{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T22:59:42Z","timestamp":1778799582326,"version":"3.51.4"},"reference-count":36,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science, Innovation, and Universities and CIBER-BBN","award":["MAT2017-84277-R"],"award-info":[{"award-number":["MAT2017-84277-R"]}]},{"name":"European University of Madrid","award":["2017\/UEM21 and 2019\/UEM06"],"award-info":[{"award-number":["2017\/UEM21 and 2019\/UEM06"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Currently, new treatments are required to supplement the current standard of care for head and neck squamous cell carcinoma (HNSCC). The phosphatidylinositol3-kinase (PI3K) signaling pathway is commonly altered and activated in HNSCC. PHT-427 is a dual PI3K-mammalian target of the AKT\/PDK1 inhibitor; however, to the best of our knowledge, the effect of the PHT-427 inhibitor on HNSCC has not been investigated. This study aims to evaluate the antitumoral effect of PHT-427-loaded polymeric nanoparticles based on \u03b1-tocopheryl succinate (\u03b1-TOS). The in vitro activity of PHT-427 was tested in hypopharynx carcinoma squamous cells (FaDu) to measure the cell viability, PI3KCA\/AKT\/PDK1 gene expression, and PI3KCA\/AKT\/PDK1 levels. Apoptosis, epidermal growth factor receptor (EGFR), and reactive oxygen species (ROS) were also measured. The presence of PHT-427 significantly enhances its antiproliferative and proapoptotic activity by inactivating the PI3K\/AKT\/PDK1 pathway. Nanoparticles (NPs) effectively suppress AKT\/PDK1 expression. Additionally, NPs loaded with PHT-427 produce high oxidative stress levels that induce apoptosis. In conclusion, these results are promising in the use of this nanoformulation as a PHT-427 delivery system for effective HNSCC treatment.<\/jats:p>","DOI":"10.3390\/pharmaceutics13081242","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T02:40:14Z","timestamp":1628736014000},"page":"1242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antitumor Activity of Nanoparticles Loaded with PHT-427, a Novel AKT\/PDK1 Inhibitor, for the Treatment of Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Joaqu\u00edn","family":"Yanes-D\u00edaz","sequence":"first","affiliation":[{"name":"Department Otolaryngology, Hospital Universitario de Getafe, Getafe (Madrid), Carretera de Toledo, km 12.500, 28905 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Palao-Suay","sequence":"additional","affiliation":[{"name":"Department of Polymeric Nanomaterials and Biomaterials Institute of Polymer Science and Technology CSIC, C\/Juan de la Cierva, 3, 28006 Madrid, Spain"},{"name":"Biomedical Research Centre in Bioengineering Biomaterials, and Nanomedicine CIBER-BBN, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7395-5754","authenticated-orcid":false,"given":"Mar\u00eda Rosa","family":"Aguilar","sequence":"additional","affiliation":[{"name":"Department of Polymeric Nanomaterials and Biomaterials Institute of Polymer Science and Technology CSIC, C\/Juan de la Cierva, 3, 28006 Madrid, Spain"},{"name":"Biomedical Research Centre in Bioengineering Biomaterials, and Nanomedicine CIBER-BBN, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Ignacio","family":"Riestra-Ayora","sequence":"additional","affiliation":[{"name":"Department Otolaryngology, Hospital Universitario de Getafe, Getafe (Madrid), Carretera de Toledo, km 12.500, 28905 Madrid, Spain"},{"name":"Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Od\u00f3n, 28670 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Ferruelo-Alonso","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n de Investigaci\u00f3n Biom\u00e9dica del Hospital Universitario de Getafe, Carretera de Toledo, km 12.500, 28905 Madrid, Spain"},{"name":"CIBER de Enfermedades Respiratorias, Instituto de Investigaci\u00f3n Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6334-6736","authenticated-orcid":false,"given":"Luis","family":"Rojo del Olmo","sequence":"additional","affiliation":[{"name":"Department of Polymeric Nanomaterials and Biomaterials Institute of Polymer Science and Technology CSIC, C\/Juan de la Cierva, 3, 28006 Madrid, Spain"},{"name":"Biomedical Research Centre in Bioengineering Biomaterials, and Nanomedicine CIBER-BBN, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5539-8026","authenticated-orcid":false,"given":"Blanca","family":"V\u00e1zquez-Lasa","sequence":"additional","affiliation":[{"name":"Department of Polymeric Nanomaterials and Biomaterials Institute of Polymer Science and Technology CSIC, C\/Juan de la Cierva, 3, 28006 Madrid, Spain"},{"name":"Biomedical Research Centre in