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2-(2-Methoxyphenyl)-3-((Piperidin-1-yl)ethyl)thiazolidin-4-One-Loaded Polymeric Nanocapsules: In Vitro Antiglioma Activity and In Vivo Toxicity Evaluation

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Abstract

Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood–brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.

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Acknowledgements

The authors thank to FAPERGS (11/2068-7; 16/2551-0000265-7) for financial support. CNPq (307330/2012-5; 310846/2014-5) is also acknowledged.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, RS, Brazil

    Elita Ferreira da Silveira & Ana Paula Horn

  2. Programa de Pós-graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, Brazil

    Luana Mota Ferreira, Mailine Gehrcke & Letícia Cruz

  3. Programa de Pós-Graduação em Bioquímica e Bioprospecção, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Pelotas, RS, Brazil

    Nathália Stark Pedra, Priscila Treptow Ramos, Natália Pontes Bona, Mayara Sandrielly Pereira Soares, Rodrigo Rodrigues, Rosélia Maria Spanevello, Wilson Cunico & Francieli M. Stefanello

  4. Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, 245 – Prédio Principal – sala 304, Porto Alegre, RS, CEP: 90.050-170, Brazil

    Juliana Hofstatter Azambuja & Elizandra Braganhol

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  1. Elita Ferreira da Silveira
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Contributions

EFS: Experimental design, culture preparation and treatment, discussion of results and manuscript preparation. LMF: Experimental design and preparation and characterization of nanocapsules. MG: Experimental design, preparation and characterization of nanocapsules and manuscript preparation. LC: Experimental design and preparation and characterization of nanocapsules. NSP: Experimental design, culture preparation and treatment, viability and cell proliferation assays. PTR: Culture preparation and treatment, viability and cell proliferation assays. NPB: Preparation of astrocyte cultures, treatment of cultures with nanocapsules, analysis of viability and cell proliferation data, treatment of animals in vivo and oxidative stress tests. MSPS: Preparation of astrocyte cultures, treatment of cultures with nanocapsules, analysis of viability and cell proliferation data, treatment of animals in vivo and oxidative stress tests. RR: Biochemical toxicity and data analysis. RMS: Experimental design, statistical analysis, interpretation and discussion of results and manuscript preparation. WC: Synthesis and design of thiazolidinones. FMS: Experimental design and interpretation and discussion of the oxidative stress results. JHA: Preparation of cell cultures, cell treatments, propidium iodide assay and analysis of the results. APH: Experimental design, statistical analysis, interpretation and discussion of results and manuscript preparation. EB: Experimental design, statistical analysis, interpretation and discussion of results and manuscript preparation.

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Correspondence to Elita Ferreira da Silveira, Juliana Hofstatter Azambuja or Elizandra Braganhol.

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All the authors declares that they have no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures used in the present study followed the Principles of Laboratory Animal Care from NIH and the Brazilian laws and were approved by the Ethical Committee of the Federal University of Pelotas (Protocol Number 9219).

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da Silveira, E.F., Ferreira, L.M., Gehrcke, M. et al. 2-(2-Methoxyphenyl)-3-((Piperidin-1-yl)ethyl)thiazolidin-4-One-Loaded Polymeric Nanocapsules: In Vitro Antiglioma Activity and In Vivo Toxicity Evaluation. Cell Mol Neurobiol 39, 783–797 (2019). https://doi.org/10.1007/s10571-019-00678-4

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