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Review
. 2016 Jul 1;23(7):757-65.
doi: 10.5551/jat.35113. Epub 2016 Apr 25.

Anti-inflammatory Nanoparticle for Prevention of Atherosclerotic Vascular Diseases

Jun-Ichiro Koga  1 , Tetsuya Matoba, Kensuke Egashira
Affiliations
Review

Anti-inflammatory Nanoparticle for Prevention of Atherosclerotic Vascular Diseases

Jun-Ichiro Koga et al. J Atheroscler Thromb. .

Abstract

Recent technical innovation has enabled chemical modifications of small materials and various kinds of nanoparticles have been created. In clinical settings, nanoparticle-mediated drug delivery systems have been used in the field of cancer care to deliver therapeutic agents specifically to cancer tissues and to enhance the efficacy of drugs by gradually releasing their contents. In addition, nanotechnology has enabled the visualization of various molecular processes by targeting proteinases or inflammation. Nanoparticles that consist of poly (lactic-co-glycolic) acid (PLGA) deliver therapeutic agents to monocytes/macrophages and function as anti-inflammatory nanoparticles in combination with statins, angiotensin receptor antagonists, or agonists of peroxisome proliferator-activated receptor-γ (PPARγ). PLGA nanoparticle-mediated delivery of pitavastatin has been shown to prevent inflammation and ameliorated features associated with plaque ruptures in hyperlipidemic mice. PLGA nanoparticles were also delivered to tissues with increased vascular permeability and nanoparticles incorporating pitavastatin, injected intramuscularly, were retained in ischemic tissues and induced therapeutic arteriogenesis. This resulted in attenuation of hind limb ischemia. Ex vivo treatment of vein grafts with imatinib nanoparticles before graft implantation has been demonstrated to inhibit lesion development. These results suggest that nanoparticle-mediated drug delivery system can be a promising strategy as a next generation therapy for atherosclerotic vascular diseases.

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Conflict of interest statement

Dr. Egashira is the inventor of an issued patent on part of the results reported in the present study (Pharmaceutical composition containing statin-encapsulated nanoparticle, WO 2008/026702). Applicants for this patent include Kyushu University (http://imaq.kyushu-u.ac.jp/), KOWA Inc (http://www.kowa.co.jp), and Sentan Medical Inc (http://sentaniryou.co.jp). Sentan Medical Inc is a drug discovery venture company from Kyushu University. Dr. Egashira is a founder of Sentan Medical Inc, possessing stocks, serves as one of Directors of the company, and reports personal fees from the company outside the submitted work. The intellectual property division of Kyushu University is reviewing that Sentan Medical Inc did not play a direct role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript in Dr. Egashira's Laboratory.

Figures

Fig. 1.
Fig. 1.
PLGA nanoparticles and their in vivo targeting of circulating inflammatory monocytes. (A) PLGA nanoparticles prepared by the emulsion solvent diffusion method. Images were taken by the transmission electron microscope (left) and scanning electron microscope (right). Scale bar indicates 1 µm. (B) Flow cytometry of circulating leukocytes. CD11b+CD115+ cells are quantified as circulating monocytes (upper panels). Inflammatory monocytes determined by Ly-6C expression were evaluated (lower panels). Right graphs show quantitative data. N = 3–4.
Fig. 2.
Fig. 2.
PLGA nanoparticles incorporating pitavastatin decrease buried fibrous caps in the brachiocephalic artery. (A) ApoE-deficient mice (16 weeks) were fed a high-fat diet for 4 weeks and then infused with angiotensin II for an additional 4 weeks. PLGA nanoparticles incorporating 0.4 mg/kg pitavastatin were injected into the tail vein once a week after starting angiotensin II. The buried fibrous cap was identified after staining with elastica van Gieson (EVG) staining (above). Macrophage accumulation was determined as Mac3 positive area (below). NP; nanoparticle. Scale bar indicates 100 µm. (B) Quantitative analyses of buried fibrous caps, the thickness of fibrous caps, and macrophage accumulation. *P < 0.05 vs. no-treatment group. N; negative control, FN; NPs containing FITC (fluorescein isothiocyanate), P; pitavastatin, PN; NPs containing pitavastatin. (Modified and cited from reference 45)
Fig. 3.
Fig. 3.
Nanoparticle-mediated delivery of pioglitazone decreases buried fibrous caps and inhibits MMP activities. (A) ApoE-deficient mice (16 weeks) were fed a high-fat diet for 4 weeks and then angiotensin II was administered for an additional 4 weeks. PLGA nanoparticles incorporating 7 mg/kg pitavastatin were injected into the tail vein once a week. The buried fibrous cap was identified after staining with elastica van Gieson (EVG) staining (above). The arrowheads indicate buried fibrous caps. (B) MMP activities were evaluated by a NIRF probe (i.e., MMPsense750). Activated MMP cleaved the quenched site of MMPsense and the emitted NIRF signal was detected in the brachiocephalic arteries. In contrast, Pio-NP inhibited MMP activities when compared to empty-NPs. N = 5–6. (Modified and cited from reference 48)
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