A GSH-Responsive Nanoprodrug System Based on Self-Assembly of Lactose Modified Camptothecin for Targeted Drug Delivery and Combination Chemotherapy
A GSH-Responsive Nanoprodrug System Based on Self-Assembly of Lactose Modified Camptothecin for Targeted Drug Delivery and Combination Chemotherapy
复制标题
基于乳糖修饰喜树碱自组装的 GSH 响应纳米前药系统，用于靶向药物递送和联合化疗
DOI：
10.2147/ijn.s276470
复制
发表时间：
2020-12-22
影响因子：
8
通讯作者：
Pei Z
中科院分区：
文献类型：
--
作者：
Hou C;Ma N;Shen Z;Chi G;Chao S;Pei Y;Chen L;Lu Y;Pei Z
背景传统的小分子抗肿瘤药物化疗存在水溶性差、毒性大、缺乏特异性等缺点。然而，通过共价修饰抗癌药物构建的前药可以克服这些限制，能够在进入肿瘤组织后通过特异性刺激反应释放其活性形式。方法通过自组装两亲性乳糖修饰喜树碱前药分子（Lac-SS-CPT），构建GSH响应性糖基纳米前药系统，用于靶向给药和联合治疗。结果以HL 7702细胞为实验模型，Lac-SS-CPT在10-30 μmol/L浓度范围内作用48 h，对HL 7702细胞有明显的细胞毒作用。值得注意的是，与游离CPT相比，Lac-SS-CPT对HL 7702细胞的细胞活力更高，这表明Lac-SS-CPT可以减少副作用。同时，我们评估了盐酸阿霉素（DOX）负载的Lac-SS-CPT糖纳米前药系统（Lac-SS-CPT@DOX）的抗癌效率，其中Lac-SS-CPT@DOX和游离DOX分别与HpeG 2细胞和HL 7702细胞孵育24、48和72小时。结果表明，Lac-SS-CPT@DOX微囊化抗癌药物（DOX）可降低DOX对HL 7702细胞的毒副作用，提高DOX的抗癌效率。更重要的是，CPT和DOX在存在较高GSH浓度的HepG 2细胞中从Lac-SS-CPT@DOX释放。此外，评价了联合治疗效率，其中游离DOX和Lac-SS-CPT@DOX分别与DOX抗性HepG 2细胞（HepG 2-ADR细胞）孵育。结论Lac-SS-CPT@DOX可增强DOX对HepG 2-ADR细胞的杀伤作用，为设计新型纳米前药系统提供了新的思路。
Background Conventional chemotherapy using small molecular antitumor drugs suffers from several limitations, for instance poor water solubility, high toxicity, and lack of specificity. However, prodrugs constructed by covalent modification of anticancer drugs can overcome these limitations, which are able to release its active form after entering the tumor tissues by specific stimulus response. Methods A GSH-responsive glyco-nanoprodrug system has been constructed by self-assembled of amphiphilic lactosemodified camptothecin prodrug molecular (Lac-SS-CPT) for targeting drug delivery and combination therapy. Results Using HL7702 cells as experimental models, the cytotoxic effects of Lac-SS-CPT were investigated to 10–30 µmol/L for 48 hours. Notably, the cell viability of Lac-SS-CPT to HL7702 cells was higher compared with free CPT which indicated that Lac-SS-CPT can reduce side-effects. Simultaneously, we have evaluated the anticancer efficiency of doxorubicin hydrochloride (DOX)-loaded Lac-SS-CPT glyco-nanoprodrug system (Lac-SS-CPT@DOX), where Lac-SS-CPT@DOX and free DOX incubated with HpeG2 cells and HL7702 cells for 24, 48, and 72 hours, respectively. It turned out that Lac-SS-CPT@DOX encapsulated anticancer drug (DOX) could decrease DOX side-effect on HL7702 cells and increase DOX anticancer efficiency. More importantly, the CPT and DOX were released from Lac-SS-CPT@DOX in HepG2 cells where a higher GSH concentration exists. Moreover, combination therapy efficiency was evaluated, where free DOX and Lac-SS-CPT@DOX incubated with DOX-resistance HepG2 cells (HepG2-ADR cells), respectively. Conclusion The results revealed that the Lac-SS-CPT@DOX could enhance the cytotoxicity of DOX for HepG2-ADR cells and provided a new idea for designing an advanced nano-prodrug system toward combination therapy.