【作者】 刘顺；

【导师】 李亚鹏；

【作者基本信息】 吉林大学 ， 高分子化学与物理， 2022， 硕士

【摘要】 动脉粥样硬化(AS)是一种进行性疾病,具有临床上不明显的病变和较长的潜伏期。AS详细的病理进展已有很好的研究,也有了多种病理学说。炎症被认为与AS发病机制密切相关,而巨噬细胞是AS炎症微环境中具有代表性的炎症细胞,在AS病灶处大量聚集。同时与炎症相关的生化信号如pH值,高活性氧(ROS)也备受人们关注,因为它们是合理设计生物刺激响应载体的病理基础。光热疗法(PTT)由于其微创入侵性小等特点也在AS治疗中崭露头角。本论文分别制备了两种可以靶向巨噬细胞的多功能智能纳米递送体系,工作如下:(1)设计了一种具有ROS敏感且靶向巨噬细胞的纳米胶束(HASC@Cur)。它是由两亲性材料透明质酸-2’-(丙烷-2,2-二烷基(硫代))二乙酸酯-姜黄素自组装而成。HASC@Cur纳米胶束尺寸形貌适当,适合生物体内应用,具有良好的稳定性和分散性。由于ROS敏感的硫缩酮键的存在,该纳米胶束在体外可以实现ROS刺激释放药物。细胞毒性显示HASC@Cur纳米胶束有出色的生物相容性。HASC@Cur纳米胶束内部药物除了当做治疗药物,还可以作为荧光探针,实现自身监测,体外细胞摄取验证了其能力,并且证明了HASC@Cur纳米胶束可以实现靶向巨噬细胞。(2)针对单一治疗的不足,设计了透明质酸靶向和pH响应的化学光热协同治疗AS的多功能纳米载体(CuS@DMSN-N=C-HA)。通过油水两相分层反应在硫化铜(CuS)表面生成了均匀的树枝状介孔二氧化硅壳层,然后作为载体,负载抗凝溶栓药物肝素(Hep),最后以pH敏感的席夫碱键在载体表面修饰具有靶向巨噬细胞的透明质酸(HA)。HA修饰赋予纳米复合材料pH响应能力和靶向巨噬细胞的能力,同时减少了药物的泄露,提高了载药量。体外释药结果表明,纳米体系可以在弱酸性环境中缓慢有效地释放药物。细胞毒性和溶血率测试表明了CuS@DMSN-N=C-HA的生物安全性优异。细胞成像显示,HA赋予了纳米载体卓越的靶向能力,与未修饰靶向物的纳米载体相比,CuS@DMSN-N=C-HA可以被巨噬细胞有效内化。与单一疗法相比,基于CuS出色的光热转换能力,H-CuS@DMSN-N=C-HA的协同治疗,在体内体外溶栓实验中显示出出色的溶栓能力。基于该多功能智能体系,我们实现了精确给药、药物控制释放和化学-光热协同治疗动脉粥样硬化。更多还原

【Abstract】 Atherosclerosis is a progressive disease with clinically inapparent lesions and a long incubation period.The detailed pathological progression of atherosclerosis has been primely studied,and there are various pathological theories.Inflammation is considered to be closely related to the pathogenesis of atherosclerosis,and macrophages are the representative inflammatory cells in the inflammatory microenvironment and accumulate in large numbers at the atherosclerosis lesions.Meanwhile,inflammation-related biochemical signals such as pH,high reactive oxygen species(ROS)have also attracted much attention,as they are the pathological basis for rational design of biostimuli-responsive vectors.Photothermal therapy(PTT)has also emerged in the treatment of atherosclerosis due to its minimally invasive and less invasive features.In this paper,two multifunctional smart nano-delivery systems that can target macrophages are prepared respectively.The work is as follows:(1)A ROS-sensitive and macrophage-targeted nanomicelle(HASC@Cur)was designed.It is self-assembled from the amphiphilic material hyaluronic acid-2’-(propane-2,2-dialkyl(thio))diacetate-curcumin.The HASC@Cur nanomicelles have appropriate size and morphology,suitable for in vivo applications,and have good stability and dispersibility.Due to the existence of ROS-sensitive thioketal bonds,the nanomicelles can achieve ROS-stimulated drug release in vitro.Cytotoxicity shows that HASC@Cur nanomicelles have excellent biocompatibility.In addition to being used as a therapeutic drug,the drug in the HASC@Cur nanomicelles can also be used as a fluorescent probe to realize self-monitoring.The in vitro cellular uptake verifies its ability and proves that the HASC@Cur nanomicelles can target macrophages.(2)We designed a hyaluronic acid-targeting and pH-responsive chemophotothermal synergistic multifunctional nanocarriers(CuS@DMSN-N=C-HA)by using PTT to address the deficiency of monotherapy.Uniform dendritic mesoporous silica nanoparticles are generated on the surface of copper sulfide(CuS)through the oil-water two-phase layering reaction,and then used as a drug-loading system to load the anticoagulant thrombolytic drug heparin(Hep).Finally,hyaluronic acid(HA)with the ability to target macrophages was modified on the surface of the carrier with pHsensitive Schiff base bonds.The HA modification endows the nanocomposite with pH responsiveness and the ability to target macrophages,while reducing drug leakage and increasing drug loading.In vitro drug release results reveal that the nanosystem exhibited excellent controlled drug release properties and could release drugs slowly and efficiently in a weakly acidic environment.Cytotoxicity and hemolysis rate tests shows the excellent biosafety of CuS@DMSN-N=C-HA.Cell imaging revealed that HA endowed the nanocarriers with superior targeting ability,and CuS@DMSN-N=CHA could be efficiently internalized by macrophages compared with the nanocarriers without the target modified.Compared with monotherapy,the synergistic treatment of H-CuS@DMSN-N=C-HA,based on the excellent photothermal conversion ability of CuS,showed excellent thrombolytic ability in vitro and in vivo thrombolysis experiments.Based on this multifunctional intelligent system,we realized precise drug delivery,controlled release and chemo-photothermal synergistic treatment of atherosclerosis.更多还原