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Peptide Amphiphile Nanostructures for Targeting of Atherosclerotic Plaque and Drug Delivery.

ABSTRACT: Co-assembled peptide amphiphile nanofibers designed to target atherosclerotic plaque and enhance cholesterol efflux are shown to encapsulate and deliver a liver X receptor agonist to increase efflux from murine macrophages in vitro. Fluorescence microscopy reveals that the nanofibers, which display an apolipoprotein-mimetic peptide, localize at plaque sites in LDL receptor knockout mice with or without the encapsulated molecule, while nanofibers displaying a scrambled, non-targeting peptide sequence do not demonstrate comparable binding. These results show that nanofibers functionalized with apolipoprotein-mimetic peptides may be effective vehicles for intravascular targeted drug delivery to treat atherosclerosis.

SUBMITTER: So MM

PROVIDER: S-EPMC6338447 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Peptide Amphiphile Nanostructures for Targeting of Atherosclerotic Plaque and Drug Delivery.

So Miranda M MM Mansukhani Neel A NA Peters Erica B EB Albaghdadi Mazen S MS Wang Zheng Z Pérez Charles M Rubert CMR Kibbe Melina R MR Stupp Samuel I SI

Advanced biosystems 20180212 3

Co-assembled peptide amphiphile nanofibers designed to target atherosclerotic plaque and enhance cholesterol efflux are shown to encapsulate and deliver a liver X receptor agonist to increase efflux from murine macrophages <i>in vitro</i>. Fluorescence microscopy reveals that the nanofibers, which display an apolipoprotein-mimetic peptide, localize at plaque sites in LDL receptor knockout mice with or without the encapsulated molecule, while nanofibers displaying a scrambled, non-targeting pepti ...[more]

PMID: 30666317

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Project description:BackgroundA direct and independent role of inflammation in atherothrombosis was recently highlighted by the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, showing the benefit of inhibiting signaling molecules, eg, interleukins. Accordingly, we sought to devise a flexible platform for preventing the inflammatory drivers at their source to preserve plaque endothelium and mitigate procoagulant risk.Methodsp5RHH-siRNA nanoparticles were formulated through self-assembly processes. The therapeutic efficacy of p5RHH-JNK2 siRNA nanoparticles was evaluated both in vitro and in vivo.ResultsBecause JNK2 is critical to macrophage uptake of oxidized lipids through scavenger receptors that engender expression of myriad inflammatory molecules, we designed an RNA-silencing approach based on peptide-siRNA nanoparticles (p5RHH-siRNA) that localize to atherosclerotic plaques exhibiting disrupted endothelial barriers to achieve control of JNK2 expression by macrophages. After seven doses of p5RHH-JNK2 siRNA nanoparticles over 3.5 weeks in ApoE-/- mice on a Western diet, both JNK2 mRNA and protein levels were significantly decreased by 26% (P=0.044) and 42% (P=0.042), respectively. Plaque-macrophage populations were markedly depleted and NF?B and STAT3-signaling pathways inhibited by 47% (P<0.001) and 46% (P=0.004), respectively. Endothelial barrier integrity was restored (2.6-fold reduced permeability to circulating 200 nm nanoparticles in vivo, P=0.003) and thrombotic risk attenuated (200% increased clotting times to carotid artery injury, P=0.02), despite blood-cholesterol levels persistently exceeding 1,000 mg/dL. No adaptive or innate immunoresponses toward the nanoparticles were observed, and blood tests after the completion of treatment confirmed the largely nontoxic nature of this approach.ConclusionThe ability to formulate these nanostructures rapidly and easily interchange or multiplex their oligonucleotide content represents a promising approach for controlling deleterious signaling events locally in advanced atherosclerosis.

Project description:The leading causes of morbidity and mortality globally are cardiovascular diseases, and nanomedicine can provide many improvements including disease-specific targeting, early detection, and local delivery of diagnostic agents. To this end, we designed fibrin-binding, peptide amphiphile micelles (PAMs), achieved by incorporating the targeting peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA), with two types of amphiphilic molecules containing the gadoliniuim (Gd) chelator diethylenetriaminepentaacetic acid (DTPA), DTPA-bis(stearylamide)(Gd), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[(poly(ethylene glycol) (PEG))-2000]-DTPA(Gd) (DSPE-PEG2000-DTPA(Gd)). The material characteristics of the resulting nanoparticle diagnostic probes, clot-binding properties in vitro, and contrast enhancement and safety for dual, optical imaging-magnetic resonance imaging (MRI) were evaluated in the atherosclerotic mouse model. Transmission electron micrographs showed a homogenous population of spherical micelles for formulations containing DSPE-PEG2000-DTPA(Gd), whereas both spherical and cylindrical micelles were formed upon mixing DTPA-BSA(Gd) and CREKA amphiphiles. Clot-binding assays confirmed DSPE-PEG2000-DTPA(Gd)-based CREKA micelles targeted clots over 8-fold higher than nontargeting (NT) counterpart micelles, whereas no difference was found between CREKA and NT, DTPA-BSA(Gd) micelles. However, in vivo MRI and optical imaging studies of the aortas and hearts showed fibrin specificity was conferred by the peptide ligand without much difference between the nanoparticle formulations or shapes. Biodistribution studies confirmed that all micelles were cleared through both the reticuloendothelial system and renal clearance, and histology showed no signs of necrosis. In summary, these studies demonstrate the successful synthesis, and the molecular imaging capabilities of two types of CREKA-Gd PAMs for atherosclerosis. Moreover, we demonstrate the differences in micelle formulations and shapes and their outcomes in vitro versus in vivo for site-specific, diagnostic strategies, and provide the groundwork for the detection of thrombosis via contrast-enhancing agents and concurrent therapeutic delivery for theranostic applications.

Dataset Information

Peptide Amphiphile Nanostructures for Targeting of Atherosclerotic Plaque and Drug Delivery.

Publications

Peptide Amphiphile Nanostructures for Targeting of Atherosclerotic Plaque and Drug Delivery.

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