Construction of a Glutathione-Responsive and Silica-Based Nanocomposite for Controlled Release of Chelator Dimercaptosuccinic Acid.

Hongqiang Zhai,Shuai Liu,Yuli Wang,Chunsheng Gao,Menghua Wang,Guiling Li,Qiang Wu,Feifei Yu

doi:10.3390/ijms19123790

Abstract

Dimercaptosuccinic acid (DMSA) is an oral heavy metal chelator. Although DMSA is the most acceptable chelator in the urinary excretion of toxic elements from children and adults, its defects in plasma binding and the membrane permeability limit its interaction with intracellular elements and affect its efficacy in chelation therapy. Herein, a novel nanocomposite composed of mesoporous silica nanoparticles (MSNs), disulfide bond, and DMSA was synthesized and characterized with a scanning/transmission electron microscope, IR and Raman spectra, and TGA analysis. The in vitro interactions with glutathione (GSH) and cellular uptake assays showed that it was able to be stable in extracellular environments such as in blood, be internalized by cells, and release DMSA inside via GSH-triggered disulfide cleavage reaction. The in vitro adsorption assays showed that MSNs-SH as its intracellular metabolite had strong adsorbability for models of Hg2+ or Pb2+. The hemolysis and cell viability assays showed that it was compatible with blood and cells even at a concentration of 1000 μg·mL−1. All above could not only enable it to be a GSH-responsive drug delivery system (DDS) for DMSA delivery but also to be a solution for its defects and efficacy. Thus, introduction of intelligent DDS might open a new avenue for DMSA-based chelation therapy.

Highlights

Multiple industrial, domestic, agricultural, medical, and technological applications have caused wide distribution of heavy metal elements in the environment such as lead (Pb), mercury (Hg), and arsenic (As) [1]
mesoporous silica nanoparticles (MSNs)-SH particles were synthesized by a modified one-pot method, according to previous reports, in which TEOS was used as a silica source, Cetyltrimethyl ammonium bromide (CTAB) and Brij-58 as the structure-directing agents, and MPTES as a co-condensation agent [32,33,34]
Morphology of MSNs-SH had no significant change after its reaction with dimercaptosuccinic acid (DMSA), but its BET surface area, pore volume, and pore size were reduced from 621 cm2·g−1, 0.88 cm3·g−1, and 2.18 nm to 565 cm2·g−1, 0.73 cm3·g−1, and 1.48 nm respectively (Figure 2a,b)

Summary

Introduction

Domestic, agricultural, medical, and technological applications have caused wide distribution of heavy metal elements in the environment such as lead (Pb), mercury (Hg), and arsenic (As) [1]. These elements can enter into the human body through the food chain, water, soil, and air and accumulate over a long time in tissues and organs [1,2]. These elements have no essential biochemical roles but can induce multiple organ damage as they bind with cell components such as the cell membrane, mitochondrial, lysosome, endoplasmic reticulum, nuclei, and enzymes [3]. Seldom efforts are made in this regard beside structural modification with the monoisoamyl group or amino acids [10,11]

Methods

Results

Conclusion