Targeted polyelectrolyte complex micelles treat vascular complications in vivo

Abstract

Vascular disease is a leading cause of morbidity and mortality in the United States and globally. Pathological vascular remodeling, such as atherosclerosis and stenosis, largely develop at arterial sites of curvature, branching, and bifurcation, where disturbed blood flow activates vascular endothelium. Current pharmacological treatments of vascular complications principally target systemic risk factors. Improvements are needed. We previously devised a targeted polyelectrolyte complex micelle to deliver therapeutic nucleotides to inflamed endothelium in vitro by displaying the peptide VHPKQHR targeting vascular cell adhesion molecule 1 (VCAM-1) on the periphery of the micelle. This paper explores whether this targeted nanomedicine strategy effectively treats vascular complications in vivo. Disturbed flow-induced microRNA-92a (miR-92a) has been linked to endothelial dysfunction. We have engineered a transgenic line (miR-92aEC-TG/Apoe−/−) establishing that selective miR-92a overexpression in adult vascular endothelium causally promotes atherosclerosis in Apoe−/− mice. We tested the therapeutic effectiveness of the VCAM-1–targeting polyelectrolyte complex micelles to deliver miR-92a inhibitors and treat pathological vascular remodeling in vivo. VCAM-1–targeting micelles preferentially delivered miRNA inhibitors to inflamed endothelial cells in vitro and in vivo. The therapeutic effectiveness of anti–miR-92a therapy in treating atherosclerosis and stenosis in Apoe−/− mice is markedly enhanced by the VCAM-1–targeting polyelectrolyte complex micelles. These results demonstrate a proof of concept to devise polyelectrolyte complex micelle-based targeted nanomedicine approaches treating vascular complications in vivo.

The Endothelium as a Hub for Cellular Communication in Atherogenesis: Is There Directionality to the Message?

“…Recent work by Distasio and colleagues demonstrated VCAM-1-targeted gene delivery of nanoparticles (NPs) containing the anti-inflammatory cytokine interleukin-10, localized to inflamed ECs and atherosclerotic plaques (102). The Fang laboratory and others have done elegant work over the past decade to not only identify that disturbed flow-induced microRNA-92a causes endothelial dysfunction (103,104), but also recently reported VCAM-1 targeted NPs can preferentially deliver microRNA-92a inhibitors to inflamed ECs and reduce aortic atherosclerotic plaque development in a murine model (105). Considering endogenous sources, there is certainly promise that endothelialderived EVs play roles in the progression of atherosclerosis (106); by focusing on those that are considered beneficial such as microRNA-10a (45) or microRNA-126 (79,107) and what drives their expression, we may likewise find strategies to interrupt early atherogenesis.…”

QnAs with Matthew V. Tirrell

“…Tirrell: We showed in 2009 that we could create nanoparticles that homed to atherosclerotic plaques (2). When I moved to the University of Chicago in 2011, I met Yun Fang, the principal coauthor on the Inaugural Article (1). During his postdoctoral work, he had done some early work discovering that microRNA-92a in endothelial cells is responsible for a proinflammatory response that leads to atherosclerosis.…”

“…Now dean of the Pritzker School of Molecular Engineering at the University of Chicago and a senior scientist at the Argonne National Laboratory, Tirrell has unraveled phase separation in polymers and nanoparticles and helped design and synthesize novel self-assembling materials with targeting and therapeutic potential. In his Inaugural Article, Tirrell describes self-assembling micelle nanoparticles that can target atherosclerotic plaques and deliver packaged nucleic acids to the plaques as potential treatments (1).…”

Robust Polyion Complex Vesicles (PICsomes) Based on PEO‐b‐poly(amino acid) Copolymers Combining Electrostatic and Hydrophobic Interactions: Formation, siRNA Loading and Intracellular Delivery

“…Efficient candidates to do so are block copolymers combining polycationic and neutral (usually PEG) blocks, coassembling with siRNA and providing a neutral protective layer around it. Among various block or stat copolymer architectures proposed so far in literature to form PIC assemblies with siRNA 5 or mRNA as potential nanomedicines 28 -for example, polyaspartamide derivatives PAsp(DET), PAsp(DPT), and PAsp(TEP), 29,30 oligosaccharide (chitosan)-b-PEO, 31 poly(alkyl-L-glutamine) copolymers, 32 diblock elastin like polypeptides (ELPs) 33,34 , linear 35 or branched 36 PEG-b-poly(Llysine) -PICsomes offer the additional advantage of possible co-encapsulation with other soluble cargos, such vesicular nanocarriers being named "siRNAsomes". 37 Another feature to consider about siRNA is that it has a rigid cylindrical structure with a length around 6 nm.…”