Abstract
Topical therapy for skin cancer is considered ineffective, due to insufficient penetration of the anticancer drug into the tumor located in the deep layers of the skin. The aim of this work was to investigate a new system, Tumorep DS, tailored to deliver the anti-cancer actives into the tumor cells in the deep skin and to induce cell differentiation. Tumorep DS containing 5-fluorouracil (5-FU) anticancer drug and a sulfoxide derivative, as a differentiation agent, was characterized and tested for storage stability. The system was tested in cell lines, in vitro and in animal models. Experiments were carried out on five cell types: three tumorigenic (TE.354.T, ES-2, and Mel624), one precancerous (HaCaT), and a primary keratinocyte (human normal keratinocytes) cell culture. Treatment of keratinocytes with Tumorep DS resulted in reduction in the percent of keratin 14-positive cells, suggesting its ability to induce cell differentiation. Skin penetration was assessed in vitro in Franz diffusion cells and in vivo. The antitumor effect of the new system evaluated in two skin cancer animal models showed a significant repression of tumor development, which was significantly better statistically than a 5-FU commercial product. Tumorep DS was found to be safe to the skin when tested in vitro in the EpiDerm™ skin irritation test and in animals.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ainbinder D, Touitou E. Testosterone ethosomes for enhanced transdermal delivery. Drug Deliv. 2005;12:297–303.
Ainbinder D, Protokin R, Chaouat M, Touitou E. Effect of honokiol and 5-FU on non-melanoma skin cancer cells. J Drug Deliv Sci Tech. 2009;19:283–7.
Ben-Bassat H, Rosenbaum-Mitrani S, Hartzstark Z, et al. Inhibitors of epidermal growth factor receptor kinase and of cyclin-dependent kinase 2 activation induce growth arrest, differentiation, and apoptosis of human papilloma virus 16-immortalized human keratinocytes. Cancer Res. 1997;57:3741–50.
Bonnotte B, Gough M, Phan V, et al. Intradermal injection, as opposed to subcutaneous injection, enhances immunogenicity and suppresses tumorigenicity of tumor cells. Cancer Res. 2003;63:2145–9.
Choi KH, Kim GM, Kim SY. The keratin-14 expression in actinic keratosis and squamous cell carcinoma: is this a prognostic factor for tumor progression? Cancer Res Treat. 2010;42:107–14.
Dayan N, Touitou E. Carriers for skin delivery of trihexyphenidyl HCl: ethosomes vs. liposomes. Biomaterials. 2000;21:1879–85.
Dillaha J, Jansen GT, Honeycutt WM, et al. Selective cytotoxic effect of topical 5-fluorouracil. Arc Dermatol. 1983;119:774–83.
Fang JY, Lee WR, Shende SC, Huangaet YL. Effect of liposome encapsulation of tea catechins on their accumulation in basal cell carcinomas. J Dermatol Sci. 2006;42:101–9.
Godin B, Touitou E. Mechanism of bacitracin permeation enhancement through the skin and cellular membranes from an ethosomal carrier. J Control Release. 2004;94:365–79.
Jacobi U, Kaiser M, Toll R, et al. Porcine ear skin: an in vitro model for human skin. Skin Res Tech. 2007;13:19–24.
Kawamata H, Tachibana M, Fujimori T, Imai Y. Differentiation-inducing therapy for solid tumors. Curr Pharm Des. 2006;12:379–85.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.
Neville JA, Welch E, Leffell DJ. Management of nonmelanoma skin cancer in 2007. Nat Clin Pract Oncol. 2007;4:432–69.
Omer L, Ruthstein S, Goldfarb D, Talmon Y. High-resolution cryogenic-electron microscopy reveals details of a hexagonal-to-bicontinuous cubic phase transition in mesoporous silica synthesis. J Am Chem Soc. 2009;131:12466–73.
Reynolds PL, Strayer SM. Treatment of skin malignancies. J Fam Pract. 2003;52:456–64.
Romano RA, Birkaya B, Sinha S. A functional enhancer of keratin 14 is a direct transcriptional target of Np63. J Invest Dermatol. 2007;127:1175–86.
Rougier A, Dupuis D, Lotte C, Roguet R, Wester RC, Maibach HI. Regional variation in percutaneous absorption in man: measurement by the stripping method. Arch Dermatol Res. 1986;278:465–9.
Shumilov M, Touitou E. Buspirone transdermal administration for menopausal syndromes, in vitro and in animal model studies. Int J Pharm. 2010;387:26–33.
Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes—novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J Control Release. 2000;65:403–18.
Yoshimoto Y, Augustine CK, Yoo JS, et al. Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents. Mol Cancer Ther. 2007;6:1492–500.
Acknowledgments
We thank Mrs. Malka Chaouat for her assistance and guidance in the experiments on HNK cells and the methylene blue assay, Dr. Mark Tarshish for guidance in the experiments on CLSM, Mr. Nikolai Kunicher for the assistance with keratin 14 cell expression measurements, and Dr. Mali Bella for tumor histology evaluation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ainbinder, D., Touitou, E. A new approach for skin tumor treatment: from delivery system characterization to in vivo evaluation. Drug Deliv. and Transl. Res. 1, 53–65 (2011). https://doi.org/10.1007/s13346-010-0006-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13346-010-0006-y