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Synthesis and characterization of chitosan-grafted-polycaprolactone micelles for modulate intestinal paclitaxel delivery

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Abstract

In this work, self-assembled amphiphilic micelles based on chitosan (CS) and polycaprolactone (PCL) were produced and used as carriers of paclitaxel (PTX) to improve its intestinal pharmacokinetic profile. Chitosan-grafted-polycaprolactone (CS-g-PCL) was synthesized through a carbodiimide reaction by amidation and confirmed by Fourier transform infrared spectroscopy (FTIR), hydrogen nuclear magnetic resonance analysis (1H NMR), and contact angle evaluation. Micelles were produced by solvent evaporation method, and the critical micelle concentration was investigated by conductimetry. The obtained micelles were of 408-nm mean particle size, narrow size distribution (polydispersity index of 0.335) and presented positive surface charge around 30 mV. The morphology of micelles assessed by transmission electron microscopy (TEM) revealed round and smooth surface, in agreement with dynamic light scattering measurements. The association efficiency determined by high-performance liquid chromatography (HPLC) was as high as 82%. The in vitro cytotoxicity of the unloaded and PTX-loaded micelles was tested against Caco-2 and HT29-MTX intestinal epithelial cells, resulting in the absence of cell toxicity for all formulations. Moreover, the permeability of PTX-loaded micelles in Caco-2 monolayer and Caco-2/HT29-MTX co-culture model was determined. Results showed that the permeability of PTX was higher in Caco-2/HT29-MTX co-culture model compared with Caco-2 monolayer due to the mucoadhesive character of micelles, acting as a platform to deliver PTX at the sites of absorption. Therefore, it can be concluded that the PTX-loaded CS-g-PCL micelles, employed for the first time as PTX carriers, may be a potential drug carrier for the intestinal delivery of hydrophobic drugs, particularly anticancer agents.

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Acknowledgements

This work was financed by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020 (NORTE-01-0145-FEDER-000012), and by Portuguese funds through Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). This research was also partially supported by CESPU/IINFACTS under the project NanoGum-CESPU-2014.

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Authors and Affiliations

  1. Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Rua Alfredo Allen, 208, 4200-393, Porto, Portugal

    Andreia Almeida & Bruno Sarmento

  2. Instituto de Química de São Carlos, Universidade de São Paulo, Avenida Trabalhador São-Carlense, São Carlos, SP, 400-13560-970, Brazil

    Daniella Silva

  3. CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, 4585-116, Gandra, Portugal

    Virginia Gonçalves & Bruno Sarmento

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  1. Andreia Almeida
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  2. Daniella Silva
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  3. Virginia Gonçalves
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Correspondence to Bruno Sarmento.

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Almeida, A., Silva, D., Gonçalves, V. et al. Synthesis and characterization of chitosan-grafted-polycaprolactone micelles for modulate intestinal paclitaxel delivery. Drug Deliv. and Transl. Res. 8, 387–397 (2018). https://doi.org/10.1007/s13346-017-0357-8

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