High Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis.
Systemic delivery of therapeutic nucleic acids to target cells and tissues outside of the liver remains a major challenge. We synthesized a biomimetic high density lipoprotein nanoparticle (HDL NP) for delivery of a cholesteryl modified therapeutic nucleic acid (RNAi) to vascular endothelial cells, a cell type naturally targeted by HDL. HDL NPs adsorb cholesteryl modified oligonucleotides and protect them from nuclease degradation. As proof of principle, we delivered RNAi targeting vascular endothelial growth factor receptor 2 (VEGFR2) to endothelial cells to effectively silence target mRNA and protein expressionin vitro.In addition, data show that treatment strongly attenuatedin vivoneovascularization measured using a standard angiogenesis assay and in hypervascular tumor allografts where a striking reduction in tumor growth was observed. For effective delivery, HDL NPs required the expression of the cell surface protein scavenger receptor type-B1 (SR-B1). No toxicity of HDL NPs was measuredin vitroor afterin vivoadministration. Thus, by using a biomimetic approach to nucleic acid delivery, data demonstrate that systemically administered RNAi-HDL NPs target SR-B1 expressing endothelial cells to deliver functional anti-angiogenic RNAi as a potential treatment of cancer and other neo-vascular diseases.
Northwestern University, Feinberg School of Medicine, Department of Urology, 303 East Chicago Avenue, Tarry 16-703, Chicago, Illinois 60611, United States ; Northwestern University, Institute for BioNanotechnology and Medicine (IBNAM), 303 East Superior Avenue, 11th Floor, Chicago, Illinois 60611, United States ; Driskill Graduate Program, Northwestern University, Chicago, Illinois 60611, United States.
Sushant
S
Tripathy
Northwestern University, Feinberg School of Medicine, Department of Urology, 303 East Chicago Avenue, Tarry 16-703, Chicago, Illinois 60611, United States.
Elena
E
Vinokour
Northwestern University, Feinberg School of Medicine, Department of Urology, 303 East Chicago Avenue, Tarry 16-703, Chicago, Illinois 60611, United States ; Northwestern University, Institute for BioNanotechnology and Medicine (IBNAM), 303 East Superior Avenue, 11th Floor, Chicago, Illinois 60611, United States ; Driskill Graduate Program, Northwestern University, Chicago, Illinois 60611, United States.
Kaylin M
KM
McMahon
Northwestern University, Feinberg School of Medicine, Department of Urology, 303 East Chicago Avenue, Tarry 16-703, Chicago, Illinois 60611, United States ; Northwestern University, Robert H. Lurie Comprehensive Cancer Center, 303 East Superior Avenue, Chicago, Illinois 60611, United States.
Olga V
OV
Volpert
Northwestern University, Feinberg School of Medicine, Department of Urology, 303 East Chicago Avenue, Tarry 16-703, Chicago, Illinois 60611, United States ; Northwestern University, Robert H. Lurie Comprehensive Cancer Center, 303 East Superior Avenue, Chicago, Illinois 60611, United States ; Northwestern University, Institute for BioNanotechnology and Medicine (IBNAM), 303 East Superior Avenue, 11th Floor, Chicago, Illinois 60611, United States ; Northwestern University, International Institute for Nanotechnology, 2145 Sheridan Road, Evanston, Illinois 60208, United States.
C Shad
CS
Thaxton
Angiogenesis; HDL; RNAi; Tumor; VEGFR2