透明质酸修饰的镧配位聚合物的合成及其靶向抗肿瘤作用

Synthesis of hyaluronic acid-modifiel lanthanide coordination polymers and their targeted antitumor effects

摘要:

目的 制备一种具有靶向抗肿瘤作用的镧配位聚合物。方法 以六水硝酸镧、透明质酸（HA）和4-二 甲氨基苯甲酸（DABA）为原料，通过水热合成法制备一种由 HA 修饰的镧配位聚合物（DAL）抗肿瘤给药系统 （HA@DAL）。采用粒径分布、Zeta电位、热重分析（TGA）、X射线衍射、红外和紫外光谱法研究 HA@DAL和 DAL 的理化性质。通过CCK8检测、细胞凋亡和活细胞成像比较DAL和HA@DAL的抗肿瘤效果。通过动物活体成像 考察 HA@DAL 在荷瘤小鼠的体内分布情况。结果 成功制备了 DAL 和 HA@DAL，平均粒径为（75.23 ± 8.39） nm，聚合物分散指数为0.19 ± 0.22，电位为（-30.60 ± 3.48） mV，保留了金属镧的荧光特性。细胞毒性和细胞凋亡检 测结果显示，HA@DAL与DAL相比具有更强的抗肿瘤活性（P < 0.01），其细胞毒性与同等剂量的阿霉素（DOX）相 近（P > 0.05）。体外活细胞成像结果显示，DAL可被细胞吸收，使其发出蓝色荧光，但缺乏选择性。HA@DAL具有 良好的肿瘤靶向能力，动物活体成像结果表明HA@DAL可以精准到达肿瘤部位。结论 制备的HA@DAL具有一 定的肿瘤靶向治疗应用前景，为开发新型纳米药物递送系统提供实验依据。

Abstract:

Objective Preparation of a lanthanum coordination polymer with targeted antitumor effects. Methods A lanthanide coordination polymer antitumor drug delivery system (HA@DAL), modified by hyaluronic acid, was prepared by hydrothermal synthesis using lanthanum nitrate hexahydrate, hyaluronic acid (HA), and 4- dimethylaminobenzoic acid (DABA) as raw materials. Particle size distribution, zeta potential, thermogravimetric analysis (TGA), X-ray diffraction, infrared and ultraviolet spectroscopy were used to study the physicochemical properties of HA@DAL and the lanthanide coordination polymer (DAL). The anti-tumor effects of DAL and HA@DAL were compared using CCK8 assay, apoptosis analysis, and live cell imaging. The in vivo distribution of HA@DAL in tumor-bearing mice was examined by live animal imaging. Results DAL and HA@DAL were successfully prepared. The average particle size was (75.23 ± 8.39) nm, the polydispersity index was 0.19 ± 0.22, and the zeta potential was (-30.60 ± 3.48) mV. The fluorescence characteristics of lanthanum metal were retained. Cytotoxicity and apoptosis assays showed that HA@DAL possessed stronger antitumor activity compared with DAL(P<0.01), and exhibited similar cytotoxicity compared with the same dose of DOX (P>0.05). In vitro live cell imaging results showed that DAL could be taken up by cells, causing them to emit blue fluorescence but lacked selectivity, whereas HA@DAL had good tumor-targeting ability. Animal live imaging results showed that HA@DAL could reach the tumor site precisely. Conclusion The prepared HA@DAL has promising prospects for tumor-targeted therapeutic applications and provides an experimental basis for the development of novel nanodrug delivery systems.