{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:54:52Z","timestamp":1789678492951,"version":"4.0.1"},"reference-count":49,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The pomegranate peel represents an important source of secondary metabolites such as hydrolysable ellagitannins, which are recognized for their antioxidant, anticancer and neuroprotective properties. In this work, the freeze-dried pomegranate peel was extracted by a combined mild maceration at room temperature and ultrasonication at 45 \u00b0C using ethanol and acetone as green solvents. The ethanol extract, with an extraction yield of 29%, and IC50 (mg\/mL) 0.1067 and 0.0414 for DPPH and ABTS, respectively, was incorporated into a polymer based on dextran, using a grafting reaction, to improve its bioavailability and preserve the chemical integrity. In addition, the potential antitumor activity against breast cancer was evaluated based on the existing literature. In vitro studies have demonstrated the safety and biocompatibility of both free pomegranate peel extract (SSE2-L) and its dextran conjugate (SSPD), with no adverse effects on fibroblasts, erythrocytes, or immune cells. Both formulations inhibited the proliferation of breast cancer cell lines (MCF-7, MDA-MB-231) in a concentration- and time-dependent manner, with SSPD consistently showing superior efficacy. This enhanced activity was corroborated by reduced clonogenic growth, G1 cell-cycle arrest, and improved stability and bioactive retention conferred by polymer conjugation. Overall, these findings highlight dextran-conjugated pomegranate polyphenols as promising candidates for next-generation nutraceuticals and phytopharmaceuticals in cancer chemoprevention and adjunctive therapy, with potential applications extending to other biomedical fields and functional foods.<\/jats:p>","DOI":"10.3390\/ijms262110618","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:15:14Z","timestamp":1762175714000},"page":"10618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antiproliferative Evaluation of Dextran Polymer-Based Pomegranate Ethanolic Extract"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5447-9497","authenticated-orcid":false,"given":"Umile Gianfranco","family":"Spizzirri","sequence":"first","affiliation":[{"name":"Ionian Department of Law, Economics and Environment, University of Bari Aldo Moro, 74123 Taranto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa Francesca","family":"Motta","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Ferraro","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Strigaro","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2590-2866","authenticated-orcid":false,"given":"Cinzia","family":"Benincasa","sequence":"additional","affiliation":[{"name":"Council for Agricultural Research and Economics (CREA), Research Centre for Olive, Fruit and Citrus Crops, Via Settimio Severo 83, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9588-9591","authenticated-orcid":false,"given":"Rosa","family":"Nicoletti","sequence":"additional","affiliation":[{"name":"Council for Agricultural Research and Economics (CREA), Research Centre for Olive, Fruit and Citrus Crops, Via Settimio Severo 83, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Astuto","sequence":"additional","affiliation":[{"name":"Ionian Department of Law, Economics and Environment, University of Bari Aldo Moro, 74123 Taranto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-9601","authenticated-orcid":false,"given":"Ubaldo","family":"Comite","sequence":"additional","affiliation":[{"name":"Department of Business Sciences, University Giustino Fortunato, 82100 Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8313-2492","authenticated-orcid":false,"given":"Rocco","family":"Malivindi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, 87036 Rende, Italy"},{"name":"Clinical Laboratory Unit, AO SS Annunziata, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-5582","authenticated-orcid":false,"given":"Francesca","family":"Aiello","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","first-page":"635","article-title":"Pomegranate and its health-promoting benefits","volume":"9","year":"2010","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_2","first-page":"128","article-title":"Therapeutic applications of pomegranate","volume":"13","author":"Jurenka","year":"2008","journal-title":"Altern. Med. