MOE Key Laboratory of Materials Physics and Chemistry in Extraordinary Condition, Shaanxi Key Laboratory of Macromolecular Science and Technology, School of Science, Northwestern Polytechnical University, Xi'an, 710072, P. R. China.
PLA No. 323 Hospital, Xi'an, Shaanxi Province, 710054, P. R. China.
Chem Asian J. 2018 Apr 16;13(8):939-943. doi: 10.1002/asia.201701697. Epub 2018 Mar 24.
Amphiphilic hyperbranched polyprodrugs (DOX-S-S-PEG) with drug repeat units in hydrophobic core linked by disulfide bonds were developed as drug self-delivery systems for cancer therapy. The hydroxyl groups and the amine group in doxorubicin (DOX) were linked by 3,3'-dithiodipropanoic acid as hydrophobic hyperbranched cores, then amino-terminated polyethylene glycol monomethyl ether (mPEG-NH ) as hydrophilic shell was linked to hydrophobic cores to form amphiphilic and glutathione (GSH)-responsive micelle of hyperbranched polyprodrugs. The amphiphilic micelles can be disrupted under GSH (1 mg mL ) circumstance. Cell viability of A549 cells and 293T cells was evaluated by CCK-8 and Muse Annexin V & Dead Cell Kit. The disrupted polyprodrugs maintained drug activity for killing tumor cells. Meanwhile, the undisrupted polyprodrugs possessed low cytotoxicity to normal cells. The cell uptake experiments showed that the micelles of DOX-S-S-PEG were taken up by A549 cells and distributed to cell nuclei. Thus, the drug self-delivery systems with drug repeat units in hydrophobic cores linked by disulfide bonds showed significant special advantages: 1) facile one-pot synthesis; 2) completely without toxic or non-degradable polymers; 3) DOX itself functions as fluorescent labeled molecule and self-delivery carrier; 4) drug with inactive form in hyperbranched cores and low cytotoxicity to normal cells. These advantages make them excellent drug self-delivery systems for potential high efficient cancer therapy.
具有疏水核中药物重复单元通过二硫键连接的两亲性超支化多前药（DOX-S-S-PEG）被开发为癌症治疗的药物自递送系统。阿霉素（DOX）中的羟基和氨基通过 3,3'-二硫代二丙酸连接作为疏水超支化核心，然后连接亲水壳氨基封端的聚乙二醇单甲醚（mPEG-NH ）到疏水核上形成两亲性和谷胱甘肽（GSH）响应的超支化多前药胶束。在 GSH（1mg/mL）的情况下，两亲胶束可以被破坏。通过 CCK-8 和 Muse Annexin V & Dead Cell Kit 评估 A549 细胞和 293T 细胞的细胞活力。破坏的多前药保持杀死肿瘤细胞的药物活性。同时，未破坏的多前药对正常细胞的细胞毒性低。细胞摄取实验表明，DOX-S-S-PEG 的胶束被 A549 细胞摄取并分布到细胞核中。因此，具有疏水核中药物重复单元通过二硫键连接的药物自递送系统具有显著的特殊优势：1）易于一锅合成；2）完全没有毒性或不可降解的聚合物；3）DOX 本身作为荧光标记分子和自递送载体；4）在超支化核心中具有非活性形式的药物，对正常细胞的细胞毒性低。这些优势使它们成为具有潜在高效癌症治疗的优秀药物自递送系统。
