Cancer cell targeting and therapeutic delivery of silver nanoparticles by mesoporous silica nanocarriers: insights into the action mechanisms using quantitative proteomics

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Abstract

An approach for safely delivering AgNPs to cancer cells and the evaluation of the affected cellular mechanism are presented.

Abstract

An approach for safely delivering AgNPs to cancer cells and the evaluation of the affected cellular mechanism are presented. The use of mesoporous silica nanoparticles (MSNs) as nanovehicles decorated with transferrin (Tf, targeting agent) provides a nanoplatform for the nucleation and immobilization of AgNPs ( MSNs-Tf-AgNPs). We performed the physico-chemical characterization of the nanosystems and evaluated their therapeutic potential using bioanalytical strategies to estimate the efficiency of the targeting, the degree of cellular internalization in two cell lines with different TfR expression, and the cytotoxic effects of the delivered AgNPs. In addition, cellular localization of the nanosystems in cells has been evaluated by a transmission electron microscopy analysis of ultrathin sections of human hepatocarcinoma (HepG2) cells exposed to MSNs-Tf-AgNPs. The in vitroassays demonstrate that only the nanosystem functionalized with Tf is able to transport the AgNPs inside the cells which overexpress transferrin receptors. Therefore, this novel nanosystem is able to deliver AgNPs specifically to cancer cells overexpressing Tf receptors and offers the possibility of a targeted therapy using reduced doses of silver nanoparticles as cytotoxic agents. Then, a quantitative proteomic experiment validated through the analysis of gene expression has been performed to identify the molecular mechanisms of action associated with the chemotherapeutic potential of the MSNs-Tf-AgNPnanocarriers.

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A New Property of MCM-41: Drug Delivery System

M Vallet-Regí, A Rámila, R. del Real … (2001)

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Endosomal escape pathways for delivery of biologicals.

Amir K Varkouhi, Marije Scholte, Gert Storm … (2011)

Despite continuous improvements in delivery systems, the development of methods for efficient and specific delivery of targeted therapeutic agents still remains an issue in biological treatments such as protein and gene therapy. The endocytic pathway is the major uptake mechanism of cells and any biological agents, such as DNA, siRNA and proteins. These agents become entrapped in endosomes and are degraded by specific enzymes in the lysosome. Thus, a limiting step in achieving an effective biological based therapy is to facilitate the endosomal escape and ensure cytosolic delivery of the therapeutics. Bacteria and viruses are pathogens which use different mechanisms to penetrate the membranes of their target cells and escape the endosomal pathway. Different mechanisms such as pore formation in the endosomal membrane, pH-buffering effect of protonable groups and fusion into the lipid bilayer of endosomes have been proposed to facilitate the endosomal escape. Several viral and bacterial proteins have been identified that are involved in this process. In addition, chemical agents and photochemical methods to rupture the endosomal membrane have been described. New synthetic biomimetic peptides and polymers with high efficacy in facilitating the endosomal escape, low pathogenicity and toxicity have been developed. Each strategy has different characteristics and challenges for designing the best agents and techniques to facilitate the endosomal escape are ongoing. In this review, several mechanisms and agents which are involved in endosomal escape are introduced. Copyright © 2010 Elsevier B.V. All rights reserved.

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Cytotoxicity and genotoxicity of silver nanoparticles in human cells.

P. V. Asharani, Grace Low Kah Mun, Manoor Prakash Hande … (2009)

Silver nanoparticles (Ag-np) are being used increasingly in wound dressings, catheters, and various household products due to their antimicrobial activity. The toxicity of starch-coated silver nanoparticles was studied using normal human lung fibroblast cells (IMR-90) and human glioblastoma cells (U251). The toxicity was evaluated using changes in cell morphology, cell viability, metabolic activity, and oxidative stress. Ag-np reduced ATP content of the cell caused damage to mitochondria and increased production of reactive oxygen species (ROS) in a dose-dependent manner. DNA damage, as measured by single cell gel electrophoresis (SCGE) and cytokinesis blocked micronucleus assay (CBMN), was also dose-dependent and more prominent in the cancer cells. The nanoparticle treatment caused cell cycle arrest in G(2)/M phase possibly due to repair of damaged DNA. Annexin-V propidium iodide (PI) staining showed no massive apoptosis or necrosis. The transmission electron microscopic (TEM) analysis indicated the presence of Ag-np inside the mitochondria and nucleus, implicating their direct involvement in the mitochondrial toxicity and DNA damage. A possible mechanism of toxicity is proposed which involves disruption of the mitochondrial respiratory chain by Ag-np leading to production of ROS and interruption of ATP synthesis, which in turn cause DNA damage. It is anticipated that DNA damage is augmented by deposition, followed by interactions of Ag-np to the DNA leading to cell cycle arrest in the G(2)/M phase. The higher sensitivity of U251 cells and their arrest in G(2)/M phase could be explored further for evaluating the potential use of Ag-np in cancer therapy.