Multifunctional PEI-entrapped gold nanoparticles enable efficient delivery of therapeutic siRNA into glioblastoma cells

Abstract

RNA interference (RNAi) has been considered as a promising strategy for effective treatment of cancer. However, the easy degradation of small interfering RNA (siRNA) limits its extensive applications in gene therapy. For safe and effective delivery of siRNA, a novel vector system possessing excellent biocompatibility, highly efficient transfection efficiency and specific targeting properties has to be considered. In this study, we report the use of polyethyleneimine (PEI)-entrapped gold nanoparticles (Au PENPs) modified with an arginine-glycine-aspartic (Arg-Gly-Asp, RGD) peptide via a poly(ethylene glycol) (PEG) spacer as a vector for Bcl-2 (B-cell lymphoma-2) siRNA delivery to glioblastoma cells. The synthesized Au PENPs were well characterized. The efficiency of siRNA delivery was appraised by flow cytometry, confocal microscopy imaging, and the protein expression level. Our results revealed that the Au PENPs were capable of delivering Bcl-2 siRNA to glioblastoma cells with an excellent transfection efficiency, leading to specific gene silencing in the target cells (22% and 25.5% Bcl-2 protein expression in vitro and in vivo, respectively) thanks to the RGD peptide-mediated targeting pathway. The designed RGD-targeted Au PENPs may hold great promise to be used as a novel vector for specific cancer gene therapy applications.

Gold nanoparticles in ophthalmology

“…Due to their unique properties, GNP are used more and more in the biomedical field, especially for drug delivery, gene delivery, and thermal treatment of cancer . GNP are usually synthesized from HAuCl 4 , a gold salt that can be reduced by various methods, such as Brust or Turkevish ones.…”

PEI-Coated Fe3O4 Nanoparticles Enable Efficient Delivery of Therapeutic siRNA Targeting REST into Glioblastoma Cells

“…For GBM, siRNA targeting MGMT (O 6 -methylguanine methyltransferase, a key factor in brain tumor resistance to TMZ) delivered by iron oxide NPs conjugated with chlorotoxin could enhance temozolomide (TMZ) toxicity [10]. Polyethyleneimine (PEI)-entrapped gold NP modified with an arginine-glycine-aspartic peptide was capable of delivering siRNA targeting Bcl-2 to GBM cells to increase cell apoptosis [11]. In our previous studies, a type of cationic PEI-coated Fe 3 O 4 NPs were proved to be effective in siRNA protection and siRNA delivery into mesenchymal stem cells [12].…”

Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

“…Metallic vehicles (primarily gold or iron oxide nanoparticles) for siRNA tend to underperform in vivo based on measurements of gene silencing efficiency, with average efficiencies of 72.3 ± 16.3% in vitro and 54.7 ± 19.6% in vivo (Table and Figure ). This trend may be attributed to the solid structure of the constructs, which leads to formulations in which the siRNA payloads are covalently bound or chemically adhered to the surface of the particles (e.g., thiol‐gold chemistry) . This surface‐loading mechanism leaves the siRNA molecules exposed to the degrading conditions of the in vivo environment during circulation, which underscores the necessity for an siRNA‐protective design; thus, metallic systems generally employ cationic polymer/lipid coatings to facilitate loading and protection of the siRNA payload …”

“…Nonetheless, metallic particles have advantages over other organic material‐based systems in their longer shelf life, their facile surface chemistry, their higher physical stability (to temperature or pH excursions), their precisely tunable physical properties, and their potential for multi‐modality (e.g., phototherapy, MRI imaging) . The surface chemistry of most metallic systems is amenable to attachment of a wide variety of targeting moieties or components that can facilitate endosomal escape (Table ) . In particular, gold‐based systems have demonstrated the ability to induce controlled release of siRNAs via light‐activation, as well as providing a photothermal therapeutic effect as a secondary function .…”

“…Eventually, the vesicle swells and ruptures to release its entrapped payload . For inorganic and polymeric nanoparticles, polyethyleneimine (PEI) is the most commonly used molecule, with its abundance of nitrogen groups available to buffer the pH and sponge up protons . While the proton sponge mechanism of PEI is still under debate, its endosomal escape phenomenon has been replicated numerous times, and has been extensively used to demonstrate effective in vivo gene silencing effect in numerous nanosystems, as shown in Table .…”