title: Real time measurement of PEG shedding from lipid nanoparticles in serum via NMR spectroscopy.
abstract: Small interfering RNA (siRNA) is a novel therapeutic modality that benefits from nanoparticle mediated delivery. The most clinically advanced siRNA-containing nanoparticles are polymer-coated supramolecular assemblies of siRNA and lipids (lipid nanoparticles or LNPs), which protect the siRNA from nucleases, modulate pharmacokinetics of the siRNA, and enable selective delivery of siRNA to target cells. Understanding the mechanisms of assembly and delivery of such systems is complicated by the complexity of the dynamic supramolecular assembly as well as by its subsequent interactions with the biological milieu. We have developed an ex vivo method that provides insight into how LNPs behave when contacted with biological fluids. Pulsed gradient spin echo (PGSE) NMR was used to directly measure the kinetics of poly(ethylene) glycol (PEG) shedding from siRNA encapsulated LNPs in rat serum. The method represents a molecularly specific, real-time, quantitative, and label-free way to monitor the behavior of a nanoparticle surface coating. We believe that this method has broad implications in gaining mechanistic insights into how nanoparticle-based drug delivery vehicles behave in biofluids and is versatile enough to be applied to a diversity of systems.
authors.affiliation: Novartis Institutes for Biomedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Wilson
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Baryza
authors.forename: Aimee J
authors.initials: AJ
authors.lastname: Reynolds
authors.forename: Keith
authors.initials: K
authors.lastname: Bowman
authors.forename: Mark E
authors.initials: ME
authors.lastname: Keegan
authors.forename: Stephany M
authors.initials: SM
authors.lastname: Standley
authors.forename: Noah P
authors.initials: NP
authors.lastname: Gardner
authors.forename: Parul
authors.initials: P
authors.lastname: Parmar
authors.forename: Vahide Ozlem
authors.initials: VO
authors.lastname: Agir
authors.forename: Sunita
authors.initials: S
authors.lastname: Yadav
authors.forename: Adnan
authors.initials: A
authors.lastname: Zunic
authors.forename: Chandra
authors.initials: C
authors.lastname: Vargeese
authors.forename: Cameron C
authors.initials: CC
authors.lastname: Lee
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Rajan
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis / Q000379:methods*; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000032:analysis*; D034741:RNA, Small Interfering / Q000737:chemistry*; D051381:Rats
chemical_list: D008055:Lipids; D008081:Liposomes; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols
keywords: LNP; PEG shedding; PEG-lipid; PGSE NMR; lipid nanoparticle; liposome; micelle; nanoparticle; siRNA