具有钾离子和谷胱甘肽双重响应特性的树状大分子药物载体的制备与控释性能
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国家自然科学基金资助项目(22078202,21991101)


Preparation and Controlled-Release Properties of Potassium Ion and Glutathione Dual Responsive Dendrimers
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    摘要:

    文中制备了一种具有钾离子(K+)和谷胱甘肽(GSH)双重响应性的树状大分子作为抗癌药物纳米载体。将具有K+响应性的聚(N-异丙基丙烯酰胺-共聚-苯并-18-冠-6-丙烯酰胺)高分子(PNB)和末端带叶酸(FA)的聚乙二醇高分子(FA-PEG-SH)先后接枝到聚酰胺-胺树状大分子(PAMAM)表面,制备得到多功能树状大分子PAMAM-g-PNB-ss-PEG-FA。该树状大分子具有明显的K+响应性,37 ℃下表现出K+诱导的分子构象转变,在K+浓度5 mmol/L的溶液中呈现收缩状态,在K+浓度150 mmol/L的溶液中呈现伸展状态。同时,PAMAM-g-PNB-ss-PEG-FA还具有明显的还原响应性,当从低浓度GSH溶液转换到高浓度GSH溶液时,二硫键断裂,PAMAM-g-PNB-ss-PEG-FA粒径显著减小。以疏水抗肿瘤药阿霉素(DOX)为模型药物,PAMAM-g-PNB-ss-PEG-FA树状大分子表现出明显的高浓度K+和GSH诱导的释药行为。并且,PAMAM-g-PNB-ss-PEG-FA在一定浓度范围内对正常细胞及肿瘤细胞均无明显毒性。体外细胞实验证实,负载DOX的PAMAM-g-PNB-ss-PEG-FA能够被4T1细胞摄取,并且在肿瘤细胞内能响应胞内高浓度K+和GSH而实现药物快速释放。

    Abstract:

    A kind of potassium ion (K+) and glutathione (GSH) dual responsive dendrimers was constructed as anticancer drug carrier. K+-responsive poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide) (PNB) and folate-polyethylene glycol (FA-PEG-SH) were successively grafted to the polyamide dendrimers PAMAM to prepare the multi-functional PAMAM-g-PNB-ss-PEG-FA dendrimers. The obtained dendrimers have obvious K+-responsive properties, which show the K+-induced isothermal contraction-to-extension molecular conformation transition at 37 ℃. Moreover, PAMAM-g-PNB-ss-PEG-FA also shows GSH-responsive properties. When transferred from solution with low GSH concentration to solution with high GSH concentration, the dendrimer size decreases by 50% due to disulfide bond breaking. The PAMAM-g-PNB-ss-PEG-FA dendrimers exhibit obvious high-K+-induced and high-GSH-induced rapid drug release behavior. In a certain concentration range, the prepared dendrimers have no obvious toxicity to normal cells and tumor cells. The in vitro cell experiments confirm that DOX-loaded dendrimers could be taken up by 4T1 cells, and the dendrimers could realize rapid drug release in response to high K+ and GSH concentrations in tumor cells.

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张 璐, 刘玉琼, 巨晓洁, 谢 锐, 汪 伟, 刘 壮, 褚良银.具有钾离子和谷胱甘肽双重响应特性的树状大分子药物载体的制备与控释性能[J].高分子材料科学与工程,2022,38(2):131-139.

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