title: Evaluation of the physicochemical properties and the biocompatibility of polyethylene glycol-conjugated gold nanoparticles: A formulation strategy for siRNA delivery.
abstract: The potential of RNA interference (RNAi)-based therapeutics for cancer has received much attention; however, delivery of RNAi effectors, such as small interfering RNA (siRNA), remains an obstacle to clinical translation. Non-viral delivery vectors have been used extensively to enhance siRNA delivery. Recently, the potential of gold nanoparticles (AuNPs) for transporting drugs, proteins and genetic materials has been demonstrated. Previously, our laboratory synthesised positively charged, surfactant-free AuNPs in water by the reduction of gold (III) chloride (AuCl3) using hydroxylamine hydrochloride (NH2OH·HCl) in the presence of L-cysteine methyl ester hydrochloride (HSCH2CH(NH2)COOCH3·HCl) as a capping agent. These AuNPs, which achieve higher cell viability in comparison to cetyl trimethyl ammonium bromide (CTAB, a surfactant)-capped counterparts, have demonstrated potential for siRNA delivery. However, it is well known that systemic administration of cationic delivery systems without biological stablising moieties causes non-specific binding with negatively charged serum proteins, resulting in particle aggregation and opsonisation. Consequently, highly stable AuNPs capped with l-cysteine methyl ester hydrochloride conjugated to poly(ethylene glycol) (PEG) were synthesised in this study. PEGylation enhanced the biocompatibility of the AuNPs by reducing toxicity in a range of cell types, by inhibiting interaction with serum proteins thus avoiding aggregation, and, by providing protection against degradation by nucleases. Moreover, these PEGylated AuNPs formed nanoparticles (NPs) with siRNA (which was first compacted with protamine), and had a diameter within the nanoscale range (∼ 250 nm) and a near neutral surface charge (∼ 10 mV). In the future a bifunctional PEG chain on the AuNPs (i.e., SH-PEG-NH2, SH-PEG-COOH) will be used to facilitate conjugation of a targeting ligand to enhance cell specific uptake.
authors: Materials Chemistry and Analysis Group, Department of Chemistry and the Tyndall National Institute, University College Cork, Cork, Ireland; AMBER (Advanced Materials and Biological Engineering Research Centre), CRANN (Centre for Research on Adaptive Nanostructures and Nanodevices), Trinity College Dublin, Dublin, Ireland; Department of Sciences, Faculty of Natural and Applied Science, Notre Dame University (Louaize), Lebanon.
authors: Kamil
authors: K
authors: Rahme
authors: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland.
authors: Jianfeng
authors: J
authors: Guo
authors: Materials Chemistry and Analysis Group, Department of Chemistry and the Tyndall National Institute, University College Cork, Cork, Ireland; AMBER (Advanced Materials and Biological Engineering Research Centre), CRANN (Centre for Research on Adaptive Nanostructures and Nanodevices), Trinity College Dublin, Dublin, Ireland.
authors: Justin D
authors: JD
authors: Holmes
authors: Pharmacodelivery Group, School of Pharmacy, University College Cork, Ireland. Electronic address: caitriona.odriscoll@ucc.ie.
authors: Caitriona M
authors: CM
authors: O'Driscoll
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D001798:Blood Proteins / Q000737:chemistry; D045744:Cell Line, Tumor; D000077286:Cetrimonium; D002593:Cetrimonium Compounds / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002712:Chlorides / Q000737:chemistry; D003545:Cysteine / Q000031:analogs & derivatives / Q000737:chemistry; D018014:Gene Transfer Techniques; D006046:Gold / Q000737:chemistry*; D006801:Humans; D006898:Hydroxylamines / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry*; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D001798:Blood Proteins; D002593:Cetrimonium Compounds; D002712:Chlorides; D006898:Hydroxylamines; D034741:RNA, Small Interfering; D013501:Surface-Active Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D006046:Gold; D003545:Cysteine; C017507:mecysteine; D000077286:Cetrimonium
keywords: Gold nanoparticles; Non-viral siRNA delivery; PEGylation; Polyethylene glycol dilemma