{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T04:41:01Z","timestamp":1785732061482,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"NIH NCI Project","doi-asserted-by":"publisher","award":["P01CA229112"],"award-info":[{"award-number":["P01CA229112"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cutaneous squamous cell carcinoma (cSCC) is the second-most common type of non-melanoma skin cancer and is linked to long-term exposure to ultraviolet (UV) radiation from the sun. Rocuronium bromide (RocBr) is an FDA-approved drug that targets p53-related protein kinase (PRPK) that inhibits the development of UV-induced cSCC. This study aimed to investigate the physicochemical properties and in vitro behavior of RocBr. Techniques such as thermal analysis, electron microscopy, spectroscopy and in vitro assays were used to characterize RocBr. A topical oil\/water emulsion lotion formulation of RocBr was successfully developed and evaluated. The in vitro permeation behavior of RocBr from its lotion formulation was quantified with Strat-M\u00ae synthetic biomimetic membrane and EpiDerm\u2122 3D human skin tissue. Significant membrane retention of RocBr drug was evident and more retention was obtained with the lotion formulation compared with the solution. This is the first systematic and comprehensive study to report these findings.<\/jats:p>","DOI":"10.3390\/ijms24108776","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T02:37:51Z","timestamp":1684204671000},"page":"8776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Innovative Rocuronium Bromide Topical Formulation for Targeted Skin Drug Delivery: Design, Comprehensive Characterization, In Vitro 2D\/3D Human Cell Culture and Permeation"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3252-8262","authenticated-orcid":false,"given":"Victor H.","family":"Ruiz","sequence":"first","affiliation":[{"name":"Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4988-9192","authenticated-orcid":false,"given":"David","family":"Encinas-Basurto","sequence":"additional","affiliation":[{"name":"Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Physics, Mathematics and Engineering, Campus Navojoa, Universidad de Sonora, Sonora 85880, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Sun","sequence":"additional","affiliation":[{"name":"Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"The University of Arizona Cancer Center, Skin Cancer Institute, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8462-4181","authenticated-orcid":false,"given":"Basanth Babu","family":"Eedara","sequence":"additional","affiliation":[{"name":"Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4385-2046","authenticated-orcid":false,"given":"Eunmiri","family":"Roh","sequence":"additional","affiliation":[{"name":"The Hormel Institute, University of Minnesota, Austin, MN 55912, USA"},{"name":"Department of Cosmetic Science, Kwangju Women\u2019s University, Gwangju 62396, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neftali Ortega","family":"Alarcon","sequence":"additional","affiliation":[{"name":"Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-6252","authenticated-orcid":false,"given":"Clara","family":"Curiel-Lewandrowski","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center, Skin Cancer Institute, Tucson, AZ 85721, USA"},{"name":"University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Department of Medicine, Division of Dermatology, The University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann M.","family":"Bode","sequence":"additional","affiliation":[{"name":"The Hormel Institute, University of Minnesota, Austin, MN 55912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3993-9210","authenticated-orcid":false,"given":"Heidi M.","family":"Mansour","sequence":"additional","affiliation":[{"name":"Skaggs Pharmaceutical Sciences Center, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Center for Translational Science, Florida International University, Port St. Lucie, FL 34987, USA"},{"name":"Department of Medicine, Division of Translational & Regenerative Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA"},{"name":"BIO5 Institute, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s40257-016-0207-3","article-title":"Cutaneous squamous cell carcinoma: A review of high-risk and metastatic disease","volume":"17","author":"Burton","year":"2016","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1001\/jamadermatol.2020.3678","article-title":"Underestimation of Cutaneous Squamous Cell Carcinoma Incidence, Even in Cancer Registries","volume":"156","author":"Wehner","year":"2020","journal-title":"JAMA Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1001\/jamadermatol.2020.3677","article-title":"Incidence of Multiple vs First Cutaneous Squamous Cell Carcinoma on a Nationwide Scale and Estimation of Future Incidences of Cutaneous Squamous Cell Carcinoma","volume":"156","author":"Tokez","year":"2020","journal-title":"JAMA Dermatol."