018) The linear quadratic model: usage, interpretation and challenges. Phys Med Biol 64(1):01TR01","journal-title":"Phys Med Biol"}],"container-title":["Cancer Nanotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12645-026-00400-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12645-026-00400-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12645-026-00400-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:05:21Z","timestamp":1791245121000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12645-026-00400-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,28]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,12]]}},"alternative-id":["400"],"URL":"https:\/\/doi.org\/10.1186\/s12645-026-00400-2","relation":{},"ISSN":["1868-6958","1868-6966"],"issn-type":[{"value":"1868-6958","type":"print"},{"value":"1868-6966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,28]]},"assertion":[{"value":"3 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All experimental procedures involved animals were carried out in conformity with Portuguese law according to the EU Guidelines for Animal Care and Ethics in Animal Experimentation by properly accredited researchers and were approved by the national authority, Dire\u00e7\u00e3o-Geral da Alimenta\u00e7\u00e3o e Veterin\u00e1ria (DGAV), and the local animal welfare committee. The project approval number is: IST-ID_ORBEA_001\/070422.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"60"}}