Published online 1 November 2004
Nucleic Acids Research, Vol. 32 No. 19 © Oxford University Press 2004; all rights reserved
Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle
1 Intradigm Corporation, 12115K Parklawn Drive, Rockville MD 20852, USA, 2 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands and 3 Department of Pathology and Laboratory Medicine, Medical Biology Section, Groningen University Institute for Drug Exploration, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
* To whom correspondence should be addressed. Tel: +1 301 984 3586; Fax: +1 301 984 0186; Email: pscaria{at}intradigm.com
Correspondence may also be addressed to Martin C. Woodle. Tel: +1 301 984 0185; Fax: +1 301 984 0186; Email: mwoodle{at}intradigm.com
Received July 9, 2004; Revised August 25, 2004; Accepted September 28, 2004
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.
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