{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T12:15:27Z","timestamp":1772799327833,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000},"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 a Tecnologia","doi-asserted-by":"publisher","award":["UIDP\/04567\/2020 and UIDB\/04567\/2020"],"award-info":[{"award-number":["UIDP\/04567\/2020 and UIDB\/04567\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Different approaches have been reported to enhance penetration of small drugs through physiological barriers; among them is the self-assembly drug conjugates preparation that shows to be a promising approach to improve activity and penetration, as well as to reduce side effects. In recent years, the use of drug-conjugates, usually obtained by covalent coupling of a drug with biocompatible lipid moieties to form nanoparticles, has gained considerable attention. Natural products isolated from plants have been a successful source of potential drug leads with unique structural diversity. In the present work three molecules derived from natural products were employed as lead molecules for the synthesis of self-assembled nanoparticles. The first molecule is the cytotoxic royleanone 7\u03b1-acetoxy-6\u03b2-hydroxyroyleanone (Roy, 1) that has been isolated from hairy coleus (Plectranthus hadiensis (Forssk.) Schweinf). ex Sprenger leaves in a large amount. This royleanone, its hemisynthetic derivative 7\u03b1-acetoxy-6\u03b2-hydroxy-12-benzoyloxyroyleanone (12BzRoy, 2) and 6,7-dehydroroyleanone (DHR, 3), isolated from the essential oil of thicket coleus (P. madagascariensis (Pers.) Benth.) were employed in this study. The royleanones were conjugated with squalene (sq), oleic acid (OA), and\/or 1-bromododecane (BD) self-assembly inducers. Roy-OA, DHR-sq, and 12BzRoy-sq conjugates were successfully synthesized and characterized. The cytotoxic effect of DHR-sq was previously assessed on three human cell lines: NCI-H460 (IC50 74.0 \u00b1 2.2 \u00b5M), NCI-H460\/R (IC50 147.3 \u00b1 3.7 \u00b5M), and MRC-5 (IC50 127.3 \u00b1 7.3 \u00b5M), and in this work Roy-OA NPs was assayed against Vero-E6 cells at different concentrations (0.05, 0.1, and 0.2 mg\/mL). The cytotoxicity of DHR-sq NPs was lower when compared with DHR alone in these cell lines: NCI-H460 (IC50 10.3 \u00b1 0.5 \u00b5M), NCI-H460\/R (IC50 10.6 \u00b1 0.4 \u00b5M), and MRC-5 (IC5016.9 \u00b1 0.5 \u00b5M). The same results were observed with Roy-OA NPs against Vero-E6 cells as was found to be less cytotoxic than Roy alone in all the concentrations tested. From the obtained DLS results, 12BzRoy-sq assemblies were not in the nano range, although Roy-OA NP assemblies show a promising size (509.33 nm), Pdl (0.249), zeta potential (\u221246.2 mV), and spherical morphology from SEM. In addition, these NPs had a low release of Roy at physiological pH 7.4 after 24 h. These results suggest the nano assemblies can act as prodrugs for the release of cytotoxic lead molecules.<\/jats:p>","DOI":"10.3390\/ijms221910210","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T22:50:48Z","timestamp":1632351048000},"page":"10210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Self-Assembly Nanoparticles of Natural Bioactive Abietane Diterpenes"],"prefix":"10.3390","volume":"22","author":[{"given":"Epole","family":"Ntungwe","sequence":"first","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal"},{"name":"Pharmacology Area (Pharmacognosy Laboratory), New Antitumor Compounds: Toxic Action on Leukemia Cells Research Group, Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcal\u00e1 de Henares, Ctra. A2, Km 33.100\u2013Campus Universitario, 28805 Alcal\u00e1 de Henares, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7884-4292","authenticated-orcid":false,"given":"Eva Mar\u00eda","family":"Dom\u00ednguez-Mart\u00edn","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal"},{"name":"Pharmacology Area (Pharmacognosy Laboratory), New Antitumor Compounds: Toxic Action on Leukemia Cells Research Group, Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcal\u00e1 de Henares, Ctra. A2, Km 33.100\u2013Campus Universitario, 28805 Alcal\u00e1 de Henares, Spain"}]},{"given":"Gabrielle","family":"Bangay","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal"},{"name":"Pharmacology Area (Pharmacognosy Laboratory), New Antitumor Compounds: Toxic Action on Leukemia Cells Research Group, Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcal\u00e1 de Henares, Ctra. A2, Km 33.100\u2013Campus Universitario, 28805 Alcal\u00e1 de Henares, Spain"}]},{"given":"Catarina","family":"Garcia","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal"},{"name":"Pharmacology Area (Pharmacognosy Laboratory), New Antitumor Compounds: Toxic Action on Leukemia Cells Research Group, Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcal\u00e1 de Henares, Ctra. A2, Km 33.100\u2013Campus Universitario, 28805 Alcal\u00e1 de Henares, Spain"}]},{"given":"Iris","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal"}]},{"given":"Eleonora","family":"Colombo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9531-4939","authenticated-orcid":false,"given":"Lucilia","family":"Saraiva","sequence":"additional","affiliation":[{"name":"LAQV-Faculty of Pharmacy of University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4216-3997","authenticated-orcid":false,"given":"Ana Mar\u00eda","family":"D\u00edaz-Lanza","sequence":"additional","affiliation":[{"name":"Pharmacology Area (Pharmacognosy Laboratory), New Antitumor Compounds: Toxic Action on Leukemia Cells Research Group, Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcal\u00e1 de Henares, Ctra. A2, Km 33.100\u2013Campus Universitario, 28805 Alcal\u00e1 de Henares, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2691-3110","authenticated-orcid":false,"given":"Andreia","family":"Rosatella","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal"},{"name":"iMed.ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9679-4022","authenticated-orcid":false,"given":"Marta M.","family":"Alves","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1046-4031","authenticated-orcid":false,"given":"Catarina Pinto","family":"Reis","sequence":"additional","affiliation":[{"name":"iMed.ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6180-9581","authenticated-orcid":false,"given":"Daniele","family":"Passarella","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7992-8343","authenticated-orcid":false,"given":"Patricia","family":"Rijo","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Universidade Lus\u00f3fona\u2019s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal"},{"name":"iMed.ULisboa, Faculdade de Farm\u00e1cia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.2147\/IJN.S127683","article-title":"A review of drug delivery systems based on nanotechnology and green chemistry: Green nanomedicine","volume":"12","author":"Jahangirian","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_2","first-page":"1","article-title":"Nanoparticle-Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions","volume":"15","author":"Liu","year":"2019","journal-title":"Small"},{"key":"ref_3","first-page":"4927312","article-title":"Cancer Nanomedicine: A New Era of Successful Targeted Therapy","volume":"2019","author":"Althubiti","year":"2019","journal-title":"J. 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