Abstract
Nanoparticle based gene delivery systems holds great promise. Superparamagnetic iron oxide nanoparticles (SPIONs) are being heavily investigated due to good biocompatibility and added diagnostic potential, rendering such nanoparticles theranostic. Yet, commonly used cationic coatings for efficient delivery of such anionic cargos, results in significant toxicity limiting translation of the technology to the clinic. Here, we describe a highly biocompatible, small and non-cationic SPION-based theranostic nanoparticles as novel gene therapy agents. We propose for the first-time, the usage of the microRNA machinery RISC complex component Argonaute 2 (AGO2) protein as a microRNA stabilizing agent and a delivery vehicle. In this study, AGO2 protein-conjugated, anti-HER2 antibody-linked and fluorophore-tagged SPION nanoparticles were developed (SP-AH nanoparticles) and used as a carrier for an autophagy inhibitory microRNA, MIR376B. These functionalized nanoparticles selectively delivered an effective amount of the microRNA into HER2-positive breast cancer cell lines in vitro and in a xenograft nude mice model of breast cancer in vivo, and successfully blocked autophagy. Furthermore, combination of the chemotherapy agent cisplatin with MIR376B-loaded SP-AH nanoparticles increased the efficacy of the anti-cancer treatment both in vitro in cells and in vivo in the nude mice. Therefore, we propose that AGO2 protein conjugated SPIONs are a new class of theranostic nanoparticles and can be efficiently used as innovative, non-cationic, non-toxic gene therapy tools for targeted therapy of cancer.
Highlights
Most human diseases are caused by abnormalities and malfunction of genes and proteins
Even after this incubation period, a significant amount of miRNA was still detected by Quantitative PCR (qPCR), indicating that Argonaute 2 (AGO2) protein bound miRNAs were protected from degradation (Additional file 1: Fig. S1c)
These results indicated that AGO2 protein may be used as a miRNA binding and stabilizing tool in gene therapy
Summary
Most human diseases are caused by abnormalities and malfunction of genes and proteins. There is an urgent need for non-toxic, small, target specific and theranostic nanoparticles, allowing efficient nucleic acid binding and delivery as well as medical imaging simultaneously. Argonaute (AGO) proteins are key components of the RISC They bind to single-stranded mature microRNAs, guiding them to their target messenger RNAs (mRNAs), and leading to mRNA degradation or translation blockage [26]. Inspired by the stability of naturally occurring AGO protein/miRNA complexes in the blood circulation, we have designed AGO2 conjugated SPIONs as tumor targeted miRNA delivery vehicles for gene therapy of cancer. SP-AH were successfully synthesized from poly(acrylic acid)-coated SPIONs with excellent colloidal stability and in small sizes This is the first example to AGO2 protein containing nanoparticles and the first demonstration of AGO2/nanoparticle conjugate as a transfection agent.
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