癌症是世界范围内难以攻克的难题，为患者及其家庭带来了沉重的负担。目前化学治疗仍然是治疗肿瘤的主要手段之一，然而大多数的化疗药物在使用过程中都会出现选择性差、毒副作用严重以及耐药性发生等问题，最终导致肿瘤化疗的失败。为了解决化疗药物的局限性问题，主动靶向纳米载药体系应运而生。主动靶向纳米载药体系是利用纳米载药系统与靶组织或靶细胞之间的配体-受体、抗原-抗体或其他形式的分子相互识别，将药物输送到特定的位置，与被动靶向相比，可进一步提高肿瘤细胞对药物的摄取，增强药物的治疗效果并显著降低机体副作用，实现增效减毒的作用。

金属有机框架（MOFs)，亦称多孔配位聚合物，由金属离子和有机配体通过配位键自组装形成，在催化、储能和分离中都有广泛应用，近年来作为药物载体更是成为了研究的热点。沸石咪唑酯骨架结构材料-8（ZIF-8）是属于MOFs种类中的一类新型多孔材料，由Zn²⁺和2-甲基咪唑配位组成，具有合成策略简单、易于功能化、负载能力高及pH响应降解的特性，是一种非常具有潜力的新型药物载体。对ZIF-8 载体表面进行主动靶向修饰，可以在增强递送的药物抗肿瘤活性的同时降低对正常组织的毒性作用。

本课题主要研究内容如下：

使用“一锅搅拌法”成功制备负载阿霉素（DOX）的ZIF-8纳米粒子，并将甘草次酸（GA）修饰于其表面，构建GA受体靶向的DOX递送系统PEG-GA@ZIF-8@DOX。通过扫描电镜（SEM）和透射电镜（TEM）观察纳米粒子形貌，发现PEG-GA@ZIF-8@DOX呈类球状，粒径均匀。动态光散射法（DLS）测得PEG-GA@ZIF-8@DOX的水合粒径为236.37 ± 0.21 nm，Zeta电位为 -6.52 ± 0.29 mV。X-射线衍射（XRD）验证纳米粒子具有标准晶体结构。傅里叶红外光谱（FT-IR）、紫外光谱（UV）以及比表面积（BET）结果证明DOX的成功负载以及GA的成功修饰。PEG-GA@ZIF-8@DOX中DOX的载药量约为11.22 ± 0.87%，在酸性环境下最终释放量为57.73%。各浓度下的PEG-GA@ZIF-8@DOX溶血率均低于5%，初步验证纳米制剂在体内的生物相容性较好。人肝癌细胞株HepG2用于考察体外细胞摄取以及溶酶体逃逸特性，CCK-8法研究药物的体外细胞毒性，结果显示PEG-GA@ZIF-8@DOX的摄取量明显优于DOX以及ZIF-8@DOX，可以成功从溶酶体中逃逸，提升DOX的抗肿瘤活性。建立H22荷瘤小鼠模型考察PEG-GA@ZIF-8@DOX的抗肿瘤效果，研究结果表明PEG-GA@ZIF-8@DOX不仅可以提升DOX的抗肿瘤活性，还可以降低DOX带来的副作用，H&E染色结果显示PEG-GA@ZIF-8@DOX对小鼠的主要脏器没有明显的毒性。

制备以ZIF-8为载体，叶酸（FA）靶向修饰的黄芩苷（BAN）纳米递送系统PEG-FA@ZIF-8@BAN。通过SEM和TEM对纳米粒子的形态进行观察，发现PEG-FA@ZIF-8@BAN粒径均匀统一。DLS测得PEG-FA@ZIF-8@BAN水合粒径为176 ± 8.1 nm，Zeta电位为 -23.83 ± 1.1 mV，具有良好的分散性。XRD结果显示PEG-FA@ZIF-8@BAN具有标准的晶型结构。FT-IR、UV以及BET表征结果表明BAN的成功负载与PEG-FA的成功修饰。BAN负载效率高达41.45 ± 1.43%，在酸性环境（pH = 5.0）中药物释放量为78.60%，而在中性环境（pH = 7.4）中释放量仅为11.03%。体外细胞实验研究结果表明PEG-FA@ZIF-8@BAN可以显著提高BAN对MCF-7细胞的杀伤作用，FA介导的靶向作用可使纳米粒子更好地被肿瘤细胞摄取，促进肿瘤细胞产生活性氧（ROS），极大增强了药物对肿瘤细胞的杀伤作用。建立4T1荷瘤小鼠模型对PEG-FA@ZIF-8@BAN的体内抗肿瘤活性进行评价，研究结果表明该体系可以显著提高BAN对乳腺癌实体瘤的增殖抑制作用，诱导肿瘤细胞凋亡，没有造成主要脏器的明显病理损伤。各组小鼠的肝肾功能指标也未发现明显异常，说明该载药系统在小鼠体内的毒性较低。

综上所述，本课题主要基于金属有机框架材料设计配体-受体主动靶向型纳米载药系统。本论文选择可以酸性环境响应型降解并且生物相容性良好的ZIF-8材料作为药物载体，构建的药物递送系统合成方法简单，反应条件温和，具有良好的分散性和稳定性。针对性地解决部分药物的生物利用度低、选择性差以及不良反应严重等问题，为毒副作用强的抗肿瘤化疗药物或天然来源的肿瘤治疗候选药物提供了“增效减毒”思路，搭建了新型、高效的抗肿瘤纳米平台，并且也拓宽了MOFs在生物医药领域的应用范围。

Cancer is an insurmountable problem worldwide and places a heavy burden on patients and their families. Chemotherapy is still one of the main means of treating tumours, yet most chemotherapeutic drugs are subject to low bioavailability, poor selectivity, severe toxic side effects and drug resistance, which ultimately lead to the failure of tumour chemotherapy. In order to address the limitations of chemotherapeutic drugs, active targeting nano-delivery systems have been developed. Active targeting nano-delivery systems use ligand-receptor, antigen-antibody or other forms of molecular recognition between the nano-delivery system and target tissues or cells to deliver drugs to specific locations, which can further enhance the uptake of drugs by tumour cells, enhance the therapeutic effect of drugs and significantly reduce the side effects of the body compared to passive targeting, thus achieving increased efficacy and reduced toxicity.

