Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle
| Autor: | Qingquan Tang, Qin Zhou, Grietje Molema, Gert Storm, Jun Xu, Aslam M. Ansari, Patrick Y. Lu, Raymond M. Schiffelers, Puthupparampil V. Scaria, Martin C. Woodle |
|---|---|
| Přispěvatelé: | Advanced drug delivery systems/drug targeting, Universiteit Utrecht, Dep Farmaceutische wetenschappen, Dep Biologie, Groningen University Institute for Drug Exploration (GUIDE), Nanotechnology and Biophysics in Medicine (NANOBIOMED), Vascular Ageing Programme (VAP), Groningen Kidney Center (GKC), Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE) |
| Rok vydání: | 2004 |
| Předmět: |
ANTI-VEGF ANTIBODY
Polymers Integrin Mice Nude Peptide Gene delivery Ligands Biomedische technologie en medicijnen Polyethylene Glycols GENE DELIVERY Farmacie/Biofarmaceutische wetenschappen (FARM) chemistry.chemical_compound RNA interference BINDING Medical technology Genetics Animals Humans Polyethyleneimine PEPTIDE Colloids RNA Small Interfering DRUG-DELIVERY NAR Methods Online Cells Cultured IN-VIVO Pharmacology chemistry.chemical_classification Oligopeptide biology Oligonucleotide Farmacie(FARM) Neoplasms Experimental MOUSE MODEL Molecular biology Vascular endothelial growth factor MICE Phenotype chemistry International RNA INTERFERENCE ENDOTHELIAL GROWTH-FACTOR Drug delivery biology.protein Cancer research Female Oligopeptides |
| Zdroj: | Scopus-Elsevier Nucleic Acids Research, 32(19):149. Oxford University Press |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gnh140 |
| Popis: | Potent sequence selective gene inhibition by siRNA 'targeted' therapeutics promises the ultimate level of specificity, but siRNA therapeutics is hindered by poor intracellular uptake, limited blood stability and non-specific immune stimulation. To address these problems, ligand-targeted, sterically stabilized nanoparticles have been adapted for siRNA. Self-assembling nanoparticles with siRNA were constructed with polyethyleneimine (PEI) that is PEGylated with an Arg-Gly-Asp (RGD) peptide ligand attached at the distal end of the polyethylene glycol (PEG), as a means to target tumor neovasculature expressing integrins and used to deliver siRNA inhibiting vascular endothelial growth factor receptor-2 (VEGF R2) expression and thereby tumor angiogenesis. Cell delivery and activity of PEGylated PEI was found to be siRNA sequence specific and depend on the presence of peptide ligand and could be competed by free peptide. Intravenous administration into tumor-bearing mice gave selective tumor uptake, siRNA sequence-specific inhibition of protein expression within the tumor and inhibition of both tumor angiogenesis and growth rate. The results suggest achievement of two levels of targeting: tumor tissue selective delivery via the nanoparticle ligand and gene pathway selectivity via the siRNA oligonucleotide. This opens the door for better targeted therapeutics with both tissue and gene selectivity, also to improve targeted therapies with less than ideal therapeutic targets. |
| Databáze: | OpenAIRE |
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