(181h) Delivery of HIF1a siRNA for Atherosclerosis Plaques Using Targeted Polyelectrolyte Complex Micelles

Atherosclerosis is a chronic inflammatory disease of the arterial wall that arises from an imbalanced lipid metabolism and a maladaptive inflammatory response, potentiated by the fluid mechanical stresses imposed on the endothelium. Inflammatory markers of atherosclerosis provide a target for drug delivery vehicles due to their overexpression and specificity. One of the most prominent markers of early stage atherosclerotic plaques is vascular cell adhesion molecule-1 (VCAM-1), which is expressed by endothelial cells that line the developing plaque. Therefore, using spherical, self-assembled polyelectrolyte complex micelles synthesized from VCAM-1 targeted peptide molecules was examined for the ability to specifically bind to atherosclerotic plaques.

Our strategy is to encapsulate HIF1α siRNA with targeting peptide-PEG (polyethylene glycol)-PLK (polylysine) molecules. This results in the formation of electrostatically driven, self-assembled micelles with a polylysine-siRNA core, protected by a PEG corona that is decorated with the targeting peptide. The formation of siRNA-containing, peptide-targeted micelles is achieved via electrostatic complexation between the negatively charged siRNA and positively charged polycations containing targeting peptides. Polycation molecule contains three functional domains, which are targeting peptides for cellular or plaque localization, a polyethylene glycol domain to prevent macrophase separation, and a polylysine domain to complex with the negatively charged siRNA. The targeting peptide has the sequence valine-histidine-proline-lysine-glycine-histidine-arginine, or VHPKQHR, which are enabled for targeting VCAM-1 on the surface of endothelial cells. By taking advantage of the benefits of self-assembly, we can tailor the micelle corona to enable the targeting of diverse cell types and load the micelles with specific siRNA, thereby providing the means to target various pathological mechanisms in a wide range of cells and contexts.