Amphiphilic macromolecule nanoassemblies suppress smooth muscle cell proliferation and platelet adhesion

Abstract

While the development of second- and third-generation drug-eluting stents (DES) have significantly improved patient outcomes by reducing smooth muscle cell (SMC) proliferation, DES have also been associated with an increased risk of late-stent thrombosis due to delayed re-endothelialization and hypersensitivity reactions from the drug-polymer coating. Furthermore, DES anti-proliferative agents do not counteract the upstream oxidative stress that triggers the SMC proliferation cascade. In this study, we investigate biocompatible amphiphilic macromolecules (AMs) that address high oxidative lipoprotein microenvironments by competitively binding oxidized lipid receptors and suppressing SMC proliferation with minimal cytotoxicity. To determine the influence of nanoscale assembly on proliferation, micelles and nanoparticles were fabricated from AM unimers containing a phosphonate or carboxylate end-group, sugar-based hydrophobic domain, and a hydrophilic poly(ethylene glycol) domain. The results indicate that when SMCs are exposed to high levels of oxidized lipid stimuli, nanotherapeutics inhibit lipid uptake, downregulate scavenger receptor expression, and attenuate scavenger receptor gene transcription in SMCs, and thus significantly suppress proliferation. Although both functional end-groups were similarly efficacious, nanoparticles suppressed oxidized lipid uptake and scavenger receptor expression more effectively compared to micelles, indicating the relative importance of formulation characteristics (e.g., higher localized AM concentrations and nanotherapeutic stability) in scavenger receptor binding as compared to AM end-group functionality. Furthermore, AM coatings significantly prevented platelet adhesion to metal, demonstrating its potential as an anti-platelet therapy to treat thrombosis. Thus, AM micelles and NPs can effectively repress early stage SMC proliferation and thrombosis through non-cytotoxic mechanisms, highlighting the promise of nanomedicine for next-generation cardiovascular therapeutics.

Athero-inflammatory nanotherapeutics: Ferulic acid-based poly(anhydride-ester) nanoparticles attenuate foam cell formation by regulating macrophage lipogenesis and reactive oxygen species generation

“…Nanoparticles were fabricated using the flash nanoprecipitation technique as shown in Figure 1 as described previously [15, 38]. Briefly, each shell and core component were dissolved separately in the appropriate solvent and mixed together.…”

Nanotherapeutics Containing Lithocholic Acid-Based Amphiphilic Scorpion-Like Macromolecules Reduce In Vitro Inflammation in Macrophages: Implications for Atherosclerosis

“…Although previous AScM micellar preparations were shown to have bioactivity at high concentrations, improved inhibition of oxLDL uptake was observed with AScM NPs in serum-containing medium compared to micelles [ 16 , 17 ]. NPs fabricated using flash nanoprecipitation are different from micelles in that the core molecule serves as a nucleation point to fabricate kinetically trapped particles that do not dissociate upon dissolution.…”

“…These unique compounds can successfully encapsulate and deliver anti-atherosclerotic therapeutics to macrophages, increasing drug bioavailability [ 11 , 15 ]. Furthermore, the AScMs exhibit inherent bioactivity against several cell types (e.g., macrophages and smooth muscle cells) involved in the atherosclerotic cascade when formulated into either micelles or kinetically trapped nanoparticles (NPs), which are advantageous due to their resistance to dissociation upon dilution [ 16 , 17 , 18 ]. NPs have demonstrated additional superiority to micelle formulations as AScM NPs lower macrophage oxLDL uptake to ~25% relative to untreated controls, decrease SR expression, and reduce plaque size and aortic occlusion in vivo [ 17 , 19 , 20 ].…”

Nanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis

“…The Moghe group has developed a series of amphiphilic macromolecules (AMs) to deliver a range of therapeutics to macrophages using amphiphilic polymers containing a carboxylic acid group that binds scavenger receptors of macrophages, thereby inhibiting the uptake of oxLDL [ 103 – 107 ]. Using sugar-based AMs that bind scavenger receptors of macrophages, Chan et al discovered that they could prevent up to 90% of LDL internalization in SMCs and inhibit up to 48% of macrophage scavenger receptor 1 (MSR1) expression and 33% of CD36 expression in an in vitro study [ 108 ].…”