},{"key":"ref_4","unstructured":"US Department of Health and Human Services (2014). Skin cancer as a major public health problem, The Surgeon General\u2019s Call to Action to Prevent Skin Cancer."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5633","DOI":"10.1038\/s41388-018-0350-9","article-title":"Targeting PRPK and TOPK for skin cancer prevention and therapy","volume":"37","author":"Roh","year":"2018","journal-title":"Oncogene"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/jdv.16024","article-title":"Medical treatment of advanced cutaneous squamous-cell carcinoma","volume":"33","author":"Gellrich","year":"2019","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jaad.2017.10.007","article-title":"Guidelines of care for the management of cutaneous squamous cell carcinoma","volume":"78","author":"Work","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_8","first-page":"30","article-title":"Effective treatment of a platinum-resistant cutaneous squamous cell carcinoma case by EGFR pathway inhibition","volume":"9","author":"Capalbo","year":"2018","journal-title":"Mol. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1158\/1535-7163.MCT-17-0115","article-title":"Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC","volume":"16","author":"Swick","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s10616-011-9334-0","article-title":"In vitro genotoxicity of rocuronium bromide in human peripheral lymphocytes","volume":"63","author":"Zan","year":"2011","journal-title":"Cytotechnology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ejps.2018.04.003","article-title":"Development and characterization of high payload combination dry powders of anti-tubercular drugs for treating pulmonary tuberculosis","volume":"118","author":"Eedara","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101975","DOI":"10.1016\/j.pupt.2020.101975","article-title":"Advanced spray dried proliposomes of amphotericin B lung surfactant-mimic phospholipid microparticles\/nanoparticles as dry powder inhalers for targeted pulmonary drug delivery","volume":"64","author":"Gomez","year":"2020","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nyquist, R.A. (2001). Interpreting Infrared, Raman, and Nuclear Magnetic Resonance Spectra, Academic Press.","DOI":"10.1016\/B978-012523475-7\/50191-1"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Larkin, P. (2017). Infrared and Raman Spectroscopy: Principles and Spectral Interpretation, Elsevier.","DOI":"10.1016\/B978-0-12-804162-8.00002-1"},{"key":"ref_15","unstructured":"(2006). The Handbook of Infrared and Raman Characteristic Frequencies of Organic Molecules, Academic Press."},{"key":"ref_16","first-page":"33","article-title":"The Pharmacology of Rocuronium Bromide (ORG 9426)","volume":"62","author":"Wicks","year":"1994","journal-title":"AANA J."},{"key":"ref_17","unstructured":"McManus, L.M., and Mitchell, R.N. (2014). Pathobiology of Human Disease, Academic Press."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/sj.onc.1206206","article-title":"Inhibition of ultraviolet B-mediated activation of nuclear factor \u03baB in normal human epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate","volume":"22","author":"Afaq","year":"2003","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1016\/j.yexcr.2012.05.023","article-title":"Reactive oxygen species stimulates epithelial mesenchymal transition in normal human epidermal keratinocytes via TGF-beta secretion","volume":"318","author":"Fukawa","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1038\/jid.2012.185","article-title":"Regulation of IL-33 Expression by IFN-\u03b3 and Tumor Necrosis Factor-\u03b1 in Normal Human Epidermal Keratinocytes","volume":"132","author":"Meephansan","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1111\/j.1365-2230.2011.04315.x","article-title":"Differential response of normal human epidermal keratinocytes and HaCaT cells to hydrogen peroxide-induced oxidative stress","volume":"37","author":"Liu","year":"2012","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1038\/sj.onc.1206537","article-title":"Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: Implications for skin and epithelial cancer","volume":"22","author":"Dazard","year":"2003","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/1523-1747.ep12285640","article-title":"HaCaT cell line as a model system for vitamin D3 metabolism in human skin","volume":"108","author":"Lehmann","year":"1997","journal-title":"J. Investig. