Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in <i>Apoe</i><sup>−/−</sup> Mice

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  • Katsuki Shunsuke
    The Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
  • Koga Jun-ichiro
    The Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
  • Matoba Tetsuya
    The Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
  • Umezu Ryuta
    The Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
  • Nakashiro Soichi
    The Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
  • Nakano Kaku
    The Department of Cardiovascular Research, Development, and Translational Medicine, Center for Disruptive Cardiovascular Innovation, Kyushu University
  • Tsutsui Hiroyuki
    The Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
  • Egashira Kensuke
    The Department of Cardiovascular Research, Development, and Translational Medicine, Center for Disruptive Cardiovascular Innovation, Kyushu University The Department of Translational Medicine, Kyushu University Graduate School of Pharmaceutical Sciences

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<p>Aim: Abdominal aortic aneurysm (AAA) is a lethal and multifactorial disease. To prevent a rupture and dissection of enlarged AAA, prophylactic surgery and stenting are currently available. There are, however, no medical therapies preventing these complications of AAA. Statin is one of the candidates, but its efficacy on AAA formation/progression remains controversial. We have previously demonstrated that nanoparticles (NPs) incorporating pitavastatin (Pitava-NPs)—clinical trials using these nanoparticles have been already conducted—suppressed progression of atherosclerosis in apolipoprotein E-deficient ( Apoe−/−) mice. Therefore, we have tested a hypothesis that monocytes/macrophages-targeting delivery of pitavastatin prevents the progression of AAA. </p><p>Methods: Angiotensin II was intraperitoneally injected by osmotic mini-pumps to induce AAA formation in Apoe−/− mice. NPs consisting of poly(lactic-co-glycolic acid) were used for in vivo delivery of pitavastatin to monocytes/macrophages. </p><p>Results: Intravenously administered Pitava-NPs (containing 0.012 mg/kg/week pitavastatin) inhibited AAA formation accompanied with reduction of macrophage accumulation and monocyte chemoattractant protein-1 (MCP-1) expression. Ex vivo molecular imaging revealed that Pitava-NPs not only reduced macrophage accumulation but also attenuated matrix metalloproteinase activity in the abdominal aorta, which was underpinned by attenuated elastin degradation. </p><p>Conclusion: These results suggest that Pitava-NPs inhibit AAA formation associated with reduced macrophage accumulation and MCP-1 expression. This clinically feasible nanomedicine could be an innovative therapeutic strategy that prevents devastating complications of AAA. </p>

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