Bioengineering Biomaterials, and Nanomedicine CIBER-BBN, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Sanz-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department Otolaryngology, Hospital Universitario de Getafe, Getafe (Madrid), Carretera de Toledo, km 12.500, 28905 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6246-0449","authenticated-orcid":false,"given":"Carolina","family":"S\u00e1nchez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Od\u00f3n, 28670 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.coms.2014.01.001","article-title":"Epidemiological trends in head and neck cancer and aids in diagnosis","volume":"26","author":"Vigneswaran","year":"2014","journal-title":"Oral Maxillofac. Surg. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3322\/caac.21166","article-title":"Cancer statistics 2013","volume":"63","author":"Siegel","year":"2013","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1002\/ijc.20740","article-title":"Trends in incidence and prognosis for head and neck cancer in the United States: A site-specific analysis of the SEER database","volume":"114","author":"Carvalho","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.3892\/ijo.2014.2505","article-title":"NVP-BEZ235, a dual PI3K\/mTOR inhibitor synergistically potentiates the antitumor effects of Cisplatin in bladder cancer cells","volume":"45","author":"Moon","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1200\/JCO.2009.25.3641","article-title":"The PI3K pathway as drug target in human cancer","volume":"28","author":"Courtney","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nrc2664","article-title":"Targeting PI3K signaling in cancer: Opportunities, challenges and limitations","volume":"9","author":"Engelman","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5497","DOI":"10.1038\/onc.2008.245","article-title":"PI3K pathway alterations in cancer: Variations on a theme","volume":"27","author":"Yuan","year":"2008","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Psyrri, A., Seiwert, T.Y., and Jimeno, A. (2013). Molecular Pathways in Head and Neck Cancer: EGFR, PI3K, and More. Am. Soc. Clin. Oncol. Educ. Book, 246\u2013255.","DOI":"10.1200\/EdBook_AM.2013.33.246"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/odi.12206","article-title":"The PI3K\/Akt\/mTOR axis in head and neck cancer: Functions, aberrations, cross-talk, and therapies","volume":"21","author":"Mohan","year":"2015","journal-title":"Oral Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1158\/1535-7163.MCT-09-0985","article-title":"Molecular pharmacology and antitumor activity of PHT-427, a novel akt\/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor","volume":"9","author":"Meuillet","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5073","DOI":"10.1158\/0008-5472.CAN-08-3839","article-title":"In vitro and In vivo Activity of Novel Small-Molecule Inhibitors Targeting the Pleckstrin Homology Domain of Protein Kinase B\/AKT","volume":"69","author":"Moses","year":"2009","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nrc.2016.108","article-title":"Cancer nanomedicine: Progress, challenges and opportunities","volume":"17","author":"Shi","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zhao, C.Y., Cheng, R., Yang, Z., and Tian, Z.M. (2018). Nanotechnology for Cancer Therapy Based on Chemotherapy. Molecules, 23.","DOI":"10.3390\/molecules23040826"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41573-020-0090-8","article-title":"Engineering precision nanoparticles for drug delivery","volume":"20","author":"Mitchell","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","first-page":"1513","article-title":"Immunogenic-cell-killing and immunosuppression-inhibiting nanomedicine","volume":"6","author":"Wang","year":"2020","journal-title":"Bioact. Mater."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.cclet.2019.01.003","article-title":"Histology and antitumor activity study of PTX-loaded micelle, a fluorescent drug delivery system prepared by PEG-TPP","volume":"30","author":"Li","year":"2019","journal-title":"Chin. Chem. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.1016\/j.cclet.2020.05.034","article-title":"Delivery of triptolide with reduction-sensitive polymer nanoparticles for liver cancer therapy on patient-derived xenografts models","volume":"31","author":"He","year":"2020","journal-title":"Chin. Chem. Lett."