还原响应性肝靶向聚合物胶束的制备及其载药性能

冯荟如; 刘艳勤; 董营; 于香香; 巩凯

doi:10.14133/j.cnki.1008-9357.20220329001

还原响应性肝靶向聚合物胶束的制备及其载药性能

Preparation of Reduction-Responsive Liver-Targeted Polymeric Micelles and Their Drug-Loading Properties

摘要

摘要: 首先，以七（6-叠氮-6-脱氧）-β-环糊精、3-炔基丁基-β-D-半乳糖苷为原料，经Click反应合成具有肝靶向功能的半乳糖-β-环糊精（Gal₇-CD）；其次，以胱胺二盐酸盐、十八烷酸为原料，经氨基保护、酰化反应、脱保护等步骤，得到胱胺基十八酰胺（NH₂-SS-SA）；再次，以金刚烷甲酸活性酯、双端氨基聚乙二醇为原料，经酰化反应得到金刚烷基聚乙二醇胺（Ad-PEG₁₀₀₀-NH₂），该产物与丁二酸酐反应，得到金刚烷基聚乙二醇胺丁二酸（Ad-PEG₁₀₀₀-COOH）；接下来，NH₂-SS-SA和Ad-PEG₁₀₀₀-COOH反应得到金刚烷基聚乙二醇胺十八酰胺（Ad-PEG₁₀₀₀-SS-C₁₈）；最后，采用透析法，Gal₇-CD与Ad-PEG₁₀₀₀-SS-C₁₈经主客体自组装形成两亲性聚合物，进而形成聚合物胶束半乳糖-胱胺-十八酰胺（Gal₇-SS-C₁₈），并以阿霉素（DOX）为模型药物，制备了相应载药聚合物胶束Gal₇-SS-C₁₈-DOX。利用动态光散射仪（DLS）测得聚合物胶束和载药聚合物胶束粒径分别为（169.2±1.3） nm和（177.9±3.0） nm。利用紫外-可见分光光度计测得载药聚合物胶束的载药量为（21.2±0.7）%，包封率为（71.1±0.5)%。在模拟正常生理环境的磷酸盐缓冲液（PBS）中，载药聚合物胶束的药物释放缓慢；在模拟癌细胞还原性微环境下的PBS中，48 h内药物释放率可达到82.38%。以肝癌细胞（HepG2）和正常组织细胞（HEK-293）为细胞模型，评价聚合物胶束的细胞毒性及抗肿瘤活性。研究结果表明，聚合物胶束具有良好的生物相容性，载药聚合物胶束表现出良好的靶向性和药物可控释放性能，对肝癌细胞的抑制作用强于游离DOX，对正常细胞的毒性较低，具有良好的治疗选择性。

Abstract: Firstly, using hepta(6-azido-6-deoxy)-β-cyclodextrin and butyl-3-ynyl-β-d-galactoside as the raw material, galactose-β-cyclodextrin (Gal₇-CD) with liver-targeting function was synthesized by Click reaction. Secondly, using cystamine dihydrochloride and octadecanoic acid as the raw material, cystamine octadecyl amide (NH₂-SS-SA) was obtained through amino protection, acylation reaction and deprotection reaction. Next, adamantyl polyethylene glycol amine (Ad-PEG₁₀₀₀-NH₂) was synthesized by using the acylation reaction of adamantanecarboxylic acid and amino polyethylene glycol, and then, which reacted with succinic anhydride to obtain adamantyl polyethylene glycol succinic acid (Ad-PEG₁₀₀₀-COOH). Then NH₂-SS-SA reacted with Ad-PEG₁₀₀₀-COOH to obtain adamantyl polyethylene glycol amine octadecanamide (Ad-PEG₁₀₀₀-SS-C₁₈). Finally, using dialysis method, Gal₇-CD and Ad-PEG₁₀₀₀-SS-C₁₈ self-assembled to form amphiphilic polymer through host-guest self-assembly, and then form polymer micelle (Gal₇-SS-C₁₈). Doxorubicin (DOX) was then used as a model drug to incorporate into Gal₇-SS-C₁₈ micelles. The particle size of polymer micelles and drug-loaded polymer micelles were determined by dynamic light scattering (DLS) to be (169.2±1.3) nm and (177.9±3.0) nm, respectively. The drug-loading capacity of the drug-loaded polymer micelles was measured by UV-Vis spectrophotometer to be (21.2±0.7)% and the encapsulation efficiency was (71.1±0.5)%. In the in vitro release experiment, the cumulative release of drug-loaded polymer micelles was lower in the simulated normal physiological environment of PBS, while the cumulative DOX release reached 82.38% within 48 h in the simulated tumor reduction microenvironment of PBS. The cytotoxicity and antitumor activity of polymer micelles were evaluated by using liver cancer cells (HepG2) and normal tissue cells (HEK-293) as cell models. The research results show that the polymer micelles have good biocompatibility. The drug-loaded polymer micelles show good targeting and controllable release properties, which have better tumor inhibition ability than free DOX.

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