炎症因子诱导的动脉粥样硬化斑块靶向的细胞递药系统研究

Atherosclerosis(AS) is the major pathological basis of cardiovascular and cerebrovascular diseases. The occurrence and development of AS is accompanied by inflammation process. This inflammation reaction inside arterial wall plays an important role in forming atherosclerotic plaque, thinning the inflamed caps and triggering the plaque rupture, which will lead to the occurrence of thrombus and threat to life. Therefore, impairing inflammation and enhancing the stability of plaque by drugs with anti-inflammation activity have important clinical significance. Recent researches have demonstrated that the effect of anti-inflammation agent for preventing inflammation in plaque presents dose-dependent, however, via traditional administration only little part of drug will accumulate in plaque. Thus, according to the pathogenesis, inflammation, pathogenic structure and microenvironment of AS, a novel atherosclerotic plaque-targeting delivery system is developed based on neutrophils carrier for simvastatin-loaded lipid nanoparticls. Guided by the inflammatory signal gradient, these simvastatin-loaded neutrophils will be recruited to the inflammatory site, penetrate the wall of vascular endothelial cell and enhance the accumulation of simvastatin into atherosclerotic plaque. For proof of neutrophils as a feasible, efficient and safe drug targeting carrier, as well as illustration of the target mechanism based on interaction between physiological and pathological factors, numerous researches are being performed including the stability of neutrophils loading simvastatin-encapsulated lipid nanoparticles, physiological activity, inflammatory signal tropism and vascular penetration effect. This design of such neutrophils self-targeting carrier provide an innovative and efficient platform for treatment of AS, which will aid in exploration of the effect and mechanism of drugs on the AS plaque and promote the development of anti-AS drug.

动脉粥样硬化（AS）是心脑血管疾病发生的主要病理基础，AS的发生和发展始终伴随着炎症反应。动脉血管壁的炎性反应是AS斑块形成的重要诱因，斑块的破裂和脱落导致血栓的形成，危及生命。利用药物阻止斑块内炎症进展和稳定斑块具有重要的临床治疗意义。药物对炎性斑块的作用呈剂量依赖性，但药物进入斑块内的浓度很低。本项目根据AS斑块的炎性特征和病理结构，将具抗炎、稳定斑块的辛伐他汀通过中性粒细胞作为载体在炎症因子的引导靶向下穿透进入炎性斑块内部，提高药物在斑块内的浓度。本项目通过构建荷载辛伐他汀的中性粒细胞传递系统和AS动物模型，研究细胞递药系统的稳定性、对斑块炎症信号的引导性靶向和穿透性等，探讨细胞递送药物治疗的可行性和有效性，揭示通过生理病理因子间相互作用实现药物诱导递送的机制等。本项目的研究为AS的治疗提供创新高效的药物载体平台，对探索药物对AS斑块的作用及机制，推动抗AS药物的发展具有重要价值。

炎症与多种重大疾病如动脉粥样硬化、癌症及糖尿病等密切相关。基于中性粒细胞对炎症的天然靶向性，为了实现治疗性药物在炎症部位的高效递送，本研究首先根据动脉粥样硬化斑块的炎性特征，以中性粒细胞作为纳米药物载体，在炎症因子的引导下主动靶向炎性斑块内部，从而提高纳米药物在斑块内的有效蓄积量。本研究成功构建中性粒细胞递药系统，系统评价了中性粒细胞递药系统的稳定性、药物释放行为和对斑块炎症信号的趋向性，探讨基于中性粒细胞递送药物治疗的可行性，揭示通过炎症生理病理因子间相互作用实现药物靶向递送的机制等。同时，本研究还成功地将中性粒细胞递药系统应用在癌症的靶向递送和治疗上。利用光热治疗后在肿瘤局部产生的炎症作为招募信号，增强中性粒细胞递药系统向炎症肿瘤组织主动靶向功能，同时克服光热治疗存在的肿瘤细胞杀伤不彻底的局限，从而获得协同抗癌效果。实验结果充分证明了中性粒细胞递药系统的炎症介导主动靶向特性，揭示中性粒细胞递药系统可作为一种新型的靶向技术平台，用于炎症部位高效药物递送，具有广阔的应用前景和价值，对推动炎症相关疾病的治疗和药物开发具有重要意义。