Document Detail


Biodegradable amphiphilic poly(ethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery.
MedLine Citation:
PMID:  18838158     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The RNA interference (RNAi) technology has been successfully used in elucidating mechanisms behind various biological events. However, in the absence of safe and effective carriers for in vivo delivery of small interfering RNAs (siRNAs), application of this technology for therapeutic purposes has lagged behind. The objective of this research was to develop promising carriers for siRNA delivery based on degradable poly(ethylene oxide)-block-polyesters containing polycationic side chains on their polyester block. Toward this goal, a novel family of biodegradable poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) based copolymers with polyamine side chains on the PCL block, i.e., PEO-b-PCL with grafted spermine (PEO-b-P(CL-g-SP)), tetraethylenepentamine (PEO-b-P(CL-g-TP)), or N,N-dimethyldipropylenetriamine (PEO-b-P(CL-g-DP)) were synthesized and evaluated for siRNA delivery. The polyamine-grafted PEO-b-PCL polymers, especially PEO-b-P(CL-g-SP), demonstrated comparable toxicity to PEO-b-PCL in vitro. The polymers were able to effectively bind siRNA, self-assemble into micelles, protect siRNA from degradation by nuclease and release complexed siRNA efficiently in the presence of low concentrations of polyanionic heparin. Based on flow cytometry and confocal microscopy, siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles showed efficient cellular uptake through endocytosis by MDA435/LCC6 cells transfected with MDR-1, which encodes for the expression of P-glycoprotein (P-gp). The siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles demonstrated effective endosomal escape after cellular uptake. Finally, MDR-1-targeted siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles exhibited efficient gene silencing for P-gp expression. The results of this study demonstrated the promise of novel amphiphilic PEO-b-P(CL-g-polyamine) block copolymers for efficient siRNA delivery.
Authors:
Xiao-Bing Xiong; Hasan Uludağ; Afsaneh Lavasanifar
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-10-05
Journal Detail:
Title:  Biomaterials     Volume:  30     ISSN:  1878-5905     ISO Abbreviation:  Biomaterials     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-10-28     Completed Date:  2009-04-01     Revised Date:  2009-06-12    
Medline Journal Info:
Nlm Unique ID:  8100316     Medline TA:  Biomaterials     Country:  England    
Other Details:
Languages:  eng     Pagination:  242-53     Citation Subset:  IM    
Affiliation:
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biocompatible Materials / chemical synthesis,  chemistry*,  pharmacology
Cell Line, Tumor
Drug Delivery Systems / methods*
Erythrocytes / cytology,  drug effects
Hemolysis / drug effects
Humans
Male
Polyesters / chemical synthesis,  chemistry*,  pharmacology
RNA, Small Interfering / administration & dosage*,  chemistry,  genetics
Rats
Rats, Sprague-Dawley
Chemical
Reg. No./Substance:
0/Biocompatible Materials; 0/Polyesters; 0/RNA, Small Interfering; 0/polyethylene oxide-polycaprolactone copolymer

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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