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Single or Mixed edge activators: a shift in transfersomes properties?
* 1 , 2 , 3, 4 , 3, 4 , 5 , 3 , 3 , 3 , 3, 6
1  Universidade Lusófona/ Universidad de Alcalá
2  School of Health Sciences and Technologies, Universidade Lusófona– Centro Universitário de Lisboa, Campo Grande 376, 1749-024, Lisbon, Portugal
3  CBIOS, Universidade Lusófona´s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024, Lisbon, Portugal
4  Department of Biomedical Sciences, University of Alcalá, Ctra. Madrid-Barcelona Km. 33.600, Alcalá de Henares, 28871, Madrid, Spain
5  School of Psychology and Life Sciences, Universidade Lusófona – Centro Universitário de Lisboa, Campo Grande 376, 1749-024, Lisbon, Portugal
6  LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto , R. de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal
Academic Editor: Maria Emília Sousa (registering DOI)

Transfersomes, a novel lipid-based vesicular system, have emerged as an innovative tool in the field of drug delivery due to their remarkable ability to enhance the skin delivery of bioactive compounds. These deformable lipid vesicles are composed of phospholipids and edge activators, which play a crucial role in conferring flexibility and deformability to the vesicles, thereby enabling efficient drug loading as well as an improved drug transport across biological barriers. [1,2]

Traditionally, transfersomes have been designed using a single edge activator; however, recent research has highlighted the potential benefits of adjusting their composition by mixing different edge activators to further optimize their performance. Having this in mind, quality-by-design strategies, like Box-Behnken factorial design (BBD) appear as a useful approach to enhance the development of new formulations. [3]

In this context, the main goals of this work were the analysis of the impact of single or mixed edge activators on transfersomes physicochemical properties and to assess their cytotoxicity profile. These nanosystems were prepared in presence and absence of two model drugs – ibuprofen sodium salt and caffeine.

To evaluate the effect of the edge activators on transfersomes’ physicochemical properties the formulations were prepared and characterized in terms of vesicle size (Vs), polydispersity index (PDI), encapsulation efficiency (EE), and loading capacity (LC) for 60 days, under storage. Moreover, In vitro cytotoxicity studies were performed using the HaCaT cell line.

All formulations composed of single or mixed surfactants presented interesting results (Vs < 300 nm, and PDI < 0.3), considering the cutaneous delivery target. The EE and LC results were reasonably good for IBU, while caffeine encapsulation still needs to be improved. These results were maintained over time under refrigerated conditions, showing that transfersomes are stable for at least 30 days. Additionally, according to the cell viability results, transfersomes were found to be compatible with human keratinocytes.

Overall, by combining the distinct physicochemical properties of diverse edge activators, it was possible to tailor transfersomes as skin delivery carriers, enhancing their characteristics and addressing challenges related to the colloidal stability.

Acknowledgements: This study was financially supported by Fundação para an Ciência e Tecnologia, I.P., through funding EXPL/BTM-MAT/0112/2021, UIDB/04567/2020, and UIDP/04567/2020, as well as by the research grant attributed to J.V.


[1] – Opatha, S.A.T.; Titapiwatanakun, V.; Chutoprapat, R. Transfersomes: A Promising Nanoencapsulation Technique for Transdermal Drug Delivery. Pharmaceutics 2020, 12, 855.

[2] – Fernández-García, R.; Lalatsa, A.; Statts, L.; Bolás-Fernández, F.; Ballesteros, M.P.; Serrano, D.R. Transferosomes as nanocarriers for drugs across the skin: Quality by design from lab to industrial scale. Int. J. Pharm. 2020, 573,

[3] – Vieira, J.; Castelo, J.; Martins, M.; Saraiva, N.; Rosado, C.; Pereira-Leite, C. Mixed Edge Activators in Ibuprofen-Loaded Transfersomes: An Innovative Optimization Strategy Using Box–Behnken Factorial Design. Pharmaceutics 2023, 15, 1209.

Keywords: Transfersomes; edge activators; physicochemical properties; cytotoxicity