Document Detail


Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells.
MedLine Citation:
PMID:  17009857     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Selective gene inhibition by antisense oligodeoxynucleotide (AS-ODN) or by small interference RNA (siRNA) therapeutics promises the treatment of diseases that cannot be cured by conventional drugs. However, antisense therapy is hindered due to poor stability in physiological fluids and limited intracellular uptake. To address these problems, a ligand targeted and sterically stabilized nanoparticle formulation has been developed in our lab. Human lung cancer cells often overexpress the sigma receptor and, thus, can be targeted with a specific ligand such as anisamide. AS-ODN or siRNA against human survivin was mixed with a carrier DNA, calf thymus DNA, before complexing with protamine, a highly positively charged peptide. The resulting particles were coated with cationic liposomes consisting of DOTAP and cholesterol (1:1, molar ratio) to obtain LPD (liposome-polycation-DNA) nanoparticles. Ligand targeting and steric stabilization were then introduced by incubating preformed LPD nanoparticles with DSPE-PEG-anisamide, a PEGylated ligand lipid developed earlier in our lab, by the postinsertion method. Nontargeted nanoparticles coated with DSPE-PEG were also prepared as a control. Antisense activities of nanoparticles were determined by survivin mRNA down-regulation, survivin protein down-regulation, ability to trigger apoptosis in tumor cells, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to anticancer drugs. We found that tumor cell delivery and antisense activity of PEGylated nanoparticles were sequence dependent and rely on the presence of anisamide ligand. The uptake of oligonucleotide in targeted, PEGylated nanoparticles could be competed by excess free ligand. Our results suggest that the ligand targeted and sterically stabilized nanoparticles can provide a selective delivery of AS-ODN and siRNA into lung cancer cells for therapy.
Authors:
Shyh-Dar Li; Leaf Huang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  3     ISSN:  1543-8384     ISO Abbreviation:  Mol. Pharm.     Publication Date:    2006 Sep-Oct
Date Detail:
Created Date:  2006-10-02     Completed Date:  2007-01-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  579-88     Citation Subset:  IM    
Affiliation:
Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Tumor
Cell Survival / drug effects
DNA / chemistry
Drug Delivery Systems / methods
Enzyme-Linked Immunosorbent Assay
Humans
Liposomes
Lung Neoplasms / genetics,  pathology,  therapy
Microtubule-Associated Proteins / genetics,  metabolism
Molecular Structure
Nanoparticles / chemistry
Neoplasm Proteins / genetics,  metabolism
Oligodeoxyribonucleotides, Antisense / administration & dosage*,  chemistry,  genetics
Polyethylene Glycols / chemistry
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / administration & dosage*,  chemistry,  genetics
Reverse Transcriptase Polymerase Chain Reaction
Technology, Pharmaceutical / methods*
Chemical
Reg. No./Substance:
0/BIRC5 protein, human; 0/Liposomes; 0/Microtubule-Associated Proteins; 0/Neoplasm Proteins; 0/Oligodeoxyribonucleotides, Antisense; 0/Polyethylene Glycols; 0/RNA, Messenger; 0/RNA, Small Interfering; 9007-49-2/DNA

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


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