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Herein, a strategy is presented to stabilize, transport, and intracellularly release a platinum<jats:sup>IV<\/jats:sup> (Pt<jats:sup>IV<\/jats:sup>) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as an anticancer drug, is promoted by the presence of glutathione in neoplastic cells that also causes the destruction of the carrier. The nanocage presents a single internal cavity in which the hydrophobic complex (Pt(dach)Cl<jats:sub>2<\/jats:sub>(OH)<jats:sub>2<\/jats:sub>), (dach = <jats:italic>R<\/jats:italic>,<jats:italic>R<\/jats:italic>\u2010diaminocyclohexane) is encapsulated. The in vitro uptake and the internalization kinetics in cancer model cells are evaluated and, using flow cytometry analysis, the successful release and activation of the Pt\u2010based drug inside cancer cells are demonstrated. The in vitro findings are confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patient\u2010derived malignant pleural mesothelioma. MPM487 confirms the well\u2010known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth is observed when mice are treated with the Pt<jats:sup>IV<\/jats:sup>, entrapped in the nanocages, at an equivalent dose of the platinum complex.<\/jats:p>","DOI":"10.1002\/adhm.202202932","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T02:15:26Z","timestamp":1678673726000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli\u2010Responsive Nanocages"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8762-5457","authenticated-orcid":false,"given":"Mar\u00eda","family":"Sancho\u2010Albero","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milan 20156 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Facchetti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science DISFARM Universit\u00e0 degli Studi di Milano  Milan 20133 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00f2","family":"Panini","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milan 20156 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Meroni","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milan 20156 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezia","family":"Bello","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milan 20156 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Rimoldi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science DISFARM Universit\u00e0 degli Studi di Milano  Milan 20133 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Zucchetti","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milan 20156 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Frapolli","sequence":"additional","affiliation":[{"name":"Laboratory of Cancer Pharmacology Department of Oncology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milan 20156 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2152-6517","authenticated-orcid":false,"given":"Luisa","family":"De Cola","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Via Mario Negri 2 Milan 20156 Italy"},{"name":"Department of Pharmaceutical Science DISFARM Universit\u00e0 degli Studi di Milano  Milan 20133 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,28]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/205698a0"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/157489206775246458"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2ee03590a"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2013.01.005"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2478\/raon-2019-0018"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/1871520611313020016"},{"key":"e_1_2_8_7_1","first-page":"534","volume":"20","author":"Pekarik V.","year":"2013","journal-title":"Curr. 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