Metal organic frameworks (MOFs), also known as porous coordination polymers, are formed by the self-assembly of metal ions and organic ligands through coordination bonds. They are widely used in catalysis, energy storage and separation, and have become a hot research topic as drug carriers in recent years. Zeolitic imidazolate framework-8 (ZIF-8) is a new type of porous material belonging to the MOFs category, consisting of Zn²⁺ and 2-methylimidazole ligands, with simple synthesis strategy, easy functionalization, high loading capacity and pH-responsive degradation, and is a very promising new drug carrier. Active targeting ligand modification on the surface of ZIF-8 carriers can enhance the antitumour activity of delivered drugs while reducing the toxic effects on normal tissues.

The main research contents and the results are as follows:

Doxorubicin (DOX) loaded ZIF-8 nanoparticles were successfully prepared by the "one pot stirring method", and glycyrrhetinic acid (GA) was modified on its surface to construct a DOX delivery system targeting GA receptors. The morphology of nanoparticles was observed by SEM and TEM, and it was found that PEG-GA@ZIF-8@DOX is spherical in shape with uniform particle size. The hydration particle size of PEG-GA@ZIF-8 @DOX is 236.37 ± 0.21 nm, and the Zeta potential is -6.52 ± 0.29 mV. XRD confirmed that the nanoparticles had standard crystal structure. The FT-IR, UV, and BET results confirmed the successful loading of DOX and the successful modification of GA ligands. The drug loading of DOX in PEG-GA@ZIF-8@DOX is approximately 11.22 ± 0.87%, and the final release in acidic environments is 57.73%. The hemolysis rate of PEG-GA@ZIF-8@DOX is lower than 5% at various concentrations, and preliminary verification shows that the biocompatibility of the nano formulation in vivo is good. The human hepatoma cell line HepG2 was used to examine the in vitro cellular uptake as well as lysosomal escape properties. The CCK-8 method was used to study the in vitro cytotoxicity of the drug, and the results showed that PEG-GA@ZIF-8@DOX had significantly better uptake than DOX and could successfully escape from the lysosome and enhance the antitumor activity of DOX. The anti-tumor effect of PEG-GA@ZIF-8@DOX was investigated by establishing H22 tumor-bearing mouse model, and the results showed that PEG-GA@ZIF-8@DOX could not only enhance the anti-tumor effect of DOX, but also reduce the side effects caused by DOX, and the H&E staining results showed that PEG-GA@ZIF-8@DOX had no obvious toxicity to the major organs of mice.

PEG-FA@ZIF-8@BAN, a baicalin (BAN) nano-delivery system with ZIF-8 as a carrier and folic acid (FA) targeting modification, was prepared. The morphology of the nanoparticles was observed by SEM and TEM, and the uniform particle size of PEG- FA@ZIF-8@BAN was found. The hydrated particle size of PEG-FA@ZIF-8@BAN was measured by DLS to be 176 ± 8.1 nm with a zeta potential of -23.83 ± 1.1 mV and good dispersion. The XRD results showed that PEG-FA@ZIF-8@BAN has a standard crystalline structure. FT-IR, UV, and BET characterization results showed successful loading of BAN and modification of PEG-FA. The loading efficiency of BAN was as high as 41.45 ± 1.43% and the drug release was 78.60% in acidic environment (pH = 5.0) and only 11.03% in neutral environment (pH = 7.4). The results of in vitro cellular experiments showed that PEG-FA@ZIF-8@BAN could significantly enhance the killing effect of BAN on MCF-7 cells, and the FA-mediated targeting could make the nanoparticles better taken up by tumor cells and promote the production of reactive oxygen species (ROS) by tumor cells, which greatly enhanced the killing effect of the drug on tumor cells. 4T1 tumor-bearing mouse model was established to evaluate the in vivo antitumor activity of PEG-FA@ZIF-8@BAN. The results of the study showed that the system could significantly enhance the proliferation inhibition and induce apoptosis of tumor cells in solid tumors of breast cancer without causing significant pathological damage to major organs. No significant abnormalities were also found in the liver and kidney function indices of all groups of mice, indicating the low toxicity of the system in mice.

In summary, this work focuses on the design of ligand-receptor active targeting drug delivery systems based on metal-organic framework materials. In this thesis, the ZIF-8 material, which is acidic environment-responsive degradable and biocompatible, was selected as the drug carrier, and the drug delivery system was constructed with simple synthesis method, mild reaction conditions and good dispersion and stability. It is a novel and highly effective anti-tumor nano platform that can address the problems of low bioavailability, poor selectivity and serious adverse reactions of some drugs, and provide a "potency and toxicity reduction" idea for anti-tumor chemotherapeutic drugs with strong toxic side effects or tumor therapeutic candidates of natural origin, and also broaden the scope of application of MOFs in biomedical field.