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Effective atherosclerotic plaque inflammation inhibition with targeted drug delivery by hyaluronan conjugated atorvastatin nanoparticles.

ABSTRACT: Atherosclerosis is associated with inflammation in the arteries, which is a major cause of heart attacks and strokes. Reducing the extent of local inflammation at atherosclerotic plaques can be an attractive strategy to combat atherosclerosis. While statins can exhibit direct anti-inflammatory activities, the high dose required for such a therapy renders it unrealistic due to their low systemic bioavailabilities and potential side effects. To overcome this, a new hyaluronan (HA)-atorvastatin (ATV) conjugate was designed with the hydrophobic statin ATV forming the core of the nanoparticle (HA-ATV-NP). The HA on the NPs can selectively bind with CD44, a cell surface receptor overexpressed on cells residing in atherosclerotic plaques and known to play important roles in plaque development. HA-ATV-NPs exhibited significantly higher anti-inflammatory effects on macrophages compared to ATV alone in vitro. Furthermore, when administered in an apolipoprotein E (ApoE)-knockout mouse model of atherosclerosis following a 1-week treatment regimen, HA-ATV-NPs markedly decreased inflammation in advanced atherosclerotic plaques, which were monitored through contrast agent aided magnetic resonance imaging. These results suggest CD44 targeting with HA-ATV-NPs is an attractive strategy to reduce harmful inflammation in atherosclerotic plaques.

SUBMITTER: Hossaini Nasr S

PROVIDER: S-EPMC7234819 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Effective atherosclerotic plaque inflammation inhibition with targeted drug delivery by hyaluronan conjugated atorvastatin nanoparticles.

Hossaini Nasr Seyedmehdi S Rashidijahanabad Zahra Z Ramadan Sherif S Kauffman Nate N Parameswaran Narayanan N Zinn Kurt R KR Qian Chunqi C Arora Ripla R Agnew Dalen D Huang Xuefei X

Nanoscale 20200501 17

Atherosclerosis is associated with inflammation in the arteries, which is a major cause of heart attacks and strokes. Reducing the extent of local inflammation at atherosclerotic plaques can be an attractive strategy to combat atherosclerosis. While statins can exhibit direct anti-inflammatory activities, the high dose required for such a therapy renders it unrealistic due to their low systemic bioavailabilities and potential side effects. To overcome this, a new hyaluronan (HA)-atorvastatin (AT ...[more]

PMID: 32314997

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Project description:Increasing evidence has highlighted the pivotal role that intimal macrophage (iMΦ) plays in the pathophysiology of atherosclerotic plaques, which represents an attractive target for atherosclerosis treatment. In this work, to address the insufficient specificity of conventional reconstituted high-density lipoprotein (rHDL) for iMΦ and its limited cholesterol efflux ability, we designed a hyaluronan (HA)-anchored core-shell rHDL. This nanoparticle achieved efficient iMΦ-targeted drug delivery via a multistage-targeting approach, and excellent cellular cholesterol removal. It contained a biodegradable poly (lactic-co-glycolic acid) (PLGA) core within a lipid bilayer, and apolipoprotein A-I (apoA-I) absorbing on the lipid bilayer was covalently decorated with HA. The covalent HA coating with superior stability and greater shielding was favorable for not only minimizing the liver uptake but also facilitating the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors in atherosclerotic plaques. The ultimate iMΦ homing was achieved via apoA-I after HA coating degraded by hyaluronidase (HAase) (abundant in atherosclerotic plaque). The multistage-targeting mechanism was revealed on the established injured endothelium-macrophage co-culture dynamic system. Upon treatment with HAase in vitro, the nanoparticle HA-(C)-PLGA-rHDL exhibited a greater cholesterol efflux capacity compared with conventional rHDL (2.43-fold). Better targeting efficiency toward iMΦ and attenuated liver accumulation were further proved by results from ex vivo imaging and iMΦ-specific fluorescence localization. Ultimately, HA-(C)-PLGA-rHDL loaded with simvastatin realized the most potent anti-atherogenic efficacies in model animals over other preparations. Thus, the HAase-responsive HDL-mimetic nanoparticle was shown in this study to be a promising nanocarrier for anti-atherogenic therapy, in the light of efficient iMΦ-targeted drug delivery and excellent function of mediating cellular cholesterol efflux.

Project description:This study sought to develop magnetic resonance contrast agents based on high-density lipoprotein (HDL) nanoparticles to noninvasively visualize intraplaque macrophages and collagen content in mouse atherosclerotic plaques.Macrophages and collagen are important intraplaque components that play central roles in plaque progression and/or regression. In a Reversa mouse model, plaque regression with compositional changes (from high macrophage, low collagen to low macrophage, high collagen) can be induced.This study labeled HDL nanoparticles with amphiphilic gadolinium chelates to enable target-specific imaging of intraplaque macrophages. To render HDL nanoparticles specific for the extracellular matrix, labeled HDL nanoparticles were functionalized with collagen-specific EP3533 peptides (EP3533-HDL) via poly(ethylene glycol) spacers embedded in the HDL lipid layers. The association of nanoparticles with collagen was examined in vitro by optical methods. The in vivo magnetic resonance efficacy of these nanoparticles was evaluated in a Reversa mouse model of atherosclerosis regression. Ex vivo confocal microscopy was applied to corroborate the in vivo findings and to evaluate the fate of the different HDL nanoparticles.All nanoparticles had similar sizes (10 ± 2 nm) and longitudinal relaxivity r1 (9 ± 1 s(-1) mmol/l(-1)). EP3533-HDL showed strong association with collagen in vitro. After 28 days of plaque regression in Reversa mice, EP3533-HDL showed significantly increased (p < 0.05) in vivo magnetic resonance signal in aortic vessel walls (normalized enhancement ratio [NERw] = 85 ± 25%; change of contrast-to-noise ratio [?CNRw] = 17 ± 5) compared with HDL (NERw = -7 ± 23%; ?CNRw = -2 ± 4) and nonspecific control EP3612-HDL (NERw = 4 ± 24%; ?CNRw = 1 ± 6) at 24 h after injection. Ex vivo confocal images revealed the colocalization of EP3533-HDL with collagen. Immunohistostaining analysis confirmed the changes of collagen and macrophage contents in the aortic vessel walls after regression.This study shows that the HDL nanoparticle platform can be modified to monitor in vivo plaque compositional changes in a regression environment, which will facilitate understanding plaque regression and the search for therapeutic interventions.

Dataset Information

Effective atherosclerotic plaque inflammation inhibition with targeted drug delivery by hyaluronan conjugated atorvastatin nanoparticles.

Publications

Effective atherosclerotic plaque inflammation inhibition with targeted drug delivery by hyaluronan conjugated atorvastatin nanoparticles.

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