多功能载紫杉醇靶向磁性纳米粒UP-MNP-C11诊治动脉粥样硬化的实验研究

The diagnosis and therapy of atherosclerosis (AS) are the hot spots in the field of cardiovascular disease. Conventionl imaging methods are insufficiently capable for elucidating AS plaque composition, and could not achieve the aim of integrated dual diagnosis treatment. Our previous study revealed that ultrasmall superparamagnetic iron oxide (USPIO) could discriminate the AS plaque composition precisely. To achieve the aim of integrated dual diagnosis treatment, in this study, we prepared the multi-functional magnetic nanoparticles loaded with paclitaxel (referred to as UP-MNP-C11), which are developed to simultaneously diagnose and treat AS. UP-MNP-C11, which are loaded with paclitaxel and USPIO, are prepared with the novel lipid-polymer hybrid nanoparticles conjugated with C11 peptide specifically targeting the AS plaque. We will thoroughly investigate the characterization, in vitro and in vivo targeting activity, nonspecific toxicity, pharmacokinetics (PK), diagnostic capabilities and therapeutic effect of UP-MNP-C11. It would be expected that UP-MNP-C11 could achieve the targeted therapy of AS and enhance the therapeutic index of AS. Simultaneously, the degree of inflammatory infiltration and discrimination of different components within the plaque could be identified by magnetic resonance imaging (MRI), achieving the purpose of real-time monitoring of the therapeutic effect of AS. Also, the therapeutic regimen could be further modulated according to the feedback of the therapeutic effect of AS and achieved the optimal treatment. In conclusion, the multi-functional nanoparticles UP-MNP-C11 integrated the molecular targeting technology, nanotechnology and the MRI molecular imaging technology and would achieve the real-time monitoring, diagnosis and therapy of AS plaque.

动脉粥样硬化（AS）的诊治是心血管领域研究的热点，目前无法实现AS诊治一体化。我们前期研究发现超微超顺磁性氧化铁纳米粒（USPIO）可精确判断AS斑块成分，为实现对AS诊治一体化，本研究拟采用新型脂质-高分子复合物为载体，同时装载紫杉醇和USPIO，并外修饰特异性靶向AS斑块的C11多肽，制备一种对AS同时具有诊断和治疗功能的靶向磁性纳米粒（UP-MNP-C11），并对其纳米表征、体内外靶向能力、毒副作用、药代动力学和诊治AS功能进行研究。UP-MNP-C11将有可能实现对AS的靶向治疗，提高AS治疗指数。通过磁共振影像可显示AS斑块内的炎性浸润程度及辨别斑块内不同成分，实现对AS治疗效果的实时监测，并通过治疗效果的反馈，进一步调整治疗方案，达到对AS的最优化治疗。该UP-MNP-C11整合了目前最先进的分子靶向、纳米技术和MRI分子成像，将有可能实现对AS斑块的实时监测、诊断和治疗。

动脉粥样硬化（artherosclerosis，AS）是严重危害人类健康的疾病，采用影像磁共振手段，检测斑块有助于判断AS的稳定程度。本项目制备一种同时包裹USPIO和治疗药物紫杉醇的靶向磁性载体系统，经靶向AS斑块IV蛋白的C11多肽修饰，构建一种新型AS斑块递药系统UP-MNP-C11，旨在利用C11多肽靶向能力，增加体系的靶向效率，实现对AS的诊断和治疗。本项目利用乳化溶剂挥发法制备了载USPIO和紫杉醇的PLGA脂质纳米粒，采用马来酸亚胺基与疏基的特异性反应将C11多肽进行连接修饰。电镜观察证实纳米粒表面存在具脂质结构，载药纳米粒的平均粒径在150 nm以下，Zeta电位约为-10 mv，纳米粒形态圆整，粒径分布均匀；包封率达80%，纳米粒中药物呈现缓释效果，多肽修饰对药物从纳米粒释放无显著影响。经巨噬细胞摄取、动物活体成像及家兔组织分布实验结果均显示，C11修饰可显著增加纳米粒的AS斑块摄取量；使用纳米系统也可以促进巨噬细胞的被动吞噬；两者结合利于纳米粒的AS部位吞噬，即可进一步提高纳米粒的AS靶向效率。机制研究结果表明，AS斑块中富含IV型蛋白（高表达量），增加巨噬细胞以及斑块部位的磁性纳米粒分布几率，而还增加药物的AS局部分布量，尽管通过药动学试验检测UP-MNP-C11药物代谢无明显差异（非靶向组相比，P>0.05），但C11修饰的纳米粒的体内药动学较游离状态的USPIO及药物的代谢行为有显著影响，其AUC显著增加，t1/2显著延长（P<0.05)，这将促进纳米粒进入斑块部位。采用高脂喂养家兔模型后，体内外的巨噬细胞杀伤结果表明，将药物制成UP-MNP-C11可提高药物对靶部位的分布，具有明显的抑制巨噬细胞生长的效果，提高动物模型的治疗效果（P<0.05）。与此同时，USPIO也具有这种分布特性，可进一步提高MRI对比显像的效果，二者对AS斑块的显像与修复具有同步叠加作用，显示出良好的靶向诊断治疗作用。综上所述，本项目所构建的C11多肽修饰、USPIO与药物紫杉醇包载于PLGA脂质纳米给药系统UP-MNP-C11可显著促进AS斑块部位的靶向效率，具有血管动脉硬化疾病的诊断治疗效果。该研究结果实现了本项目最初的设计目标。

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