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"G\u00f6rg\u00fc\u00e7, A., Gen\u00e7da\u011f, E., and Y\u0131lmaz, F. (2022). Industrial Pomegranate Wastes and their Functional Benefits in Novel Food Formulations. Mediterranean Fruits Bio-Wastes, Springer International Publishing.","DOI":"10.1007\/978-3-030-84436-3_31"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"130465","DOI":"10.1016\/j.foodchem.2021.130465","article-title":"Novel trends in extraction and optimization methods of bioactives recovery from pomegranate fruit biowastes: Valorization purposes for industrial applications","volume":"365","author":"Farag","year":"2021","journal-title":"Food Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1007\/s13197-016-2222-z","article-title":"Standardization of the conditions for extraction of polyphenols from pomegranate peel","volume":"53","author":"Venkataramanamma","year":"2016","journal-title":"J. Food Sci. Technol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1007\/s13197-017-2727-0","article-title":"Antioxidant properties and phenolic profile characterization by LC-MS\/MS of selected Tunisian pomegranate peels","volume":"54","author":"Abid","year":"2017","journal-title":"J. Food Sci. Technol."},{"key":"ref_7","first-page":"130682","article-title":"Ellagitannins and their metabolites as bioactive constituents of pomegranate: Recent advances and future directions","volume":"367","author":"Fahmy","year":"2021","journal-title":"Food Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.1002\/fsn3.3320","article-title":"Nutritional importance and industrial uses of pomegranate peel: A critical review","volume":"11","author":"Ain","year":"2023","journal-title":"Food Sci. Nutr."},{"key":"ref_9","first-page":"1375","article-title":"Phenolic compounds and related enzymes as determinants of quality in fruits and vegetables","volume":"89","year":"2009","journal-title":"J. Sci. Food Agric."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6535","DOI":"10.1021\/jf5024615","article-title":"Ellagic acid metabolism by human gut microbiota: Consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status","volume":"62","author":"Selma","year":"2014","journal-title":"J. Agric. Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Noreen, S., Hashmi, B., Aja, P.M., and Atoki, A.V. (2025). Phytochemicals and pharmacology of pomegranate (Punica granatum L.): Nutraceutical benefits and industrial applications: A review. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1528897"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.clnu.2017.03.012","article-title":"The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome","volume":"37","author":"Selma","year":"2018","journal-title":"Clin. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1002\/mc.21995","article-title":"Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells","volume":"53","author":"Shirode","year":"2014","journal-title":"Mol. Carcinog."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1158\/1940-6207.CAPR-08-0225","article-title":"Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro","volume":"3","author":"Adams","year":"2010","journal-title":"Cancer Prev. Res."},{"key":"ref_15","first-page":"193","article-title":"Anticancer effects of pomegranate extract on breast cancer cell lines: A systematic review","volume":"5","author":"Esmaeli","year":"2025","journal-title":"Discov. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1080\/01635581.2017.1359318","article-title":"Pomegranate extract alters breast cancer stem cell properties and inhibits epithelial-to-mesenchymal transition","volume":"69","author":"Nallanthighal","year":"2017","journal-title":"Nutr. Cancer"},{"key":"ref_17","first-page":"982","article-title":"The potent in vivo antioxidant ellagic acid derivatives from pomegranate juice","volume":"24","author":"Parra","year":"2005","journal-title":"Clin. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6485","DOI":"10.1021\/jf902107d","article-title":"Interaction between phenolics and gut microbiota: Role in human health","volume":"57","author":"Selma","year":"2009","journal-title":"J. Agric. Food Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1021\/acs.jafc.2c08889","article-title":"Gut Bacteria Involved in Ellagic Acid Metabolism to Yield Human Urolithin Metabotypes Revealed","volume":"71","author":"Selma","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rudrapal, M., Mishra, A.K., Rani, L., Sarwa, K.K., Zothantluanga, J.H., Khan, J., Kamal, M., Palai, S., Bendale, A.R., and Talele, S.G. (2022). Nanodelivery of Dietary Polyphenols for Therapeutic Applications. Molecules, 27.","DOI":"10.3390\/molecules27248706"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"116666","DOI":"10.1016\/j.lwt.2024.116666","article-title":"Screening of the antioxidant and vasorelaxant activity of wine waste ultrasonic extracts, and HRMS targeted and semi-targeted profiling of glycosylated polyphenols vs free polyphenols","volume":"208","author":"Medana","year":"2024","journal-title":"LWT Food Sci. Technol."},{"key":"ref_22","first-page":"335","article-title":"Dextrans: From biochemistry to biotechnology","volume":"3","author":"Bataille","year":"1985","journal-title":"Biotechnol. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1517\/17425247.2012.673580","article-title":"Dextran conjugates in drug delivery","volume":"9","author":"Varshosaz","year":"2012","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"131635","DOI":"10.1016\/j.foodchem.2021.131635","article-title":"Pomegranate peel-derived punicalagin: Ultrasonic-assisted extraction, purification, and its \u03b1-glucosidase inhibitory mechanism","volume":"374","author":"Liu","year":"2022","journal-title":"Food Chem."},{"key":"ref_25","first-page":"414","article-title":"Isolation and Standardization of Various Phytochemical Constituents from Methanolic Extracts of Fruit Rinds of Punica granatum","volume":"9","author":"Jain","year":"2011","journal-title":"Chin. J. Nat. Med."},{"key":"ref_26","first-page":"56","article-title":"Formulation and evaluation of niosomes containing punicalagin from peels of punica granatum","volume":"2","author":"Priya","year":"2012","journal-title":"J. Drug Deliv. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.jfca.2013.01.003","article-title":"Phenolic profile characterization of pomegranate (Punica granatum) juice by high-performance liquid chromatography with diode array detection coupled to an electrospray ion trap mass analyzer","volume":"30","author":"Sentandreu","year":"2013","journal-title":"J. Food Compos. Anal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1016\/j.foodchem.2011.11.106","article-title":"Quantitative determination of major polyphenol constituents in pomegranate products","volume":"132","author":"Qu","year":"2012","journal-title":"Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/fft2.65","article-title":"Available technologies on improving the stability of polyphenols in food processing","volume":"2","author":"Cao","year":"2021","journal-title":"Food Front."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lopes de Oliveira, I., Dom\u00ednguez-Rodr\u00edguez, G., Montero, L., Vigan\u00f3, J., Cifuentes, A., Arial Rostagno, M., and Ib\u00e1\u00f1ez, E. (2024). Advanced Extraction Techniques Combined with Natural Deep Eutectic Solvents for Extracting Phenolic Compounds from Pomegranate (Punica granatum L.) Peels. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25189992"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1002\/jssc.201601310","article-title":"Phenolic composition of pomegranate peel extracts using a liquid chromatography-mass spectrometry approach with silica hydride columns","volume":"40","author":"Young","year":"2017","journal-title":"J. Sep. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.fct.2018.02.023","article-title":"Antioxidant activity and total phenolic content of ethanolic extract of pomegranate peels, juice and seeds","volume":"114","author":"Derakhshana","year":"2018","journal-title":"Food Chem. Toxicol."},{"key":"ref_33","first-page":"4724","article-title":"Total phenolic contents and antioxidant activities of pomegranate peel, seed, leaf and flower","volume":"6","author":"Elfalleh","year":"2015","journal-title":"J. Med Plants Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4086","DOI":"10.1111\/ijfs.15724","article-title":"Milk Kefir Enriched with Inulin Grafted Seed Extract from White Wine Pomace: Chemical Characterization, Antioxidant Profile and in vitro Gastrointestinal Digestion","volume":"57","author":"Carullo","year":"2022","journal-title":"Int. J. Food Sci. Technol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109221","DOI":"10.1016\/j.foodhyd.2023.109221","article-title":"Recent advances in the conjugation approaches for enhancing the bioavailability of polyphenols","volume":"146","author":"Sahraeian","year":"2024","journal-title":"Food Hydrocoll."