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/j.1600-0625.1993.tb00030.x","article-title":"Lipid composition and synthesis of HaCaT cells, an immortalized human keratinocyte line, in comparison with normal human adult keratinocytes","volume":"2","author":"Schliep","year":"1993","journal-title":"Exp. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7435621","DOI":"10.1155\/2017\/7435621","article-title":"HaCaT Cells as a Reliable In Vitro Differentiation Model to Dissect the Inflammatory\/Repair Response of Human Keratinocytes","volume":"2017","author":"Colombo","year":"2017","journal-title":"Mediators Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhang, N., Liang, H., Farese, R.V., Li, J., Musi, N., and Hussey, S.E. (2015). Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132575"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15196","DOI":"10.1038\/s41598-020-71315-0","article-title":"Characterisation of the novel spontaneously immortalized and invasively growing human skin keratinocyte line HaSKpw","volume":"10","author":"Stricker","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ejps.2014.11.002","article-title":"Prediction of skin permeation by chemical compounds using the artificial membrane, Strat-M\u2122","volume":"67","author":"Uchida","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ijpharm.2018.01.029","article-title":"Membrane properties for permeability testing: Skin versus synthetic membranes","volume":"539","author":"Haq","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.ijpharm.2018.06.012","article-title":"Strat-M\u00ae synthetic membrane: Permeability comparison to human cadaver skin","volume":"547","author":"Haq","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1208\/s12249-018-0959-6","article-title":"A Mechanistic Study to Determine the Structural Similarities Between Artificial Membrane Strat-M\u2122 and Biological Membranes and Its Application to Carry Out Skin Permeation Study of Amphotericin B Nanoformulations","volume":"19","author":"Kaur","year":"2018","journal-title":"AAPS PharmSciTech"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1080\/10837450.2020.1860087","article-title":"An evaluation of tocotrienol ethosomes for transdermal delivery using Strat-M\u00ae membrane and excised human skin","volume":"26","author":"Nair","year":"2021","journal-title":"Pharm. Dev. Technol."},{"key":"ref_33","unstructured":"(2021, December 06). Available online: https:\/\/mattek.com\/products\/epiderm\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ejpb.2005.03.004","article-title":"The human epidermis models EpiSkin\u00ae, SkinEthic\u00ae and EpiDerm\u00ae: An evaluation of morphology and their suitability for testing phototoxicity, irritancy, corrosivity, and substance transport","volume":"60","author":"Netzlaff","year":"2005","journal-title":"European J. Pharm. Biopharm."},{"key":"ref_35","unstructured":"Bode, A.M., Dong, Z., and Roh, E. (2020). Skin Care Formulations and Skin Cancer Treatment. (US-2020179404-A1), U.S. Patent, Available online: https:\/\/patents.google.com\/patent\/US20200179404A1#patentCitations."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.chroma.2006.12.041","article-title":"Simultaneous determination of rocuronium and its eight impurities in pharmaceutical preparation using high-performance liquid chromatography with amperometric detection","volume":"1149","author":"Boruta","year":"2007","journal-title":"J. Chromatogr. A"},{"key":"ref_37","unstructured":"(2010). United States Pharmacopoeia 33 National Formulary 28, The United States Pharmacopoeial Convention."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.ijpharm.2012.07.054","article-title":"Phase behavior of itraconazole\u2013phenol mixtures and its pharmaceutical applications","volume":"436","author":"Park","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_39","unstructured":"Sciences, M.L. (2021, September 13). Download the EpiDerm Percutaneous Absorption Protocol. Available online: https:\/\/mattek.com\/download-the-epiderm-percutaneous-absorption-protocol\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8776\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:35:17Z","timestamp":1760124917000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,15]]},"references-count":39,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108776"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108776","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,15]]}}}