新型多功能纳米系统靶向治疗动脉粥样硬化研究

The morbidity and mortality of cardiovascular diseases (CVDs) is on the first place among all the diseases, severely threatening the human health. In China, more than 2700 millions of people suffer from CVDs, and the morbidity has been significantly increasing every year. Atherosclerosis (AS) is the common pathological change of a broad spectrum of seriously lethal CVDs such as myocardial infarction and stroke. Efficient AS therapy by systemic administration has been largely limited due to critical issues such as lower drug concentration at sites of interest and severe side effects. Rapid development in nanomedicine has offered great promising for the targeted therapy of AS. Recently, our group has developed novel biomaterials based on acetalated cyclodextrins (aCDs), which can serve as carrier materials for controlled drug delivery. Nanoparticles (NPs) based on these materials exhibited excellent biocompatibility in vivo, which can sustain the release of rapamycin (RAP) to efficiently delay the development of AS. With the aim to overcome adverse effects due to systemic administration and dramatically increase the therapeutic efficacy, herein we designed novel long-circulating RAP multifunctional NPs (mfNPs) based on aCDs, which are integrated with multiple targeting, multimodal imaging, and therapeutic capacity. In this study, the biophysicochemical properties of the designed nanomedicines will be carefully characterized. In addition, we will systemically evaluate their in vivo circulation, tissue distribution, and both in vitro and in vivo biocompatibility. By establishing AS animal models based on mice, the targeting effect and therapeutic efficacy of the newly developed multifunctional nanomedicines will be investigated. On the basis of these studies, we attempt to establish the interdependence between the biophysicochemical characteristics of mfNPs and their targeting capability as well as therapeutic significance. Successful implement of current study may provide important fundamentals for the development of novel nanomedicines that are useful for the personalized medicine of CVDs.

心血管疾病的发病率和死亡率居所有疾病首位，严重威胁人类健康。我国心血管病患者已超过2.7亿，且发病率逐年攀升。动脉粥样硬化（AS）是心肌梗死、中风等严重致命性心血管疾病的共同病理改变。全身给药治疗AS存在病灶部位药物浓度低、不良反应严重等问题。纳米医学的快速发展为AS靶向治疗带来新希望。本课题组近来开发了基于缩醛化环糊精的新型控释材料，其纳米微粒具有极其良好的体内相容性；该类微粒缓释雷帕霉素（RAP）能有效抑制AS发展。在此基础上，为克服全身给药引起的不良反应、有效提高治疗效果，本课题设计并制备集多重靶向性、多模式成像及治疗于一体的RAP长循环多功能纳米微粒（mfNP），深入表征其生物理化特性，系统评价其体内循环特征、组织分布及体内外相容性；并建立小鼠AS动物模型，研究mfNP的靶向效应及治疗作用；建立mfNP生物理化性能与其靶向及治疗效果间相关性，为开发个体化治疗用新型纳米系统奠定基础。

心血管疾病的发病率和死亡率居所有疾病首位，严重威胁人类健康。我国心血管病患者已超过2.7亿，且发病率逐年攀升。动脉粥样硬化（AS）是诸多严重致死和致残性心血管疾病的共同病理改变。全身给药治疗AS 存在病灶部位药物浓度低、不良反应严重等问题。本项目旨在构建多功能纳米粒，以其负载抗AS药物雷帕霉素（RAP），以实现AS的靶向防治。为此，我们首先合成了具有炎症微环境响应性的环糊精载体材料。其中，pH敏感性材料通过对环糊精的缩醛化合成，而活性氧（ROS）响应性材料通过对环糊精的功能化改性得到。在对其结构和理化性能表征的基础上，以其制备了pH或活性氧（ROS）响应性的纳米粒，并在不同细胞株和动物水平对其体内外安全性进行了深入细致的评价，表明该类纳米载体具有良好的安全性，可以用于局部注射或静脉注射给药系统的载体。证明了该类纳米粒可以有效负载包括RAP在类的不同结构的药物分子，并实现其良好的控制释放，验证了RAP等不同药物的pH或ROS响应性释放行为。同时，以具有不同电荷的量子点为模型纳米载体，研究了纳米载体静脉注射后在体内主要组织和脏器的分布，为设计并构建AS靶向纳米药物奠定了基础。以载脂蛋白E敲除（ApoE-/-）小鼠建立了AS模型，证明了所制备的纳米粒腹腔注射或静脉注射后可以靶向于AS斑块部位。基于此，制备了可以口服、局部注射和静脉注射的RAP纳米药物，研究了给药后其体内药动学行为，并在ApoE-/-小鼠体内评价了其抗AS作用，初步评价了其长期给药的安全性。结果证明，一方面通过所构建的载体能够有效提高RAP的生物利用度，另一方面大大提高了其体内抗AS的疗效，具体表现为有效减少斑块面积、抑制炎症细胞水平、降低炎症因子表达、增加斑块纤维冒厚度。因此，该类RAP释药系统能够显著延缓AS的发展，并增加斑块的稳定性；同时，其长期给药具有良好的体内安全性。