One-pot synthesis of pH-responsive hybrid nanogel particles for the intracellular delivery of small interfering RNA

Abstract

This report describes a novel, one-pot synthesis of hybrid nanoparticles formed by a nanostructured inorganic silica core and an organic pH-responsive hydrogel shell. This easy-to-perform, oil-in-water emulsion process synthesizes fluorescently-doped silica nanoparticles wrapped within a tunable coating of cationic poly(2-diethylaminoethyl methacrylate) hydrogel in one step. Transmission electron microscopy and dynamic light scattering analysis demonstrated that the hydrogel-coated nanoparticles are uniformly dispersed in the aqueous phase. The formation of covalent chemical bonds between the silica and the polymer increases the stability of the organic phase around the inorganic core as demonstrated by thermogravimetric analysis. The cationic nature of the hydrogel is responsible for the pH buffering properties of the nanostructured system and was evaluated by titration experiments. Zeta-potential analysis demonstrated that the charge of the system was reversed when transitioned from acidic to basic pH and vice versa. Consequently, small interfering RNA (siRNA) can be loaded and released in an acidic pH environment thereby enabling the hybrid particles and their payload to avoid endosomal sequestration and enzymatic degradation. These nanoparticles, loaded with specific siRNA molecules directed towards the transcript of the membrane receptor CXCR4, significantly decreased the expression of this protein in a human breast cancer cell line (i.e., MDA-MB-231). Moreover, intravenous administration of siRNA-loaded nanoparticles demonstrated a preferential accumulation at the tumor site that resulted in a reduction of CXCR4 expression.

Designing hydrogels for controlled drug delivery

“…177,178 This has been shown in the design of hybrid nanogels for the delivery of small interfering RNA; the nanogels contain a rigid silica core to stabilize the pH-responsive hydrogel matrix, which would otherwise be fragile when undergoing a pH transition. 179 …”

DNA Microcapsule for Photo‐Triggered Drug Release Systems

“…Several stimuli-responsive devices based on conventional delivery platforms such as liposomes and micelles have been reported. [24][25][26] In addition, DNA-layered CaCO 3 microparticles with various sensing units [27,28] and spherically arranged drug-conjugated DNA having redox sensing systems have been demonstrated. [29] Thus, the installation of stimuli-responsive devices on DNA microcapsules has the potential for therapeutic utility for spatiotemporal drug delivery.…”

Endosomal Escape of Polymer‐Coated Silica Nanoparticles in Endothelial Cells

“…These hybrid nanoparticles (HNP) have been shown to buffer the surrounding environment through the protonation of the tertiary amines exposed on the nanoparticle surface. [8] This likely contributed to the success observed in escaping endosomal vesicles in breast cancer cells and subsequent cytoplasmic delivery of a biological payload. [8] Protonatable surfaces with buffering properties are necessary conditions to induce endosomal damage, though these mechanisms are still under investigation.…”

“…Herein, our carrier model is represented by a nanoplatform designed and characterized for achieving endosomal escape. [8] The system was generated through a one-pot synthesis protocol, allowing for the fabrication of fluorescent silica nanoparticles (SNP) encapsulated within a pH-responsive poly(diethylaminoethyl methacrylate) (PDEAEM) shell. The polymer was crosslinked and stabilized onto the surface of the particles with polyethylene glycol methacrylate (PEGMA) and triethylene glycol dimethacrylate (TEGDMA) linkers.…”