A systematic comparison of clinically viable nanomedicines targeting HMG-CoA reductase in inflammatory atherosclerosis

JOURNAL OF CONTROLLED RELEASE

卷:262

Article

Alaarg, Amr^1,2,3  Senders, Max L.^2,4  Varela-Moreira, Aida^3,5  Perez-Medina, Carlos²  Zhao, Yiming²  Tang, Jun⁶  Fay, Francois^2,7  Reiner, Thomas^6,8  Fayad, Zahi A.²  Hennink, Wim E.³  Metselaar, Josbert M.^1,9,10  Mulder, Willem J. M.^2,4  Storm, Gert^1,3,11 

[1] Univ Twente, MIRA Inst Biomed Technol & Tech Med, Dept Biomat Sci & Technol, NL-7500 AE Enschede, Netherlands

[2] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA

[3] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Dept Pharmaceut, NL-3584 CG Utrecht, Netherlands

[4] Acad Med Ctr, Dept Med Biochem, NL-1105 AZ Amsterdam, Netherlands

[5] Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, NL-3584 CX Utrecht, Netherlands

[6] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA

[7] CUNY York Coll, Dept Chem, New York, NY 11451 USA

[8] Weill Cornell Med Coll, Dept Radiol, New York, NY 10065 USA

[9] Rhein Westfal TH Aachen, Univ Clin, Dept Expt Mol Imaging, D-52074 Aachen, Germany

[10] Rhein Westfal TH Aachen, Helmholtz Inst Biomed Engn, D-52074 Aachen, Germany

[11] Univ Med Ctr Utrecht, Imaging Div, NL-3584 CX Utrecht, Netherlands

关键词: Atherosclerosis;    Inflammation;    Targeted drug delivery;    Statins;    Nanomedicine;    Liposomes;    Polymers;    High-density lipoprotein;    Macrophages;   

DOI  :  10.1016/j.jconrel.2017.07.013

来源: Elsevier

【 摘 要 】

Atherosclerosis is a leading cause of worldwide morbidity and mortality whose management could benefit from novel targeted therapeutics. Nanoparticles are emerging as targeted drug delivery systems in chronic inflammatory disorders. To optimally exploit nanomedicines, understanding their biological behavior is crucial for further development of clinically relevant and efficacious nanotherapeutics intended to reduce plaque inflammation. Here, three clinically relevant nanomedicines, i.e., high-density lipoprotein ([S]-HDL), polymeric micelles ([S]-PM), and liposomes ([S]-LIP), that are loaded with the HMG-CoA reductase inhibitor simvastatin [S], were evaluated in the apolipoprotein E-deficient (Apoe(-/-)) mouse model of atherosclerosis. We systematically employed quantitative techniques, including in vivo positron emission tomography imaging, gamma counting, and flow cytometry to evaluate the biodistribution, nanomedicines' uptake by plaque-associated macrophages/monocytes, and their efficacy to reduce macrophage burden in atherosclerotic plaques. The three formulations demonstrated distinct biological behavior in Apoe(-/-)mice. While [S]-PM and [S]-LIP possessed longer circulation half-lives, the three platforms accumulated to similar levels in atherosclerotic plaques. Moreover, [S]-HDL and [S]-PM showed higher uptake by plaque macrophages in comparison to [S]-LIP, while [S]-PM demonstrated the highest uptake by Ly6C(high) monocytes. Among the three formulations, [S]-PM displayed the highest efficacy in reducing macrophage burden in advanced atherosclerotic plaques. In conclusion, our data demonstrate that [S]-PM is a promising targeted drug delivery system, which can be advanced for the treatment of atherosclerosis and other inflammatory disorders in the clinical settings. Our results also emphasize the importance of a thorough understanding of nanomedicines' biological performance, ranging from the whole body to the target cells, as well drug retention in the nanoparticles. Such systematic investigations would allow rational applications of nanomaterials', beyond cancer, facilitating the expansion of the nanomedicine horizon.

【 授权许可】

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