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

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.

Transferrin-Decorated PLGA Nanoparticles Loaded with an Organoselenium Compound as an Innovative Approach to Sensitize MDR Tumor Cells: An In Vitro Study Using 2D and 3D Cell Models

“…The organoselenium compound ACAT-Se was nanoencapsulated on PLGA NPs (ACAT-Se-PLGA-NPs) as previously reported by Macedo et al [ 12 ]. Firstly, ACAT-Se was added to a solution containing PLGA and Span ® 80 in acetone; this organic solution was kept for 20 min under magnetic stirring.…”

“…The drug content was determined following the extraction procedure and RP-LC method previously described [ 12 ].…”

“…An aliquot of the NP suspension (500 µL) was placed in a dialysis bag (Sigma–Aldrich, São Paulo, Brazil 14,000 MWCO), sealed, and soaked in 50 mL of phosphate buffer solution (pH 7.4) at 37 °C and kept under constant shaking (150 rpm) for 24 h. At predetermined time intervals, an aliquot of the release medium was collected and replaced with an equivalent amount of fresh release medium to maintain the sink conditions. The amount of ACAT-Se released was determined using the previously published RP-LC method [ 12 ]. The release of free ACAT-Se (methanolic solution) was also evaluated, for comparison purposes.…”

“…In this sense, a new nucleoside derived from zidovudine, containing selenium (Se), 5′-Se-(phenyl)-3-(amino)-thymidine (ACAT-Se) ( Figure S1 ), was developed by [ 11 ] and presented a promising in vitro antitumor activity. Previously, we used this compound to design pH-sensitive NPs [ 12 ]. The NPs were prepared using poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) [ 13 ]; poloxamer as a surfactant, due its great potential to sensitize MDR cells [ 14 ]; and 77KL (N α ,N ε -dioctanoyl lysine with an inorganic lithium counterion) as a pH-responsive adjuvant.…”

Chitosan-Based Nano-Smart Drug Delivery System in Breast Cancer Therapy

“…The pH is lowered to 6.0–7.0 as a result of glycolysis, which creates a slightly acidic environment in a low-oxygen environment. Additionally, the pH of lysosomes within cancer cells is significantly lower, only reaching 5 [ 128 , 129 ]. The Warburg effect can provide advantages for cell growth in a multicellular environment.…”