Phenylboronic acid-functionalized polyamidoamine-mediated Bcl-2 siRNA delivery for inhibiting the cell proliferation.
Phenylboronic acid-functionalized polyamidoamine-mediated Bcl-2 siRNA delivery for inhibiting the cell proliferation.
复制标题
DOI：
10.1016/j.colsurfb.2016.06.034
复制
发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Di Wu;Jiebing Yang;Zhen Xing;Haobo Han;Tingting Wang;Aijun Zhang;Yan Yang;Quanshun Li
中科院分区：
文献类型：
--
作者：
Di Wu;Jiebing Yang;Zhen Xing;Haobo Han;Tingting Wang;Aijun Zhang;Yan Yang;Quanshun Li
本研究采用异双功能交联剂NHS-PEG 5 k-Mal，将端氨基聚酰胺胺（PAMAM）与苯硼酸（PBA）偶联，制备了一种新型的肿瘤靶向基因载体PBA功能化的PAMAM（PPP），该载体具有良好的siRNA缩合能力，并能保护siRNA不被RNase和血清降解。激光共聚焦显微镜和流式细胞仪检测结果表明，PBA的引入可促进Bcl-2 siRNA的细胞摄取和进一步转染。同时，PPP介导的Bcl-2 siRNA转染能显著抑制Bcl-2基因在mRNA和蛋白水平的表达。此外，PPP/siRNA通过敲低Bcl-2的表达，诱导细胞凋亡，抑制细胞增殖，并通过抑制肿瘤细胞对化疗药物的耐药性，增强阿霉素的抗肿瘤作用。结论：PPP介导的Bcl-2 siRNA递送有望成为解决肿瘤耐药性的有效平台，并进一步实现肿瘤化疗和基因治疗的联合应用。
In this study, the conjugation of phenylboronic acid (PBA) to amine-terminated polyamidoamine (PAMAM) was successfully conducted to prepare a tumor-targeted gene carrier PBA-functionalized PAMAM (PPP) for Bcl-2 siRNA delivery, using a heterobifunctional crosslinker NHS-PEG5k-Mal. The carrier possessed favorable capacity for siRNA condensation and could protect siRNA from the degradation against RNase and serum. The introduction of PBA could facilitate the cellular uptake and further transfection of Bcl-2 siRNA demonstrated by confocal laser scanning microscopy and flow cytometry. Meanwhile, PPP-mediated transfection of Bcl-2 siRNA could significantly inhibit the expression of Bcl-2 gene at both mRNA and protein levels. Furthermore, owing to the knock-down of Bcl-2, PPP/siRNA could significantly inhibit the cell proliferation by inducing the cell apoptosis, and also enhance the antitumor efficiency of doxorubicin by suppressing the resistance of tumor cells to chemotherapeutics. In conclusion, the PPP-mediated Bcl-2 siRNA delivery could potentially be an effective platform for solving the drug resistance and further achieving the combined chemotherapy and gene therapy in tumor treatment.