4.7 Article

Overcoming MDR by Associating Doxorubicin and pH-Sensitive PLGA Nanoparticles Containing a Novel Organoselenium Compound-An In Vitro Study

期刊

PHARMACEUTICS
卷 14, 期 1, 页码 -

出版社

MDPI
DOI: 10.3390/pharmaceutics14010080

关键词

selenium compounds; pH-responsive nanoparticles; combination therapy; tumor cell lines; multidrug resistance (MDR)

资金

  1. Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil) [447548/2014-0, 401069/2014-1]
  2. Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)

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In this study, PLGA nanoparticles were developed as an effective carrier for ACAT-Se, a promising nucleoside analogue with antitumor activity. The nanoparticles showed increased antioxidant and antitumor activity in cancer cells, and were hemocompatible. When combined with doxorubicin, the nanoparticles exhibited a synergistic effect in both sensitive and resistant tumor cells, suggesting their potential as a promising delivery system for cancer therapy.
In this study, we developed PLGA nanoparticles (NPs) as an effective carrier for 5 '-Se-(phenyl)-3-(amino)-thymidine (ACAT-Se), an organoselenium compound, nucleoside analogue that showed promising antitumor activity in vitro. The PLGA NPs were prepared by the nanoprecipitation method and modified with a pH-responsive lysine-based surfactant (77KL). The ACAT-Se-PLGA-77KL-NPs presented nanometric size (around 120 nm), polydispersity index values < 0.20 and negative zeta potential values. The nanoencapsulation of ACAT-Se increased its antioxidant (DPPH and ABTS assays) and antitumor activity in MCF-7 tumor cells. Hemolysis study indicated that ACAT-Se-PLGA-77KL-NPs are hemocompatible and that 77KL provided a pH-sensitive membranolytic behavior to the NPs. The NPs did not induce cytotoxic effects on the nontumor cell line 3T3, suggesting its selectivity for the tumor cells. Moreover, the in vitro antiproliferative activity of NPs was evaluated in association with the antitumor drug doxorubicin. This combination result in synergistic effect in sensitive (MCF-7) and resistant (NCI/ADR-RES) tumor cells, being especially able to successfully sensitize the MDR cells. The obtained results suggested that the proposed ACAT-Se-loaded NPs are a promising delivery system for cancer therapy, especially associated with doxorubicin.

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