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Fusion of Tumor-Derived Exosomes with Long-Circulating and pH-Sensitive Liposomes Loaded with Doxorubicin for the Treatment of Breast Cancer

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Abstract

Doxorubicin (DOX) is a chemotherapeutic agent that has been used in the treatment of breast cancer. However, serious toxic effects have limited its use, mainly cardiotoxicity. To minimize the adverse effects, liposomal preparations containing DOX have been developed. These preparations can reach the target in the tumor region as well as bypass the resistance-related problems. An alternative to increased therapeutic efficacy may be the fusion of liposomes with exosomes released from tumor cells to facilitate membrane and fusion interactions, achieving greater cell uptake. Thus, the purpose of this study was the fusion of exosomes derived from breast tumor cells with long-circulating and pH-sensitive liposomes loading DOX (ExoSpHL-DOX) for the treatment of breast cancer. The mean diameter of ExoSpHL-DOX was 100.8 ± 7.8 nm, the polydispersity index was 0.122 ± 0.004, and the encapsulated DOX content was equal to 83.5 ± 2.5%. The fusion of exosomes with long-circulating and pH-sensitive liposomes was confirmed by Fourier transform infrared spectroscopy, Raman spectroscopy, and nano-flow cytometry. The physicochemical characteristics of ExoSpHL-DOX were maintained for 60 days, at 4 °C. The study of the release of DOX from ExoSpHL-DOX in dilution media with different pH values showed the pH sensitivity characteristic of the nanosystem, since 96.6 ± 0.2% of DOX was released from ExoSpHL-DOX at pH 5.0, while at pH 7.4, the release was 70.1 ± 1.7% in the medium. The cytotoxic study against the breast cancer cell line demonstrated that ExoSpHL-DOX treatment significantly reduced the cancer cell viability.

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Acknowledgements

We thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for the scholarship provided to Eliza Rocha Gomes.

Funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (PPM-00703–18, CDS-APQ-01588–15, and CDS-RED-00007–14-Rede Mineira de Pesquisas em Nanobiotecnologia) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (306197/2014–6 and 307098/2018–4).

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Authors and Affiliations

  1. Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    E. R. Gomes & M. C. Oliveira

  2. Instituto René Rachou, Fiocruz Minas, Av. Augusto de Lima, 1715, Barro Preto, Belo Horizonte, Minas Gerais, 30190-002, Brazil

    A. T. Carvalho

  3. Centro de Tecnologia Em Nanomateriais E Grafeno (CTNano-UFMG), Rua Professor José Vieira de Mendonça, 520, Engenho Nogueira, Belo Horizonte, Minas Gerais, 31310-260, Brazil

    T. C. Barbosa

  4. Department of Chemistry, ICEx, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    L. L. Ferreira & H. D. R. Calado

  5. Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    A. P. Sabino

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  1. E. R. Gomes
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  3. T. C. Barbosa
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  4. L. L. Ferreira
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  5. H. D. R. Calado
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  6. A. P. Sabino
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  7. M. C. Oliveira
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Contributions

ERG designed and performed the analysis, collected the data, interpreted all the studies, and wrote the article; ATC performed the analysis, collected the data, and interpreted the nano-flow cytometry studies; TCB, LLF, and HDRC performed the analysis, collected the data, and interpreted the Raman and Fourier transform infrared spectroscopy; APS and MCF were responsible for revising the article for intellectual content. All the authors read and approved the manuscript.

Corresponding author

Correspondence to M. C. Oliveira.

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Gomes, E.R., Carvalho, A.T., Barbosa, T.C. et al. Fusion of Tumor-Derived Exosomes with Long-Circulating and pH-Sensitive Liposomes Loaded with Doxorubicin for the Treatment of Breast Cancer. AAPS PharmSciTech 23, 255 (2022). https://doi.org/10.1208/s12249-022-02349-y

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