{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:13:11Z","timestamp":1787847191764,"version":"build-2784847793"},"reference-count":330,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Skin cancer (SC) is the most prevalent malignancy worldwide, with subtypes varying in aggressiveness: basal cell carcinoma tends to be locally invasive, squamous cell carcinoma has a higher metastatic risk, and melanoma remains the deadliest form. Current treatments such as surgery, radiotherapy, and systemic chemotherapy are associated with aesthetic and functional morbidity, recurrence, and\/or systemic toxicity. Although targeted therapies and immunotherapies offer clinical benefits, their high cost and limited accessibility underscore the need for innovative, affordable alternatives. Metal-based compounds (metallopharmaceuticals) are promising anticancer agents due to their ability to induce oxidative stress, modulate redox pathways, and interact with DNA. However, clinical translation has been limited by poor aqueous solubility, rapid degradation, and low skin permeability. This review discusses the most recent preclinical findings on gold, silver, platinum, palladium, ruthenium, vanadium, and copper complexes, mainly in topical and systemic treatments of SC. Advances in chemical and physical enhancers, such as hydrogels and microneedles, and in drug delivery systems, including bacterial nanocellulose membranes and nanoparticles, as well as liposomes and micelles, for enhancing skin permeation and protecting the integrity of metal complexes are also discussed. Additionally, we examine the contribution of photodynamic therapy to SC treatment and the use of mathematical and computational modeling to simulate skin drug transport, predict biodistribution, and support rational nanocarrier design. Altogether, these strategies aim to bridge the gap between physicochemical innovation and clinical applicability, paving the way for more selective, stable, and cost-effective SC treatments.<\/jats:p>","DOI":"10.3390\/pharmaceutics18020145","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T10:41:34Z","timestamp":1769164894000},"page":"145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Navigating the Challenges of Metallopharmaceutical Agents: Strategies and Predictive Modeling for Skin Cancer Therapy"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4632-7813","authenticated-orcid":false,"given":"Fernanda van Petten Vasconcelos","family":"Azevedo","sequence":"first","affiliation":[{"name":"School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-894, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0844-8702","authenticated-orcid":false,"given":"Ana L\u00facia Tasca Gois","family":"Ruiz","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, University of Campinas (UNICAMP), Campinas 13083-871, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0016-1715","authenticated-orcid":false,"given":"Diego Samuel","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"School of Technology, University of Campinas (UNICAMP), Limeira 13484-332, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas Hideki","family":"Nakahata","sequence":"additional","affiliation":[{"name":"Donostia International Physics Center\u2014DIPC, 20018 Donostia, Gipuzkoa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael Enoque Ferraz","family":"de Paiva","sequence":"additional","affiliation":[{"name":"Donostia International Physics Center\u2014DIPC, 20018 Donostia, Gipuzkoa, Spain"},{"name":"Chemistry Department, Faculty of Sciences, Universitat Aut\u00f2noma de Barcelona, 08193 Cerdanyola del Vall\u00e8s, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9289-4229","authenticated-orcid":false,"given":"Daniele Ribeiro","family":"de Araujo","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Paulista Medical School, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04023-062, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3301-6213","authenticated-orcid":false,"given":"Ana Carola","family":"de La Via","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC (UFABC), Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8394-2751","authenticated-orcid":false,"given":"Wendel Andrade","family":"Alves","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC (UFABC), Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8690-3053","authenticated-orcid":false,"given":"Michelle","family":"Barreto Requena","sequence":"additional","affiliation":[{"name":"Institute of Physics of S\u00e3o Carlos (IFSC), University of S\u00e3o Paulo (USP), S\u00e3o Carlos 13566-590, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Kurachi","sequence":"additional","affiliation":[{"name":"Institute of Physics of S\u00e3o Carlos (IFSC), University of S\u00e3o Paulo (USP), S\u00e3o Carlos 13566-590, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5197-9162","authenticated-orcid":false,"given":"Mirian Denise","family":"Stringasci","sequence":"additional","affiliation":[{"name":"Institute of Physics of S\u00e3o Carlos (IFSC), University of S\u00e3o Paulo (USP), S\u00e3o Carlos 13566-590, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Dirceu","family":"Vollet-Filho","sequence":"additional","affiliation":[{"name":"Institute of Physics of S\u00e3o Carlos (IFSC), University of S\u00e3o Paulo (USP), S\u00e3o Carlos 13566-590, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilton Rog\u00e9rio","family":"Lustri","sequence":"additional","affiliation":[{"name":"Institute of Biosciences, University of Araraquara (UNIARA), Araraquara 14801-340, SP, 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