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Poly (ɛ-Caprolactone) Nanoparticles with pH-Responsive Behavior Improved the In Vitro Antitumor Activity of Methotrexate

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Abstract

A promising approach to achieve a more efficient antitumor therapy is the conjugation of the active molecule to a nanostructured delivery system. Therefore, the main objective of this research was to prepare nanoparticles (NPs), with the polymer poly (ε-caprolactone) (PCL), as a carrier for the antitumor drug methotrexate (MTX). A pH-responsive behavior was obtained through conjugation of the amino acid-based amphiphile, 77KL, to the NP matrix. The NPs showed mean hydrodynamic diameter and drug entrapment efficiency of 178.5 nm and 20.52%, respectively. Owing to its pH-sensitivity, the PCL-NPs showed membrane-lytic behavior upon reducing the pH value of surrounding media to 5.4, which is characteristic of the endosomal compartments. The in vitro antitumor assays demonstrated that MTX-loaded PCL-NPs have higher antiproliferative activity than free drug in MCF-7 cells and, to a lesser extent, in HepG2 cells. This same behavior was also achieved at mildly acidic conditions, characteristic of the tumor microenvironment. Altogether, the results evidenced the pH-responsive properties of the designed NPs, as well as the higher in vitro cytotoxicity compared to free MTX, representing thus a promising alternative for the antitumor therapy.

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Funding

This research was supported by Grants 447548/2014-0 and 401069/2014-1 of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - Brazil) and 2293-2551/14-0 of Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS - Brazil). Letícia B. Macedo and Daniele R. Nogueira-Librelotto acknowledge Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES - Brazil) and CNPq - Brazil for the Master’s and Postdoctoral fellowships, respectively.

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Authors and Affiliations

  1. Department of Industrial Pharmacy, Universidade Federal de Santa Maria, Av. Roraima 1000, Santa Maria, RS, 97105-900, Brazil

    Letícia Bueno Macedo, Daniele Rubert Nogueira-Librelotto, Josiele de Vargas, Laís Engroff Scheeren & Clarice Madalena Bueno Rolim

  2. PostGraduate Program in Pharmaceutical Sciences, Universidade Federal de Santa Maria, Av. Roraima 1000, Santa Maria, RS, 97105-900, Brazil

    Letícia Bueno Macedo, Daniele Rubert Nogueira-Librelotto, Laís Engroff Scheeren & Clarice Madalena Bueno Rolim

  3. Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Joan XXIII 27-31, 08028, Barcelona, Spain

    María Pilar Vinardell

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  1. Letícia Bueno Macedo
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Correspondence to Clarice Madalena Bueno Rolim.

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Macedo, L.B., Nogueira-Librelotto, D.R., de Vargas, J. et al. Poly (ɛ-Caprolactone) Nanoparticles with pH-Responsive Behavior Improved the In Vitro Antitumor Activity of Methotrexate. AAPS PharmSciTech 20, 165 (2019). https://doi.org/10.1208/s12249-019-1372-5

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