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Development of a liver-targeted siRNA delivery platform with a broad therapeutic window utilizing biodegradable polypeptide-based polymer conjugates.
- Source :
-
Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2014 Jun 10; Vol. 183, pp. 124-37. Date of Electronic Publication: 2014 Mar 21. - Publication Year :
- 2014
-
Abstract
- The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.<br /> (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Autoradiography
Biocompatible Materials chemistry
Biocompatible Materials pharmacokinetics
Biocompatible Materials toxicity
Drug Carriers chemistry
Drug Carriers pharmacokinetics
Drug Carriers toxicity
Drug Design
Drug Stability
Female
Hep G2 Cells
Hepatocytes metabolism
Humans
Liver diagnostic imaging
Macaca mulatta
Nylons chemistry
Nylons pharmacokinetics
Nylons toxicity
Peptides chemistry
Peptides pharmacokinetics
Peptides toxicity
RNA, Small Interfering genetics
RNA, Small Interfering pharmacokinetics
RNA, Small Interfering toxicity
Radionuclide Imaging
Rats, Sprague-Dawley
Species Specificity
Structure-Activity Relationship
Tissue Distribution
Biocompatible Materials chemical synthesis
Drug Carriers chemical synthesis
Liver metabolism
Nylons chemical synthesis
Peptides chemical synthesis
RNA, Small Interfering administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4995
- Volume :
- 183
- Database :
- MEDLINE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Publication Type :
- Academic Journal
- Accession number :
- 24657948
- Full Text :
- https://doi.org/10.1016/j.jconrel.2014.03.028