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Education, University, and Research (MIUR)","award":["DM1062\/2021"],"award-info":[{"award-number":["DM1062\/2021"]}]},{"name":"Italian Ministry of Education, University, and Research (MIUR)","award":["SIR2014"],"award-info":[{"award-number":["SIR2014"]}]},{"name":"Italian Ministry of Education, University, and Research (MIUR)","award":["FISR2020IP 03461"],"award-info":[{"award-number":["FISR2020IP 03461"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["IG 2018-ID. 21352"],"award-info":[{"award-number":["IG 2018-ID. 21352"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["ID.23928"],"award-info":[{"award-number":["ID.23928"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["ID.26617"],"award-info":[{"award-number":["ID.26617"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["DM1062\/2021"],"award-info":[{"award-number":["DM1062\/2021"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["SIR2014"],"award-info":[{"award-number":["SIR2014"]}]},{"name":"Italian Ministry of University and Research (MUR)","award":["FISR2020IP 03461"],"award-info":[{"award-number":["FISR2020IP 03461"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances made in CLL therapy with the new target agents, in some cases, relapses and resistance could occur, making the discovery of new alternatives to manage CLL refractoriness necessary. To provide new therapeutic strategies for CLL, we investigated the anti-leukemic activity of silver nanoparticles (AgNPs), whose impact on CLL cells has been poorly explored. Methods: We studied the action mechanisms of AgNPs in vitro through flow cytometry and molecular analyses. To improve the bioavailability of AgNPs, we generated AgNPs coated with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) and carried out imaging-based approaches and in vivo experiments to evaluate specificity, drug uptake, and efficacy. Results: AgNPs reduced the viability of primary CLL cells and the HG-3 cell line by inducing an intrinsic apoptotic pathway characterized by Bax\/Bcl-2 imbalance, caspase activation, and PARP degradation. Early apoptotic events triggered by AgNPs included enhanced Ca2+ influx and ROS overproduction. AgNPs synergistically potentiated the cytotoxicity of Venetoclax, Ibrutinib, and Bepridil. In vitro, the AgNPs@Rituximab conjugates were rapidly internalized within CLL cells and strongly prolonged the survival of CLL xenograft models compared to each unconjugated single agent. Conclusions: AgNPs showed strong anti-leukemic activity in CLL, with the potential for clinical translation in combination with agents used in CLL. The increased specificity of AgNPs@Rituximab toward CLL cells could be relevant for overcoming in vivo AgNPs\u2019 non-specific distribution and increasing their efficacy.<\/jats:p>","DOI":"10.3390\/cancers15143618","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T08:40:06Z","timestamp":1689324006000},"page":"3618","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Therapeutic Targeting Potential of Novel Silver Nanoparticles Coated with Anti-CD20 Antibody against Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"15","author":[{"given":"Francesco Maria","family":"Adamo","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estevao Carlos","family":"Silva Barcelos","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"},{"name":"Postgraduate Program in Biotechnology, Federal University of Esp\u00edrito Santo, Vit\u00f3ria 29043-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4008-2752","authenticated-orcid":false,"given":"Filomena","family":"De Falco","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Dorillo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Rompietti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Sorcini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Stella","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Del Papa","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Baldoni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"},{"name":"Department of Medicine and Sciences of Aging, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clelia","family":"Geraci","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Arcaleni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Pennetta","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnologies, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ragonese","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnologies, University of Perugia, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Moretti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariagrazia","family":"Mameli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, 06129 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6701-4023","authenticated-orcid":false,"given":"Mauro","family":"Di Ianni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Sciences of Aging, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Rosati","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Biosciences and Medical Embryology Section, University of Perugia, 06129 Perugia, 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