Liu Jie, He Jinlin, Zhang Mingzu, Xu Guoqiang, Ni Peihong
College of Chemistry, Chemical Engineering and Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, Soochow University, Suzhou 215123, P. R. China.
J Mater Chem B. 2018 May 28;6(20):3262-3273. doi: 10.1039/c8tb00746b. Epub 2018 May 2.
Lung cancer is one of the most frequently occurring cancers worldwide and its pathological complexity necessitates combination therapies of various therapeutic elements such as anti-cancer drugs and genes to achieve synergistic treatment. In this study, we designed a co-delivery carrier of the anti-cancer drug doxorubicin (DOX) and the tumor suppressor gene p53 for lung cancer treatment. First, a copolymer precursor (mPEG-b-PBYP) was prepared via ring-opening polymerization of 2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane (BYP). Subsequently, on the basis of the precursor, a pH-sensitive prodrug (abbreviated as mPEG-b-PBYP-hyd-DOX) and a polycation gene vector (abbreviated as mPEG-b-PBYP-g-DAE) were separately prepared via CuAAC and thiol-yne "click" chemistry, wherein DAE represents 2-dimethylaminoethanethiol hydrochloride. After that, the prodrug and the gene vector copolymers were mixed in an aqueous solution in order to self-assemble into hybrid micelles, which could then condense the p53 gene and finally form DOX prodrug/p53 co-loaded nanoparticles. The average particle size and morphologies of the hybrid micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The gel retardation assay showed that the p53 gene could be well immobilized and maintained stably under the electronegative conditions, similar to those in the blood circulation. A cytotoxicity assay showed the obvious antitumor effect of the hybrid micelle/p53 gene nanoparticles on A549 and H1299 cells when compared to drug or gene therapy applied alone, respectively. Furthermore, the results from the live cell imaging system revealed that the hybrid micelle/p53 gene nanoparticles could effectively deliver and release DOX and the p53 genes into A549 cells. All of the results showed that the hybrid micelles containing the DOX prodrug and p53 genes could be widely used in the treatment of lung cancer.
肺癌是全球最常见的癌症之一，其病理复杂性需要多种治疗元素（如抗癌药物和基因）联合治疗以实现协同治疗。在本研究中，我们设计了一种用于肺癌治疗的抗癌药物阿霉素（DOX）和肿瘤抑制基因p53的共递送载体。首先，通过2-(丁-3-炔-1-基氧基)-2-氧代-1,3,2-二氧磷杂环戊烷（BYP）的开环聚合制备了一种共聚物前体（mPEG-b-PBYP）。随后，在前体的基础上，通过铜催化的叠氮-炔环加成反应（CuAAC）和硫醇-炔“点击”化学分别制备了一种pH敏感前药（简称为mPEG-b-PBYP-hyd-DOX）和一种聚阳离子基因载体（简称为mPEG-b-PBYP-g-DAE），其中DAE代表2-二甲基氨基乙硫醇盐酸盐。之后，将前药和基因载体共聚物在水溶液中混合以自组装成混合胶束，然后混合胶束可以浓缩p53基因并最终形成DOX前药/p53共负载纳米颗粒。分别通过动态光散射（DLS）和透射电子显微镜（TEM）测量混合胶束的平均粒径和形态。凝胶阻滞试验表明，p53基因可以在类似于血液循环中的电负性条件下很好地固定并稳定维持。细胞毒性试验表明，与单独应用药物或基因治疗相比，混合胶束/p53基因纳米颗粒对A549和H1299细胞具有明显的抗肿瘤作用。此外，活细胞成像系统的结果表明，混合胶束/p53基因纳米颗粒可以有效地将DOX和p53基因递送至A549细胞并释放。所有结果表明，含有DOX前药和p53基因的混合胶束可广泛用于肺癌治疗。
