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Rethinking Breast Cancer Chemoprevention: Technological Advantages and Enhanced Performance of a Nanoethosomal-Based Hydrogel for Topical Administration of Fenretinide

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Abstract

Herein, we developed an ethosomal hydrogel based on three types of ethosomes: simple, mixed (surfactant-based micelles and lipid vesicles) or binary (comprising two type of alcohols). Ethanol injection was employed for vesicles preparation, and sodium alginate, as gelling agent. We purposed the local-transdermal administration of the off-the-shelf retinoid fenretinide (FENR) for chemoprevention of breast cancer. Rheograms and flow index values for alginate dispersion (without ethosomes) and hydrogels containing simple, mixed or binary ethosomes suggested pseudoplastic behavior. An increase in the apparent viscosity was observed upon ethosome incorporation. The ethosomal hydrogel displayed increased bioadhesion compared to the alginate dispersion, suggesting that the lipid vesicles contribute to the gelling and bioadhesion processes. In the Hen’s Egg Test–Chorioallantoic Membrane model, few spots of lysis and hemorrhage were observed for formulations containing simple (score of 2) and mixed vesicles (score 4), but not for the hydrogel based on the binary system, indicating its lower irritation potential. The binary ethosomal hydrogel provided a slower FENR in vitro release and delivered 2.6-fold less drug into viable skin layers compared to the ethosome dispersion, supporting the ability of the gel matrix to slow down drug release. The ethosomal hydrogel decreased by ~ five-fold the IC50 values of FENR in MCF-7 cells. In conclusion, binary ethosomal gels presented technological advantages, provided sustained drug release and skin penetration, and did not preclude drug cytotoxic effects, supporting their potential applicability as topical chemopreventive systems.

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Acknowledgements

The authors would like to acknowledge Dr. Leticia Costa-Lotufo (Institute of Biomedical Sciences, University of Sao Paulo) for use of the cell culture facility.

Funding

This study was supported by São Paulo Research Foundation (FAPESP, grant# 2018/ 13877–1) and CAPES (finance code 001). Fellowships from FAPESP (grant# 2018/14375–0 to A.C. Apolinário) and National Council of Technological and Scientific Development (306866/2020–0 to L.B. Lopes) are greatly appreciated. This study is part of the National Institute of Science and Technology in Pharmaceutical Nanotechnology: a transdisciplinary approach INCT-NANOFARMA, which is supported by FAPESP (grant #2014/50928–2) and CNPq (grant # 465687/2014–8). The authors are grateful to CENTD for support with the confocal microscopy facility. CENTD is supported by São Paulo Research Foundation (FAPESP) grant number 2020/13139–0 (FAPESP/GSK/Instituto Butantan).

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil

    Alexsandra Conceição Apolinário, Giovanna Cassone Salata & Luciana Biagini Lopes

  2. Centre of Excellence in New Target Discovery (CENTD), Butantan Institute, São Paulo, Brazil

    Marcelo Medina de Souza

  3. School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, São Paulo, Brazil

    Marlus Chorilli

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  1. Alexsandra Conceição Apolinário
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  2. Giovanna Cassone Salata
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  3. Marcelo Medina de Souza
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  4. Marlus Chorilli
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  5. Luciana Biagini Lopes
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Contributions

Conceptualization—A.C.A. and L.B.L.; confocal microscopy assay—M.M.S.; HET-CAM and rheology assay—G.C.S.; bioadhesion: M.C.; writing—original draft preparation—A.C.A., M.C. and L.B.L.; funding acquisition—L.B.L.

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Correspondence to Alexsandra Conceição Apolinário or Luciana Biagini Lopes.

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The authors filed for a patent application in Brazil in a topic related to this study.

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Apolinário, A.C., Salata, G.C., de Souza, M.M. et al. Rethinking Breast Cancer Chemoprevention: Technological Advantages and Enhanced Performance of a Nanoethosomal-Based Hydrogel for Topical Administration of Fenretinide. AAPS PharmSciTech 23, 104 (2022). https://doi.org/10.1208/s12249-022-02257-1

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