Document Detail

Nonionic polymeric micelles for oral gene delivery in vivo.
MedLine Citation:
PMID:  15144578     Owner:  NLM     Status:  MEDLINE    
The main aim of this study was to investigate the feasibility of using nonionic polymeric micelles of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) as a carrier for oral DNA delivery in vivo. The size and appearance of DNA/PEO-PPO-PEO polymeric micelles were examined, respectively, by dynamic light scattering and atomic force microscopy, and their zeta potential was measured. Expression of the delivered lacZ gene in various tissues of nude mice was assessed qualitatively by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining of sections and quantitatively by measuring enzyme activity in tissue extracts, using the substrate of beta-galactosidase, chlorophenol red-beta-D-galactopyranoside. In addition, the types of cells expressing the lacZ gene in the duodenum were identified by histological analysis. DNA/PEO-PPO-PEO polymeric micelles are a single population of rounded micelles with a mean diameter of 170 nm and a zeta potential of -4.3 mV. Duodenal penetration of DNA/PEO-PPO-PEO polymeric micelles was evaluated in vitro by calculating the apparent permeability coefficient. The results showed a dose-independent penetration rate of (5.75 +/- 0.37) x 10(-5) cm/sec at low DNA concentrations (0.026-0.26 microg/microl), but a decrease to (2.89 +/- 0.37) x 10(-5) cm/sec at a concentration of 1.3 microg/microl. Furthermore, when 10 mM RGD peptide or 10 mM EDTA was administered before and concurrent with the administration of DNA/PEO-PPO-PEO polymeric micelles, transport was inhibited ([0.95 +/- 0.57] x 10(-5) cm/sec) by blocking endocytosis or enhanced ([29.8 +/- 5.7] x 10(-5) cm/sec) by opening tight junctions, respectively. After oral administration of six doses at 8-hr intervals, the highest expression of transferred gene lacZ was seen 48 hr after administration of the first dose, with gene expression detected in the villi, crypts, and goblet cells of the duodenum and in the crypt cells of the stomach. Reporter gene activity was seen in the duodenum, stomach, and liver. Activity was also seen in the brain and testis when mice were administered 10 mM EDTA before and concurrent with DNA/PEO-PPO-PEO polymeric micelle administration. lacZ mRNA was detected in these five organs and in the blood by reverse transcription-polymerase chain reaction. Taken together, these results show efficient, stable gene transfer can be achieved in mice by oral delivery of PEO-PPO-PEO polymeric micelles.
Shwu-Fen Chang; Han-Yi Chang; Yaw-Chong Tong; Sy-Hann Chen; Fei-Chin Hsaio; Shao-Chun Lu; Jiahorng Liaw
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human gene therapy     Volume:  15     ISSN:  1043-0342     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-05-17     Completed Date:  2004-11-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  481-93     Citation Subset:  IM    
Graduate Institute of Cell and Molecular Biology, School of Medicine, Taipei Medical University, Taipei 110, Taiwan.
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MeSH Terms
Administration, Oral
Dose-Response Relationship, Drug
Duodenum / cytology
Edetic Acid / pharmacology
Endocytosis / drug effects
Epithelial Cells / metabolism
Feasibility Studies
Gene Transfer Techniques*
Mice, Nude
Microscopy, Atomic Force
Oligopeptides / pharmacology
Particle Size
Polyethylene Glycols / administration & dosage,  chemistry
Polymers / administration & dosage*,  chemistry*
Propylene Glycols / administration & dosage,  chemistry
Reverse Transcriptase Polymerase Chain Reaction
Scattering, Radiation
Tight Junctions / drug effects
Tissue Distribution
Reg. No./Substance:
0/Micelles; 0/Oligopeptides; 0/PEO-PPO-PEO; 0/Polyethylene Glycols; 0/Polymers; 0/Propylene Glycols; 60-00-4/Edetic Acid; 99896-85-2/arginyl-glycyl-aspartic acid

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

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