用于靶向动脉粥样硬化正电子发射断层成像的聚合物纳米颗粒的设计与模块化构建：25%（64）铜 - CANF - 组合的故事
Design and Modular Construction of a Polymeric Nanoparticle for Targeted Atherosclerosis Positron Emission Tomography Imaging: A Story of 25% (64)Cu-CANF-Comb.
作者信息
Woodard Pamela K, Liu Yongjian, Pressly Eric D, Luehmann Hannah P, Detering Lisa, Sultan Deborah E, Laforest Richard, McGrath Alaina J, Gropler Robert J, Hawker Craig J
机构信息
Department of Radiology, Washington University, St. Louis, Missouri, USA.
Materials Research Laboratory, University of California, Santa Barbara, California,, USA.
出版信息
Pharm Res. 2016 Oct;33(10):2400-10. doi: 10.1007/s11095-016-1963-8. Epub 2016 Jun 10.
PURPOSE
To assess the physicochemical properties, pharmacokinetic profiles, and in vivo positron emission tomography (PET) imaging of natriuretic peptide clearance receptors (NPRC) expressed on atherosclerotic plaque of a series of targeted, polymeric nanoparticles.
METHODS
To control their structure, non-targeted and targeted polymeric (comb) nanoparticles, conjugated with various amounts of c-atrial natriuretic peptide (CANF, 0, 5, 10 and 25%), were synthesized by controlled and modular chemistry. In vivo pharmacokinetic evaluation of these nanoparticles was performed in wildtype (WT) C57BL/6 mice after (64)Cu radiolabeling. PET imaging was performed on an apolipoprotein E-deficient (ApoE(-/-)) mouse atherosclerosis model to assess the NPRC targeting efficiency. For comparison, an in vivo blood metabolism study was carried out in WT mice.
RESULTS
All three (64)Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted (64)Cu-comb. Of the three nanoparticles, the 25% (64)Cu-CANF-comb demonstrated the best NPRC targeting specificity and sensitivity in ApoE(-/-) mice. Metabolism studies showed that the radiolabeled CANF-comb was stable in blood up to 9 days. Histopathological analyses confirmed the up-regulation of NPRC along the progression of atherosclerosis.
CONCLUSION
The 25% (64)Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status.
目的
评估一系列靶向聚合物纳米颗粒在动脉粥样硬化斑块上表达的利钠肽清除受体（NPRC）的物理化学性质、药代动力学特征及体内正电子发射断层扫描（PET）成像情况。
方法
通过可控的模块化化学方法合成与不同量的C型心房利钠肽（CANF，0%、5%、10%和25%）偶联的非靶向和靶向聚合物（梳状）纳米颗粒，以控制其结构。对这些纳米颗粒进行⁶⁴Cu放射性标记后，在野生型（WT）C57BL/6小鼠体内进行药代动力学评估。在载脂蛋白E缺陷（ApoE⁻/⁻）小鼠动脉粥样硬化模型上进行PET成像，以评估NPRC靶向效率。作为对照，在WT小鼠体内进行血液代谢研究。
结果
与非靶向⁶⁴Cu-梳状纳米颗粒相比，所有三种⁶⁴Cu-CANF-梳状纳米颗粒均显示出改善的生物分布特征，包括肝脏和脾脏中的蓄积显著减少。在这三种纳米颗粒中，25%的⁶⁴Cu-CANF-梳状纳米颗粒在ApoE⁻/⁻小鼠中表现出最佳的NPRC靶向特异性和敏感性。代谢研究表明，放射性标记的CANF-梳状纳米颗粒在血液中长达9天都是稳定的。组织病理学分析证实，随着动脉粥样硬化的进展，NPRC上调。
结论
25%的⁶⁴Cu-CANF-梳状纳米颗粒显示出作为PET成像剂检测动脉粥样硬化进展和状态的潜力。
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