Peptide-Functionalized Nanogels for Targeted siRNA Delivery

Abstract

A major bottleneck in the development of siRNA therapies is their delivery to the desired cell type or tissue, followed by effective passage across the cell membrane with subsequent silencing of the targeted mRNA. To address this problem, we describe the synthesis of core/shell hydrogel nanoparticles (nanogels) with surface-localized peptides that specifically target ovarian carcinoma cell lines possessing high expression levels of the Eph2A receptor. These nanogels are also demonstrated to be highly effective in the noncovalent encapsulation of siRNA and enable cellspecific delivery of the oligonucleotides in serum-containing medium. Cell toxicity and viability assays reveal that the nanogel construct is nontoxic under the conditions studied, as no toxicity or decrease in cell proliferation is observed following delivery. Importantly, a preliminary investigation of gene silencing illustrates that nanogel-mediated delivery of siRNA targeted to the EGF receptor results in knockdown of that receptor. Excellent protection of siRNA during endosomal uptake and endosomal escape of the nanogels is suggested by these results since siRNA activity in the cytosol is required for gene silencing.

Polymers in Small-Interfering RNA Delivery

“…Blackburn et al prepared a peptide-functionalized core/shell nanogel for cancer cell specific siRNA delivery (Blackburn et al, 2009). This core/shell nanogel was composed of cross-linked poly(N-isopropylmethacrylamide) (pNIPMAm), an amphiphilic, thermoresponsive polymer that was strongly hydrated at physiological temperature.…”

Microgels and Nanoparticles: Where Micro and Nano Go Hand in Hand

“…In this context, fluorescent co-monomers can be copolymerized into the polymer network, allowing for confocal fluorescence microscopy imaging [33]. Fluorescent energy transfer studies have been performed during the collapse of pNIPAM-based core-shell systems containing donor and acceptor fluorophores, respectively [34].…”

“…An example comprises core-shell pNIPAMbased beads with sizes below 100 nm (nano-gels), loaded with small interfering RNA (SiRNA). It has been shown that these systems bioconjugated with peptides can carry out selective targeting and SiRNA delivery to ovarian cancer cells, thereby reducing gene expression [33]. The ability of analytes to diffuse through the micro-or nanogel layer allows for a vast palette of potential detection routes as described below.…”

“…perature, pH, magnetic and/or electric fields, osmotic pressure, to detect specific molecules such as glucose or antigens, their properties as scaffolds to repair tissues, and their potential use as delivery systems for therapeutic or imaging agents [1][2][3][4][5][6]. In fact, their response to external stimuli has granted these materials the consideration of smart or intelligent gels.…”

Nanocarriers for siRNA delivery to overcome cancer multidrug resistance

“…Nanogels, which have been widely used in drug delivery and medical diagnosis, can also deliver siRNA to targeted cells [93]. Nanogels are able to be loaded with siRNA via "breathing-in" manner besides electrostatic attraction [94]. Dickerson et al [95] investigated core/shell nanogels composed of poly (N-isopropylmethacrylamide) (pNIPMAm) cross-linked with N,N′-methylene(bisacrylamide) to deliver siRNA targeting epidermal growth factor receptor (EGFR).…”