Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 8, Pages 3137-3142Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1200718109
Keywords
pharmacokinetics; glomerulus
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Funding
- Materials Research Science & Engineering Center of the National Science Foundation [DMR-0520565]
- National Cancer Institute [CA119347]
- Sanofi-Aventis
- California Institute of Technology-University of California, Los Angeles Joint Center for Translational Medicine
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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).
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