Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine.
Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine.
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DOI：
10.1016/j.biomaterials.2015.05.027
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发表时间：
2015-08
期刊：
影响因子：
14
通讯作者：
Bing-Feng Zhang;Lei Xing;Peng-Fei Cui;Feng-zhen Wang;Rongrong Xie;Jia-Liang Zhang;Mei Zhang;
中科院分区：
文献类型：
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作者：
Bing-Feng Zhang;Lei Xing;Peng-Fei Cui;Feng-zhen Wang;Rongrong Xie;Jia-Liang Zhang;Mei Zhang;
由于线粒体中存在细胞自杀武器，因此线粒体介导的细胞凋亡途径是癌症治疗的有效选择。然而，在许多恶性肿瘤的线粒体中过表达的抗凋亡蛋白，如Bcl-2蛋白，可以使癌细胞逃避凋亡，大大降低这种类型的化疗的疗效。在这里，我们构建了一个分级靶向递送系统，可以将siRNA和化疗药物依次递送到肿瘤细胞和线粒体。具体地说，通过将靶向靶向配体三苯基膦（TPP）和治疗药物氯尼达明（LND）在壳聚糖接枝PEI（CP）中偶联到聚乙烯亚胺上，然后与siRNA复合，合成共聚物TPP-CP-LND（TCPL）。然后将复合物用聚（丙烯酸）-聚乙二醇-叶酸（PPF）共聚物包覆以形成分级靶向共递送系统（TCPL/siRNA/PPF NPs）。TCPL/siRNA/PPF NP具有中性表面电荷，在血浆中稳定，并表现出pH响应性壳分离。值得注意的是，TCPL/siRNA/PPF NP在FA引导的内化后同时将siBcl-2释放到细胞质中并将LND递送到同一癌细胞中的线粒体中，甚至协同激活线粒体凋亡途径。这项工作证明了RNA干扰和靶向化疗药物协同刺激线粒体凋亡途径用于癌症治疗的潜力。
The mitochondria-mediated apoptosis pathway is an effective option for cancer therapy due to the presence of cell-suicide weapons in mitochondria. However, anti-apoptotic proteins that are over-expressed in the mitochondria of many malignant tumors, such as Bcl-2 protein, could allow the cancer cells to evade apoptosis, greatly reducing the efficacy of this type of chemotherapy. Here, we constructed a hierarchical targeted delivery system that can deliver siRNA and chemotherapeutic agents sequentially to tumor cells and mitochondria. In detail, the copolymer TPP-CP-LND (TCPL) was synthesized by the mitochondria-targeting ligand triphenylphosphine (TPP) and therapeutic drug lonidamine (LND) conjugated to the polyethyleneimine in chitosan-graft-PEI (CP), and then complexed with siRNA. Followed, the complexes were coated with poly(acrylic acid)-polyethylene glycol-folic acid (PPF) copolymer to form a hierarchical targeted co-delivery system (TCPL/siRNA/PPF NPs). The TCPL/siRNA/PPF NPs had a neutral surface charge, were stable in plasma and exhibited pH-responsive shell separation. Remarkably, the TCPL/siRNA/PPF NPs simultaneously released siBcl-2 into the cytoplasm and delivered LND to mitochondria in the same cancer cell after FA-directed internalization, and even synergistically activated mitochondria apoptosis pathway. This work demonstrated the potential of RNA-interference and mitochondria-targeted chemotherapeutics to collaboratively stimulate the mitochondria apoptosis pathway for cancer therapy.