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3390\/suschem2020015","article-title":"Green Chemistry Approach for Fabrication of Polymer Composites","volume":"2","author":"Blessy","year":"2021","journal-title":"Sustain. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Carullo, G., Scarpelli, F., Belsito, E.L., Caputo, P., Oliviero Rossi, C., Mincione, A., Leggio, A., Crispini, A., Restuccia, D., and Spizzirri, U.G. (2020). Formulation of New Baking (+)-Catechin Based Leavening Agents: Effects on Rheology, Sensory and Antioxidant Features during Muffin Preparation. Foods, 9.","DOI":"10.3390\/foods9111569"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1111\/ijfs.14045","article-title":"Autochthonous white grape pomaces as bioactive source for functional jams","volume":"54","author":"Restuccia","year":"2019","journal-title":"Int. J. Food Sci. Technol."},{"key":"ref_39","unstructured":"(2009). Biological Evaluation of Medical Devices\u2014Part 5: Tests for In vitro Cytotoxicity (Standard No. ISO 10993-5:2009)."},{"key":"ref_40","unstructured":"(2021). Biological Evaluation of Medical Devices\u2014Part 12: Sample Preparation and Reference Materials (Standard No. ISO 10993-12:2021)."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Aiello, F., Malivindi, R., Motta, M.F., Crupi, P., Nicoletti, R., Benincasa, C., Clodoveo, M.L., Rago, V., Spizzirri, U.G., and Restuccia, D. (2023). Synthesis and Characterization of a Biopolymer Pectin\/Ethanolic Extract from Olive Mill Wastewater: In Vitro Safety and Efficacy Tests on Skin Wound Healing. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015075"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3844\/ajbbsp.2025.120.128","article-title":"Antiproliferative Potential of Pomegranate Peel Extract in MDA-MB Breast Cancer Cell Lines","volume":"21","author":"Manal","year":"2025","journal-title":"Am. J. Biochem. Biotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Petrovici, A.R., Pinteala, M., and Simionescu, N. (2023). Dextran Formulations as Effective Delivery Systems of Therapeutic Agents. Molecules, 28.","DOI":"10.3390\/molecules28031086"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4895","DOI":"10.2147\/IJN.S379758","article-title":"A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues","volume":"17","author":"Liu","year":"2022","journal-title":"Int. J. Nanomed."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e38354","DOI":"10.1016\/j.heliyon.2024.e38354","article-title":"Carob pulp flour as an innovative source of bioactive molecules for the preparation of high-value-added jellies","volume":"10","author":"Spizzirri","year":"2024","journal-title":"Helyion"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1021\/acsfoodscitech.4c00098","article-title":"Biostimulants for Sustainable Food Production: Effects of Wood Distillate to Fortify Chickpea Flour for Development of Functional Bakery Products","volume":"4","author":"Fedeli","year":"2024","journal-title":"ACS Food Sci. Technol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Aiello, F., Caputo, P., Oliviero Rossi, C., Restuccia, D., and Spizzirri, U.G. (2024). Formulation of Antioxidant Gummies Based on Gelatin Enriched with Citrus Fruit Peels Extract. Foods, 13.","DOI":"10.3390\/foods13020320"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Brindisi, M., Bouzidi, C., Frattaruolo, L., Loizzo, M.R., Tundis, R., Dugay, A., Deguin, B., Cappello, A.R., and Cappello, M.S. (2020). Chemical Profile, Antioxidant, Anti-Inflammatory, and Anti-Cancer Effects of Italian Salvia rosmarinus Spenn. Methanol Leaves Extracts. Antioxidants, 9.","DOI":"10.3390\/antiox9090826"},{"key":"ref_49","unstructured":"Universit\u00e0 della Calabria (2021). Unical: AOO1 Amministrazione Centrale, Universit\u00e0 della Calabria. Doc. No. 234, 14 January 2021."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10618\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:19:53Z","timestamp":1762175993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":49,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110618"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110618","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,31]]}}}