Biological Effect Evaluation of Glutathione-Responsive Cyclodextrin-Based Nanosponges: 2D and 3D Studies.

Monica Argenziano,Fabrizio Caldera,Francesco Trotta,Carlo Della Pepa,Rita Spagnolo,Roberta Cavalli,Loredana Serpe,Federica Foglietta,Roberto Canaparo

doi:10.3390/molecules25122775

Monica Argenziano, Fabrizio Caldera + Show 7 more

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https://doi.org/10.3390/molecules25122775

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Journal: Molecules (Basel, Switzerland)	Publication Date: Jun 16, 2020
Citations: 13	License type: CC BY 4.0

Affiliation: University of Turin

Abstract

This study aims to evaluate the bioeffects of glutathione-responsive β-cyclodextrin-based nanosponges (GSH-NSs) on two- (2D) and three-dimensional (3D) cell cultures. The bioeffects of two types of GSH-NS formulations, with low (GSH-NS B) and high (GSH-NS D) disulfide-bond content, were evaluated on 2D colorectal (HCT116 and HT-29) and prostatic (DU-145 and PC3) cancer cell cultures. In particular, the cellular uptake of GSH-NS was evaluated, as their effects on cell growth, mitochondrial activity, membrane integrity, cell cycle distribution, mRNA expression, and reactive oxygen species production. The effect of GSH-NSs on cell growth was also evaluated on multicellular spheroids (MCS) and a comparison of the GSH-NS cell growth inhibitory activity, in terms of inhibition concentration (IC)50 values, was performed between 2D and 3D cell cultures. A significant decrease in 2D cell growth was observed at high GSH-NS concentrations, with the formulation with a low disulfide-bond content, GSH-NS B, being more cytotoxic than the formulation with a high disulfide-bond content, GSH-NS D. The cell growth decrease induced by GSH-NS was owing to G1 cell cycle arrest. Moreover, a significant down-regulation of mRNA expression of the cyclin genes CDK1, CDK2, and CDK4 and up-regulation of mRNA expression of the cyclin inhibitor genes CDKN1A and CDKN2A were observed. On the other hand, a significant decrease in MCS growth was also observed at high GSH-NS concentrations, but not influenced by the nanosponge disulfide-bond content, with the MCS IC50 values being significantly higher than those obtained on 2D cell cultures. GSH-NSs are suitable nanocarries as they provoke limited cellular effects, as cell cycle arrest only occurred at concentrations significantly higher than those used for drug delivery.

Highlights

The ideal nanoparticle-based drug delivery system assures the safe delivery and selective action of a drug to a target site
GSH-NSs are suitable nanocarries as they provoke limited cellular effects, as cell cycle arrest only occurred at concentrations significantly higher than those used for drug delivery
Nanoscience in drug development is in its early stages, the fusion of engineered nanomaterials and nanopharmaceutical research is paving the way for the development of stimuli-responsive drug delivery systems, especially in cancer treatment

Summary

Introduction

The ideal nanoparticle-based drug delivery system assures the safe delivery and selective action of a drug to a target site. Nanomaterials can add further functionality to the conjugated/loaded drug and, taking advantage of their unique size, are able to play a crucial therapeutic role. This has triggered an increased interest in nanopharmaceuticals [1,2] and the development of a wide range of nanoparticle systems, such as liposomes, nanoparticles, micelles, dendrimers, and nanotubes [3,4,5]. Molecules 2020, 25, 2775 few nanoparticle-based systems have been FDA-approved for cancer therapy to date [6,7]. Nanoscience in drug development is in its early stages, the fusion of engineered nanomaterials and nanopharmaceutical research is paving the way for the development of stimuli-responsive drug delivery systems, especially in cancer treatment. Several chemically modified polymers [8,9]

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