pH-responsive complexes using prefunctionalized polymers for synchronous delivery of doxorubicin and siRNA to cancer cells
pH-responsive complexes using prefunctionalized polymers for synchronous delivery of doxorubicin and siRNA to cancer cells
复制标题
使用预功能化聚合物的 pH 响应复合物将阿霉素和 siRNA 同步递送至癌细胞
DOI：
10.1016/j.biomaterials.2013.03.018
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发表时间：
2013-07-01
期刊：
影响因子：
14
通讯作者：
Qi, Xian-Rong
中科院分区：
文献类型：
--
作者：
Dong, Da-Wen;Xiang, Bai;Qi, Xian-Rong
一种可以同时向肿瘤递送化疗药物和 siRNA 的纳米载体递送系统正在成为一种有前途的癌症治疗策略。在本研究中，通过一步组装预功能化聚合物：PEI-HZ-DOX (PHD) 和 PEI-PEG-Folate (PPF) 与 siRNA，开发了一种多功能 PHD/PPF/siRNA 复合物。 PHD 是 PEI（聚乙烯亚胺）与阿霉素 (DOX) 通过 pH 响应性腙连接形成的缀合物，可实现 pH 控制的药物释放。 PPF 是一种靶向肿瘤的叶酸配体，使用聚乙二醇 (PEG) 作为连接体与 PEI 缀合，可实现免疫逃避和细胞特异性靶向。预功能化的 PHD 和 PPF 以及自组装复合物在 siRNA 递送的进一步应用中显示出安全性优势。通过在纳米复合物配制过程中利用 PHD、PPF 和 siRNA 的不同三重比例，可以精确且可重复地改变叶酸表面密度、DOX 负载量和 siRNA 复合。研究表明，该复合物能够将 siRNA 和 DOX 递送至癌细胞，并通过酸触发方式在细胞中同步释放，即使用流式细胞术和共聚焦激光扫描显微镜分析腙键断裂和内体/溶酶体逃逸。结果凸显了使用 RT-PCR 和非侵入性体内成像系统在体外和体内进行治疗性基因沉默的潜力。 PHD/PPF/siRNA复合物通过纳米载体的EPR效应、pH触发的药物释放、叶酸介导的靶向递送以及DOX和siRNA的协同作用的组合，可以增加癌细胞中DOX和siRNA的积累，并减少正常组织中的非特异性分布。 (C) 2013 Elsevier Ltd. 保留所有权利。
A nanocarrier delivery system that can simultaneously deliver a chemotherapeutic drug and siRNA to the tumor is emerging as a promising treatment strategy for cancer treatment. In this study, a multifunctional PHD/PPF/siRNA complexes was developed by one-step assembly of prefunctionalized polymers: PEI-HZ-DOX (PHD) and PEI-PEG-Folate (PPF) with siRNA. The PHD, a conjugate of PEI (polyethylenimine) with doxorubicin (DOX) via a pH-responsive hydrazone linkage, enables pH-controlled drug release. The PPF, a tumor-targeting folate ligand conjugated to PEI using polyethyleneglycol (PEG) as a linker, enables immune evasion and cell-specific targeting. The prefunctionalized PHD and PPF as well as the self-assembly complexes reveals advantage on safety in further application for siRNA delivery. By exploiting distinct triple ratios of PHD, PPF and siRNA during nanocomplexes formulation, the folate surface density, DOX loading amount and siRNA complexation can be precisely and reproducibly changed. The studies showed that the complexes was capable of delivering siRNA and DOX to cancerous cells and release synchronously in cell by acid-triggered manner, i.e. hydrazone bond cleavage and endosome/lysosome escape using flow cytometry and confocal laser scanning microscopy analysis. The results highlight the potential for therapeutic gene silencing in vitro and in vivo using RT-PCR and non-invasive in vivo imaging systems. The PHD/PPF/siRNA complexes can increase DOX and siRNA accumulation in cancerous cells and decrease the nonspecific distribution in normal tissues by the combination of EPR effect of nanocarriers, pH-triggered drug release, folate-mediated targeted delivery, and synergistic action of DOX and siRNA. (C) 2013 Elsevier Ltd. All rights reserved.