Peptide Amphiphile Supramolecular Nanostructures as a Targeted Therapy for Atherosclerosis

Abstract

The rising prevalence of cardiovascular disease worldwide necessitates novel therapeutic approaches to manage atherosclerosis. Intravenously administered nanostructures are a promising noninvasive approach to deliver therapeutics that reduce plaque burden. The drug liver X receptor agonist GW3965 (LXR) can reduce atherosclerosis by promoting cholesterol efflux from plaque but causes liver toxicity when administered systemically at effective doses, thus preventing its clinical use. The ability of peptide amphiphile nanofibers containing apolipoprotein A1–derived targeting peptide 4F to serve as nanocarriers for LXR delivery (ApoA1‐LXR PA) in vivo is investigated here. These nanostructures are found to successfully target atherosclerotic lesions in a mouse model within 24 h of injection. After 8 weeks of intravenous administration, the nanostructures significantly reduce plaque burden in both male and female mice to a similar extent as LXR alone in comparison to saline‐treated controls. Furthermore, they do not cause increased liver toxicity in comparison to LXR treatments, which may be related to more controlled release by the nanostructure. These findings demonstrate the potential of supramolecular nanostructures as safe, effective drug nanocarriers to manage atherosclerosis.

Intravenous Delivery of Lung‐Targeted Nanofibers for Pulmonary Hypertension in Mice

“…Similar results have been reported by our laboratories during development of targeted PA nanofibers for atherosclerotic disease. [ 47–49 ] Accordingly, we aimed to identify the co‐assembly ratio that best induced fiber formation for each targeted PA. In general, the highest concentration of targeted epitope that produced well‐formed fibers was selected for further investigation.…”

“…To support this theory, previous experiments by our laboratories using similarly constructed PA nanofibers composed of carbon‐chained backbones have reported no adverse effects, including renal or hepatic toxicity, following in vivo injection. [ 22,48 ] In an atherosclerotic mouse model treated with 3 different PAs, [ 47 ] we previously reported average aspartate aminotransferase (AST) levels of 74 to 155 U L −1 per PA. Although these diseased mice developed hepatotoxicity at baseline from their atherosclerotic disease, AST did not significantly change after PA injection.…”

Anchoring Supramolecular Polymers to Human Red Blood Cells by Combining Dynamic Covalent and Non‐Covalent Chemistries

“…In particular, supramolecular polymers assembling into 1D fibers in water have been extensively investigated for their similarity with natural fibrillar structures and even applied as biomaterials . Peptide amphiphiles are successfully used for neural regeneration, angiogenesis enhancement, and atherosclerosis treatment, while ureido‐pyrimidinone (Upy)‐based materials have been exploited as constituent of elastomeric valve implants for tissue engineering . Water‐compatible supramolecular benzene‐1,3,5‐tricarboxamide (BTA) polymers are still in their infancy in terms of bioapplications, but they have been comprehensively studied from the fundamental point of view .…”

Development of Fractalkine-Targeted Nanofibers that Localize to Sites of Arterial Injury

“…LDLR-/-mice develop severe hypercholesterolemia (>800 mg/dL) and hypertriglyceridemia (>300 mg/dL) as early as 2 weeks and atherosclerotic lesions after 12 weeks on high fat diet. At 16 weeks of age, aortic roots were harvested as previously described [19]. Tissue was harvested at 16 weeks of age to identify maximal atherosclerotic burden and later stages of atherosclerosis.…”