基于海藻酸钠衍生物的肝靶向纳米前药的构建及抗肿瘤活性研究

利用寡聚乙二醇(mOEG)修饰海藻酸钠(ALG), 有效降低了ALG的黏度, 提高了其对疏水性肝靶向配体甘草次酸(GA)的负载量. 结果表明, 靶向材料(GA-ALG-mOEG)的GA负载量为11.8%, 是对照组(GA-ALG)的1.97倍. 在此基础上, 以物理交联的方式引入pH响应的阿霉素前药(DOX-ALG-mOEG), 制备了肝靶向纳米前药(DOX-ALG-mOEG/GA-ALG-mOEG NPs). 细胞实验及抑瘤实验结果表明, 该前药较对照组(DOX-ALG/GA-ALG NPs)具有更高的肝靶向性和药物利用率, 其对肝癌细胞的半致死率浓度(IC₅₀)为58.1 ng/mL, 是对照组(IC₅₀=141.7 ng/mL)的41%; 动物实验结果显示, 该前药的抑瘤率达到了88.4%, 比对照组提高了11.5%.

Preparation of Liver-targeted Nano-prodrug Based on Sodium Alginate Derivative and the Study on Antitumor Activity†

The high viscosity of sodium alginate(ALG) causes its insufficient targeted ligand loading, and further influences the targeted recognition effect of nano-prodrug. Here, oligomeric ethylene glycol modified-sodium alginate(ALG-mOEG) was used as a carrier to improve the targeted-ligands loading. Results showed that ALG-mOEG significantly improved glycyrrhetinic acid(GA) loading compared with unmodified ALG(11.8% vs. 6.9%, 1.97-fold increase). On this basis, the liver targeted nano-prodrug(DOX-ALG-mOEG/GA-ALG-mOEG NPs) was self-assembled via dialysis method by mixing GA-ALG-mOEG and DOX-ALG-mOEG. Cell cytotoxicity experiment showed that DOX-ALG-mOEG/GA-ALG-mOEG NPs inhibited HepG2 proliferation with an half maximal inhibitory concentration(IC₅₀) value of 58.1 ng/mL while the IC₅₀ of control group was 141.7 ng/mL; the tumor growth inhibition rate(IR) reached to 88.4%, improved by 11.5% compared to that of the control group. This study show that the liver targeted nano-prodrug based on ALG-mOEG can effectively improve the drug utilization, and provide a reference for the preparation of other polysaccharide targeted nano-prodrug.