Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane
Abstract
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).
Additional Information
© 2012 by the National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Mark E. Davis, January 17, 2012 (sent for review December 22, 2011). We thank Paul Webster (House Ear Institute) for providing equipment for TEM sample preparation and Carol M. Garland (California Institute of Technology) and Dr. Alasdair McDowall (California Institute of Technology) for help obtaining electron microscopy images. This work benefited from the use of the California Institute of Technology Materials Science TEM facility, which is partially supported by the Materials Research Science & Engineering Center Program of the National Science Foundation under Award DMR-0520565. We thank Derek W. Bartlett and Isabel J. Hildebrandt for performing the PET experiments and Devin Wiley for reading the manuscript and discussion. This work was supported by National Cancer Institute Grant CA119347 and Sanofi-Aventis. J.E.Z. is also supported by the California Institute of Technology- University of California, Los Angeles Joint Center for Translational Medicine. Author contributions: J.E.Z. and M.E.D. designed research; J.E.Z., C.H.J.C., and H.H. performed research; J.E.Z., C.H.J.C., H.H., and M.E.D. analyzed data; and J.E.Z., C.H.J.C., and M.E.D. wrote the paper. The authors declare no conflict of interest.Attached Files
Published - Zuckerman2012p17378P_Natl_Acad_Sci_Usa.pdf
Supplemental Material - sapp.pdf
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Additional details
- PMCID
- PMC3286910
- Eprint ID
- 29728
- Resolver ID
- CaltechAUTHORS:20120314-154828359
- NSF
- DMR-0520565
- NIH
- CA 119347
- Caltech-UCLA Joint Center for Translational Medicine
- Sanofi-Aventis
- Created
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2012-03-15Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field