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

Daniele Rubert Nogueira-Librelotto,Josiele Melo De Vargas,Daniela Mathes,Maria Pilar Vinardell,Oscar Endrigo Dorneles Rodrigues,Raquel Mello Da Rosa,Clarice Madalena Bueno Rolim,Letícia Bueno Macedo,Montserrat Mitjans

doi:10.3390/pharmaceutics14010080

Abstract

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.

Highlights

IntroductionChemotherapy is the most common treatment for many types of cancer
Some studies suggest that selenium compounds present synergism with different cancer therapies, increasing the efficacy of the treatment and reducing the toxicity in the normal tissue [1,28,29]. In this context we evaluated if the NPs present synergic antitumor activity with doxorubicin (DOX), an antineoplastic drug commonly used for the treatment of a wide range of cancers [30]
Our results indicate that the plasma or cell culture medium proteins did not bind to the an effective carrier for -Se(phenyl)-3-(amino)-thymidine (ACAT-Se)-poly(lactic-co-glycolic acid) (PLGA)-77KL-NPs surface

Summary

Introduction

Chemotherapy is the most common treatment for many types of cancer. The majority of the currently available chemotherapeutic agents show poor specificity by the tumor site, causing significant side effects and drug resistance [1–3]. In this regard, it is of the utmost importance the development of new compounds as well as new drug delivery systems to achieve a more effective antitumor treatment. Nucleoside analogues represent an important class of chemotherapeutic agents used for the treatment of patients with cancer [4,5]. They are synthetic compounds, analogues of Pharmaceutics 2022, 14, 80.

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