title: Acute in vivo toxicity mitigation of PEI-coated maghemite nanoparticles using controlled oxidation and surface modifications toward siRNA delivery.
abstract: A ceric ammonium nitrate (CAN)-based doping step was used for the fabrication of core maghemite nanoparticles (NPs) that enabled the obtainment of colloid particles with a view to a high-level nanoparticle (NP) surface doping by Ce(III/IV). Such doping of Ce(III/IV) cations enables one to exploit their quite rich coordination chemistry for ligand coordinative binding. In fact, they were shown to act as powerful Lewis acid centers for attaching any organic (Lewis base) ligand such as a 25 kDa branched PEI polymer. Resulting conPEI25-CAN-γ-Fe2O3 NPs have been fully characterized before a successful implementation of siRNA loading and cell delivery/gene silencing using a well-known dual luciferase system. This attractive result emphasized their significant potential as an NP platform technology toward additional MRI and/or drug delivery (peptide)-relating end applications. However, due to their high positive charge, PEI polymers can cause severe in vivo toxicity due to their interaction with negatively charged red blood cells (RBC), resulting in RBC aggregation and lysis, leading to thrombosis and, finally, to animal death. In order to mitigate these acute toxic effects, two different types of surface modifications were performed. One modification included the controlled oxidation of 0.1-5% of the PEI amines before or after conjugation to the NPs, using hydrogen peroxide or potassium persulfate. The other type of modification was the addition of a second biocompatible polyanionic polymer to the PEI grafted NPs, based on the concept of a layer-by-layer (LbL) technique. This modification is based on the coordination of another polyanionic polymer on the NPs surface in order to create a combined hybrid PEI and polyanionic polymer nanosystem. In both cases, the surface modification successfully mitigated the NP acute in vivo toxicity, without compromising the silencing efficiency.
authors.forename: Liron Limor
authors.initials: LL
authors.lastname: Israel
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lellouche
authors.forename: Stella
authors.initials: S
authors.lastname: Ostrovsky
authors.forename: Valeria
authors.initials: V
authors.lastname: Yarmiayev
authors.forename: Moshe
authors.initials: M
authors.lastname: Bechor
authors.forename: Shulamit
authors.initials: S
authors.lastname: Michaeli
authors.forename: Jean-Paul Moshe
authors.initials: JP
authors.lastname: Lellouche
mesh_terms: D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D005290:Ferric Compounds / Q000737:chemistry; D020868:Gene Silencing; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry*; D010084:Oxidation-Reduction; D011094:Polyethyleneimine / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics* / Q000633:toxicity; D013499:Surface Properties
chemical_list: D004337:Drug Carriers; D005290:Ferric Compounds; D034741:RNA, Small Interfering; C000499:ferric oxide; D011094:Polyethyleneimine
keywords: PEI oxidation; PEI toxicity mitigation; design of experiments (DoE); gene silencing; layer-by-layer (LbL) nanoparticle surface modifications; maghemite nanoparticle surface engineering; nanoparticle-based drug delivery systems; siRNA delivery