Document Detail


Degradation of poly(glycoamidoamine) DNA delivery vehicles: polyamide hydrolysis at physiological conditions promotes DNA release.
MedLine Citation:
PMID:  20058913     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Poly(glycoamidoamine)s (PGAAs) are a group of efficient and degradable gene delivery vehicles that consist of three main functionalities: carbohydrate groups, secondary amines, and amide bonds. Herein, we have created nonhydroxylated models to these structures by polymerizing oxylate, succinate, or adipate groups with pentaethylenehexamine. The resulting polymers (named O4, S4, and A4, respectively) were created to understand how the absence of hydroxyl groups and changes in the amide bond spacing affect polymer degradation, plasmid DNA (pDNA) complexation, toxicity, and transfection efficiency in vitro. An additional model was also created that retains a galactaramide unit, but we have replaced the secondary amines with ethyleneoxide units (GO2) to understand the effects of the amine groups on polymer degradation. We have found that the secondary amines and hydroxyls are necessary to facilitate rapid degradation of these polymers, and analogues lacking hydroxyls or amines did not degrade over the time course of the study. Through electron-withdrawing and hydrogen bonding, the hydroxyls appear to activate the carbonyls of the amide bond to hydrolysis via an inductive electron withdrawing effect. Through titration experiments, PGAA degradation appears not to affect the polymer buffering capacity. Furthermore, we have found that PGAA degradation may enhance gene expression by releasing pDNA from polyplexes (polymer-pDNA complexes) and, thus, exposing it to undergo transcription and translation. The difference in the optimal pH that promotes degradation of the PGAAs and the hydroxyl-free analogues may prove to be a useful means to achieve pH-regulated DNA release from polyplexes by specifically modulating the chemical structures.
Authors:
Yemin Liu; Theresa M Reineke
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Biomacromolecules     Volume:  11     ISSN:  1526-4602     ISO Abbreviation:  Biomacromolecules     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-08     Completed Date:  2010-09-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100892849     Medline TA:  Biomacromolecules     Country:  United States    
Other Details:
Languages:  eng     Pagination:  316-25     Citation Subset:  IM    
Affiliation:
Virginia Tech, Department of Chemistry, Macromolecules and Interfaces Institute, Blacksburg, Virginia 24061, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Survival / drug effects,  physiology
DNA / administration & dosage,  metabolism*
Gene Transfer Techniques*
Hela Cells
Humans
Hydrolysis
Nylons / chemistry,  metabolism*
Polyamines / chemistry,  metabolism*
Polymers / chemistry,  metabolism
Vehicles
Chemical
Reg. No./Substance:
0/Nylons; 0/Polyamines; 0/Polymers; 0/Vehicles; 9007-49-2/DNA

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


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