High‐Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis

Abstract

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 expression in vitro. In addition, data show that treatment strongly attenuated in vivo neovascularization 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 measured in vitro or after in vivo administration. 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.

Lipoproteins and lipoprotein mimetics for imaging and drug delivery

“…These HDL nanoparticles were also shown to bind cholesterylated RNA, which was effective at reducing the cellular expression of vascular endothelial growth factor receptor 2 (VEGFR2). [206] Systemic administration of these conjugates resulted in decreased VEFGR2 expression in SR-B1 expressing cells, leading to decreased angiogenesis and a marked reduction in the volume of lung tumor xenografts. [206] Regardless of the type of nucleic acid adsorbed to the surface of this HDL platform, no toxicity was observed in normal, healthy cells and tissues both in vitro and in vivo .…”

“…[206] Systemic administration of these conjugates resulted in decreased VEFGR2 expression in SR-B1 expressing cells, leading to decreased angiogenesis and a marked reduction in the volume of lung tumor xenografts. [206] Regardless of the type of nucleic acid adsorbed to the surface of this HDL platform, no toxicity was observed in normal, healthy cells and tissues both in vitro and in vivo . [92, 206] These studies indicate that gold core HDL is an excellent carrier for therapeutic nucleic acids.…”

“…[206] Regardless of the type of nucleic acid adsorbed to the surface of this HDL platform, no toxicity was observed in normal, healthy cells and tissues both in vitro and in vivo . [92, 206] These studies indicate that gold core HDL is an excellent carrier for therapeutic nucleic acids.…”

High-density lipoproteins for therapeutic delivery systems

“…Tripathy et al then demonstrated that gold nanoparticle templated spherical HDL can formulate cholesterylated antisense RNA. 81 In the system tested, antisense RNA to vascular endothelial growth factor receptor 2 (VEGFR2) could knockdown VEGFR2 mRNA levels and reduce endothelial survival and morphogenesis. Further data demonstrate that delivery of the HDL NP conjugates is dependent on expression of SR-B1.…”

Collaborative Enhancement of Endothelial Targeting of Nanocarriers by Modulating Platelet-Endothelial Cell Adhesion Molecule-1/CD31 Epitope Engagement

“…9–16 In particular, the surface of carriers coated with Abs to the cell adhesion molecule PECAM (platelet endothelial cell adhesion molecule 1, PECAM-1, CD31) enables endothelial delivery of NCs, improving therapeutic effects of their drug cargoes in animal models. 17–21 These encouraging results justify further optimization of endothelial targeting and effect of anti-PECAM/NC (indicated as Ab/NC unless indicated otherwise).…”