},{"key":"ref_19","first-page":"5653","article-title":"Nanoparticle delivery of an AKT\/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer","volume":"3","author":"Jeffery","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/mabi.201500265","article-title":"Mitochondrially targeted nanoparticles based on \u03b1-TOS for the selective cancer treatment","volume":"16","author":"Aguilar","year":"2016","journal-title":"Macromol. Biosci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Rodr\u00edguez, C., Palao-Suay, R., Rodrig\u00e1\u00f1ez, L., Aguilar, M.R., Mart\u00edn-Salda\u00f1a, S., San Rom\u00e1n, J., and Sanz-Fern\u00e1ndez, R. (2018). \u03b1-Tocopheryl Succinate-Based Polymeric Nanoparticles for the Treatment of Head and Neck Squamous Cell Carcinoma. Biomolecules, 8.","DOI":"10.3390\/biom8030097"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11103-012-9885-2","article-title":"miRDeepFinder: A miRNA analysis tool for deep sequencing of plant small RNAs","volume":"80","author":"Xie","year":"2012","journal-title":"Plant Mol. Biol."},{"key":"ref_23","first-page":"3","article-title":"Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes","volume":"18","author":"Vandesompele","year":"2002","journal-title":"Genome Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3892\/ijo.2015.3306","article-title":"Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use","volume":"48","author":"Nitulescu","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1097\/MPA.0000000000000607","article-title":"Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded with a Novel AKT\/PDK1","volume":"45","author":"Kobes","year":"2016","journal-title":"Inhibitor. Pancreas"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1158\/1535-7163.MCT-15-0281","article-title":"A Novel Inhibitor of AKT1-PDPK1 Interaction Efficiently Suppresses the Activity of AKT Pathway and Restricts Tumor Growth In Vivo","volume":"14","author":"Viil","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1158\/1940-6207.CAPR-15-0419","article-title":"Inhibition of Akt enhances the chemopreventive effects of topical rapamycin in mouse skin","volume":"9","author":"Dickinson","year":"2016","journal-title":"Cancer Prev. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tian, L., Wang, L., Qiao, Y., Lu, L., Lee, P., Chang, A., Ravi, S., Rogers, T.A., and Melancon, M.P. (2019). Antitumor Efficacy of Liposome-Encapsulated NVP-BEZ235 Combined with Irreversible Electroporation for Head and Neck Cancer. Molecules, 24.","DOI":"10.3390\/molecules24193560"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/s13277-012-0350-2","article-title":"Targeted therapy in head and neck cancer","volume":"33","author":"Kundu","year":"2012","journal-title":"Tumor Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1097\/CAD.0b013e328341071e","article-title":"New advances in targeted therapies for squamous cell carcinoma of the head and neck","volume":"22","author":"Machiels","year":"2011","journal-title":"Anticancer Drugs"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41420-018-0060-7","article-title":"NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin","volume":"4","author":"Hsu","year":"2018","journal-title":"Cell Death Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.radonc.2017.08.001","article-title":"Antitumor activity of the dual PI3K\/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer","volume":"124","author":"Tonlaar","year":"2017","journal-title":"Radiother. Oncol."},{"key":"ref_33","first-page":"175","article-title":"In vitro anticancer activity of PI3K alpha selective inhibitor BYL719 in head and neck cancer","volume":"35","author":"Keam","year":"2015","journal-title":"Anticancer. Res."},{"key":"ref_34","first-page":"6489","article-title":"Adenosine induces intrinsic apoptosis via the PI3K\/AKT\/MTOR signaling pathway in human pharyngeal squamous carcinoma FaDu cells","volume":"15","author":"Choi","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3808","DOI":"10.1158\/1078-0432.CCR-12-2716","article-title":"PI3K\/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer","volume":"19","author":"Herzog","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3389\/fonc.2018.00160","article-title":"Phosphoinositide 3-Kinase\/Akt signaling and redox metabolism in cancer","volume":"8","author":"Koundouros","year":"2018","journal-title":"Front. Oncol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/8\/1242\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:44:28Z","timestamp":1760165068000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/8\/1242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,12]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["pharmaceutics13081242"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13081242","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,12]]}}}