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Sorbitan Monolaurate–Containing Liposomes Enhance Skin Cancer Cell Cytotoxicity and in Association with Microneedling Increase the Skin Penetration of 5-Fluorouracil

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Abstract

Squamous cell carcinoma (SCC) represents 20% of cases of non-melanoma skin cancer, and the most common treatment is the removal of the tumor, which can leave large scars. 5-Fluorouracil (5FU) is a drug used in the treatment of SCC, but it is highly hydrophilic, resulting in poor skin penetration in topical treatment. Some strategies can be used to increase the cutaneous penetration of the drug, such as the combination of liposomes containing penetration enhancers, for instance, surfactants, associated with the use of microneedling. Thus, the present work addresses the development of liposomes with penetration enhancers, such as sorbtitan monolaurate, span 20, for topical application of 5-FU and associated or not with the use of microneedling for skin delivery. Liposomes were developed using the lipid film hydration, resulting in particle size, polydispersity index, zeta potential, and 5-FU encapsulation efficiency of 88.08 nm, 0.169, −12.3 mV, and 50.20%, respectively. The presence of span 20 in liposomes potentiated the in vitro release of 5-FU. MTT assay was employed for cytotoxicity evaluation and the IC50 values were 0.62, 30.52, and 24.65 μM for liposomes with and without span 20 and 5-FU solution, respectively after 72-h treatment. Flow cytometry and confocal microscopy analysis evidenced high cell uptake for the formulations. In skin penetration studies, a higher concentration of 5-FU was observed in the epidermis + dermis, corresponding to 1997.71, 1842.20, and 2585.49 ng/cm2 in the passive penetration and 3214.07, 2342.84, and 5018.05 ng/cm2 after pretreatment with microneedles, for solution, liposome without and with span 20, respectively. Therefore, herein, we developed a nanoformulation for 5-FU delivery, with suitable physicochemical characteristics, potent skin cancer cytotoxicity, and cellular uptake. Span 20–based liposomes increased the skin penetration of 5-FU in association of microneedling. Altogether, the results shown herein evidenced the potential of the liposome containing span 20 for topical delivery of 5-FU.

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Acknowledgements

The authors would like to thank the Central Analítica-UFC (funded by Finep-CT-INFRA, CAPES-Pró-Equipamentos, and MCTI-CNPq-SisNano2.0) for confocal microscopy measurements. The authors would like to thank Maria Karolina de Araújo Barroso (Department of Pharmacy - Federal University of Ceará) for technical assistance in cell studies.

Funding

This work was supported by the Coordination for the Improvement of Higher Education Personnel (CAPES) and the National Council for Scientific and Technological Development (CNPq) (grants # 409352/2018-7; #409362/ 2018-2).

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Authors and Affiliations

  1. Faculty of Pharmacy, Dentistry and Nursing, Department of Pharmacy, Fortaleza Universidade Federal do Ceará, Fortaleza, CE, Brazil

    Luiziana Cavalcante Costa Fernandes Crisóstomo, Genuína Stephanie Guimarães Carvalho, Luzia Kalyne Almeida Moreira Leal, Tamara Gonçalves de Araújo & Josimar O. Eloy

  2. Center of Technology, Department of Chemical Engineering, Federal University of Ceará, Fortaleza, Brazil

    Karina Alexandre Barros Nogueira

  3. Research Center on Biodiversity and Biotechnology (BIOTEC), Federal University of Delta do Parnaíba, Parnaíba, PI, Brazil

    Durcilene Alves da Silva & Fábio de Oliveira Silva Ribeiro

  4. Institute of Health Sciences, University of International Integration of the Afro-Brazilian Lusophony- UNILAB, Redenção, CE, Brazil

    Raquel Petrilli

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Luiziana C.C. Fernandes Crisótomo: data acquistion, interpretation, and manuscript writing; Genuína Stephanie G. Carvalho: data acquisition; Luzia Kalyne A. M. Leal: analysis and interpretation; Tamara Gonçalves de Araújo: analysis and interpretation; Karina Alexandre B. Nogueira: data acquisition and interpretation; Durcilene Alves da Silva: data acquisition; Fabio de Oliveira Silva Ribeiro: data acquisition; Raquel Petrilli: data analysis and interpretation, revision and approval of the final version; Josimar O. Eloy: funding, data analysis and interpretation, revision and approval of the final version.

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Crisóstomo, L.C.C.F., Carvalho, G.S.G., Leal, L.K.A.M. et al. Sorbitan Monolaurate–Containing Liposomes Enhance Skin Cancer Cell Cytotoxicity and in Association with Microneedling Increase the Skin Penetration of 5-Fluorouracil. AAPS PharmSciTech 23, 212 (2022). https://doi.org/10.1208/s12249-022-02356-z

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