Tumor regression by targeted gene delivery to the neovasculature.
Efforts to influence the biology of blood vessels by gene delivery have been hampered by a lack of targeting vectors specific for endothelial cells in diseased tissues. Here we show that a cationic nanoparticle (NP) coupled to an integrin alphavbeta3-targeting ligand can deliver genes selectively to angiogenic blood vessels in tumor-bearing mice. The therapeutic efficacy of this approach was tested by generating NPs conjugated to a mutant Raf gene, ATPmu-Raf, which blocks endothelial signaling and angiogenesis in response to multiple growth factors. Systemic injection of the NP into mice resulted in apoptosis of the tumor-associated endothelium, ultimately leading to tumor cell apoptosis and sustained regression of established primary and metastatic tumors.
Hood
John D
JD
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bednarski
Mark
M
Frausto
Ricardo
R
Guccione
Samira
S
Reisfeld
Ralph A
RA
Xiang
Rong
R
Cheresh
David A
DA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002412:Cations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D008024:Ligands; D008055:Lipids; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D036103:Nanotechnology; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D019030:Receptors, Vitronectin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002412:Cations; D008024:Ligands; D008055:Lipids; D019030:Receptors, Vitronectin; D000255:Adenosine Triphosphate; D019908:Proto-Oncogene Proteins c-raf