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Development and characterization of a temozolomide-loaded nanoemulsion and the effect of ferrocene pre and co-treatments in glioblastoma cell models

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Abstract

Background

Glioblastoma is a severe brain tumor that requires aggressive treatment involving surgery, radiotherapy, and chemotherapy, offering a survival rate of only 15 months. Fortunately, recent nanotechnology progress has enabled novel approaches and, alongside ferrocenes’ unique properties of cytotoxicity, sensitization, and interaction with reactive oxygen species, have brought new possibilities to complement chemotherapy in nanocarrier systems, enhancing treatment results.

Methods

In this work, we developed and characterized a temozolomide-loaded nanoemulsion and evaluated its cytotoxic potential in combination with ferrocene in the temozolomide-resistant T98G and temozolomide-sensitive U87 cell lines. The effects of the treatments were assessed through acute assays of cell viability, cell death, mitochondrial alterations, and a treatment protocol simulation based on different two-cycle regimens.

Results

Temozolomide nanoemulsion showed a z-average diameter of 173.37 ± 0.86 nm and a zeta potential of – 6.53 ± 1.13 mV. Physicochemical characterization revealed that temozolomide is probably associated with nanoemulsion droplets instead of being entrapped within the nanostructure, allowing a rapid drug release. In combination with ferrocene, temozolomide nanoemulsion reduced glioblastoma cell viability in both acute and two-cycle regimen assays. The combined treatment approach also reversed T98G’s temozolomide-resistant profile by altering the mitochondrial membrane potential of the cells, thus increasing reactive oxygen species generation, and ultimately inducing cell death.

Conclusions

Altogether, our results indicate that using nanoemulsion containing temozolomide in combination with ferrocene is an effective approach to improve glioblastoma therapy outcomes.

Graphical abstract

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

BBB:

Blood–brain barrier

DMEM:

Dulbecco’s Modified Eagle Medium

DDS:

Drug delivery system

EE%:

Encapsulation efficiency

FBS:

Fetal bovine serum

Fc:

Ferrocene

FITC:

Fluorescein isothiocyanate

GB:

Glioblastoma

LOD:

Limit of detection

LOQ:

Limit of quantification

MCT:

Medium chain triglycerides

NE:

Nanoemulsion

NRU:

Neutral red uptake

PBS:

Phosphate-buffered saline

PDI:

Polydispersity index

PI:

Propidium iodide

ROS:

Reactive oxygen species

TEM:

Transmission electron microscopy

TMRE:

Tetramethylrhodamine ethyl ester

TMZ:

Temozolomide

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Acknowledgements

This study was supported in parts by grants and/or scholarships from FAPERGS (Fundação de Apoio à Pesquisa do Rio Grande do Sul, Brazil, Grant nº 21/2551-0001965-4), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil). The graphical abstract was created with BioRender.com.

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Authors and Affiliations

  1. Laboratório de Genética Toxicológica, Universidade Federal de Ciências da Saúde de Porto Alegre, 245 Sarmento Leite Street, Lab. 714, Porto Alegre, Rio Grande do Sul, 90050-170, Brazil

    Jeferson Gustavo Henn, Matheus Bernardes Ferro, Victória Rapack Jacinto Silva, Ana Carolina Silva Pinheiro, Luiza Steffens Reinhardt, Ana Moira Morás & Dinara Jaqueline Moura

  2. Materials Research Institute, Technological University of the Shannon: Midlands Midwest, Athlone, Co. Westmeath, N37HD68, Ireland

    Jeferson Gustavo Henn & Michael Nugent

  3. Laboratório de Farmacociências, Universidade Federal de Ciências da Saúde de Porto Alegre, 245 Sarmento Leite Street, Porto Alegre, Rio Grande do Sul, 90050-170, Brazil

    Gabriel Antonio Lopes Alves, Flávia Pires Peña, João Vitor Raupp de Oliveira & Tanira Alessandra Silveira Aguirre

  4. Departamento de Química Inorgânica, Universidade Federal do Rio Grande do Sul, 9500 Bento Gonçalves Avenue, Porto Alegre, Rio Grande do Sul, 91501-970, Brazil

    Bárbara Müller de Souza, Leonardo Fonseca da Silva & Ricardo Gomes da Rosa

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  1. Jeferson Gustavo Henn
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Contributions

JGH: conceptualization, data curation, formal analysis, investigation, methodology, project administration, validation, visualization, writing – original draft, and writing – review & editing. MBF, JVRO, BMS, LFS, VRJS, and ACSP: data curation, and investigation. GALA and FPP: data curation, investigation, methodology, and validation. LSR, AMM, and RGR: investigation, methodology, resources, and writing – review & editing. MN: resources, and writing – review & editing. TASA: conceptualization, funding acquisition, methodology, project administration, resources, validation, and writing – review & editing. DJM: conceptualization, funding acquisition, methodology, project administration, resources, supervision, validation, and writing – review & editing. All authors reviewed the final manuscript.

Corresponding author

Correspondence to Dinara Jaqueline Moura.

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43440_2023_537_MOESM1_ESM.tif

Fig. S1. Schematic representation of ferrocene (A), monopegylated ferrocene (B) and dipegylated ferrocene (C). Supplementary file1 (TIF 32 KB)

43440_2023_537_MOESM2_ESM.tif

Fig. S2. Schematic representation of different treatment protocol simulation based on two-cycle regimens: T98G cells were treated for different days either with 100 µM of Fc and/or TMZ on their own, or TMZ-NE on its own or in combination with Fc, dissolved in DMEM + FBS (5%). In all recovery periods cells were kept in culture media with DMEM + FBS (10 %). All regimens comprised two treatment cycles and in the end cell viability was carried out by NRU assay. Fc ferrocene, TMZ temozolomide, NE nanoemulsion, FBS fetal bovine serum, NRU neutral red uptake. Supplementary file2 (TIF 147 KB)

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Henn, J.G., Bernardes Ferro, M., Lopes Alves, G.A. et al. Development and characterization of a temozolomide-loaded nanoemulsion and the effect of ferrocene pre and co-treatments in glioblastoma cell models. Pharmacol. Rep 75, 1597–1609 (2023). https://doi.org/10.1007/s43440-023-00537-6

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