Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier—the glomerular basement membrane (GBM)—can d...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (8), p.3137-3142
Main Authors: Zuckerman, Jonathan E, Choi, Chung Hang J, Han, Han, Davis, Mark E
Format: Article
Language:English
Subjects:
Animals
Basement membrane
Basement membranes
Biological Sciences
Blood
Blood plasma
Electron microscopy
electrostatic interactions
Electrostatic properties
Filtration
Gels
Glomerular Basement Membrane - diagnostic imaging
Glomerular Basement Membrane - metabolism
Heparitin Sulfate - chemistry
Injections, Intravenous
Kidney
Kidneys
Kinetics
Membranes
Mice
Models, Biological
Nanoparticles
Nanoparticles - administration & dosage
Nanoparticles - chemistry
Nanoparticles - ultrastructure
nucleic acids
Plasmas
Polyamines - metabolism
Polymers
Positron emission tomography
Renal clearance
Ribonucleic acid
RNA
RNA, Small Interfering - administration & dosage
RNA, Small Interfering - metabolism
siRNA
Small interfering RNA
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Description
Summary:Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier—the glomerular basement membrane (GBM)—can disassemble cationic cyclodextrin-containing polymer (CDP)-based siRNA nanoparticles and, thereby, facilitate their rapid elimination from circulation. Using confocal and electron microscopies, positron emission tomography, and compartment modeling, we demonstrate that siRNA nanoparticles, but not free siRNA, accumulate and disassemble in the GBM. We also confirm that the siRNA nanoparticles do not disassemble in blood plasma in vitro and in vivo. This clearance mechanism may affect any nanoparticles that assemble primarily by electrostatic interactions between cationic delivery components and anionic nucleic acids (or other therapeutic entities).
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1200718109