Duivenvoorden R, Tang J, Cormode DP et al.
Nat Commun. 2014 Jan 20;5:3065. doi: 10.1038/ncomms4065

Background

Despite the success of preventive behavioural and lipid-lowering drugs for atherosclerotic disease, residual cardiovascular risk remains substantial even when treatment goals are met. The risk of recurrent acute coronary syndrome is high in patient who suffered a myocardial infarction, specifically in the first year after the event. A recent study suggested that this may be because of a systemic response to ischaemic injury that aggravates inflammation in atherosclerotic plaques[1]. The inflammatory process involving macrophages can result in plaque rupture, as a result of production of proteolytic enzymes that digest extracellular matrix [2]. Plaque inflammation is therefore considered a therapeutic target to prevent atherothrombotic events [3].
The authors developed a nanomedicine-based delivery strategy based on reconstituted high-density lipoprotein (rHDL) nanoparticles that can deliver drugs to atherosclerotic plaques. A statin was chosen as cargo on the rHDL particles, for its immunomodulating effects in inflammatory cells [4-6]. High-dose statins reduced plaque formation in an atherosclerotic mouse model in which statins did not affect lipid levels [7]. In humans, these high doses are not feasible due to adverse effects [8].
This study evaluated whether intravenous administration of statin-loaded rHDL nanoparticles ([S]-rHDL) can improve bioavailability by facilitating the delivery of statins to the plaques in the apolipoprotein E-knockout (apoE-KO) mouse model of atherosclerosis.

Main results

• Cellular in vitro studies showed that [S]-rHDL reduced inflammatory cytokines monocyte chemotactic protein-1 (MCP-1) and TNF-α, and reduced macrophage viability, similar to addition of free statin.
• Labelling [S]-rHDL with two different dyes for the corona and the core allowed studying the biodistribution. Nanoparticles were found in heart, aorta, liver, spleen and kidney, but not in muscle tissue.
• In apoE-KO mice who had been on a high-cholesterol diet for 28 weeks, pronounced accumulation of labelled [S]-rHDL in the vessel wall was seen. Excision of intact aortas of mice revealed that labelled [S]-rHDL accumulated in regions rich in plaques.
• Statins do not affect blood cholesterol levels in apoE-KO mice. To only study the effect of [S]-rHDL on plaque inflammation, apoE-KO mice were put on a high-cholesterol diet for 14 weeks, and then received biweekly infusions of [S]-rHDL, or bare rHDL. Vessel wall thickness was higher in the  placebo group. Total plaque area in the [S]-rHDL treated mice was significantly decreased by 37% as compared with placebo (P=0.002), and by 28% as compared with rHDL (P=0.006). Plaque macrophage content was decreased with 57% (P=0.001) after [S]-rHDL treatment as compared to placebo, and by 40% as compared to rHDL (P=0.03). As expected, no differences in cholesterol content of the thoracic aortas were seen between the treatment groups.
• A short-term high-dose [S]-rHDL in mice with advanced atherosclerotic lesions gave a reduction of total plaque area of 34% as compared to high-dose rHDL (P=0.005) and of 36% as compared to low-dose [S]-rHDL (P=0.006) and trend towards a decrease of 31% as compared to placebo (P=0.053).
• mRNA expression levels of monocyte-recruited and pro-inflammatory genes were clearly decreased in plaque macrophages after [S]-rHDL, as compared to administration of oral statins and placebo.
• Inflammatory protease activity was reduced in apoE-KO mice treated with [S]-rHDL, as compared with placebo.

Conclusion

These data demonstrate the potent local anti-inflammatory effects of statin-loaded rHDL nanoparticles in atherosclerotic plaques. The nanoparticles accumulate in the plaques, and are taken up by macrophages, after which they suppress the inflammatory response of macrophages. Macrophage content is reduced in the plaque after both prolonged low-dose therapy and shorter but higher-dose therapy. No toxic effects were seen in muscles or liver.
rHDL protects the statin from catabolism in the serum, thus its bioavailability is increased and [S]-rHDL can deliver the statin to the plaque. This is the first study to demonstrate that locally delivered statins have anti-inflammatory effects and decrease plaque burden.
In humans, these nanoparticles will likely also be taken up by hepatocytes, where the statin will upregulate LDL-receptor expression, thus exerting an additional therapeutic effect, namely cholesterol-lowering. It is postulated that also in the clinic [S]-rHDL nanotherapy holds promise to suppress plaque inflammation in the vulnerable period following acute coronary syndrome

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E-Learning • Raphaël Duivenvoorden

Statin-loaded HDL nanoparticle

In Nature Communications  January 2014 Raphaël Duivenvoorden describes an innovative nanotechnique to reduce the risk of a recurrent myocard infarct, in which inflammation is a key factor. A statin-loaded HDL-nanoparticle which by nature attaches itself to a plaque, appeares to be able to reduce inflammation in an animal model.

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