Polyamino Acid Layer-by-Layer (LbL) Constructed Silica-Supported Mesoporous Titania Nanocarriers for Stimuli-Responsive Delivery of microRNA 708 and Paclitaxel for Combined Chemotherapy
Polyamino Acid Layer-by-Layer (LbL) Constructed Silica-Supported Mesoporous Titania Nanocarriers for Stimuli-Responsive Delivery of microRNA 708 and Paclitaxel for Combined Chemotherapy
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DOI：
10.1021/acsami.8b06642
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发表时间：
2018-07-25
影响因子：
9.5
通讯作者：
Kim, Jong Oh
中科院分区：
文献类型：
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作者：
Gupta, Biki;Ruttala, Hima Bindu;Kim, Jong Oh
细胞Fas相关蛋白具有死亡结构域样白介素1β转换酶抑制蛋白(c-flIP)，常在多种肿瘤中强表达，在抑制肿瘤细胞凋亡和诱导化疗耐药中发挥关键作用。一种结合化疗和抑制c-flip水平的综合方法可能被证明在治疗c-fllip过表达的癌症中至关重要。在这项研究中，我们利用二氧化硅支撑的介孔二氧化钛纳米颗粒(MTNst)的聚合物逐层组装(LBL)来共传递紫杉醇(PTX)和microRNA708(MiR708)，用于同时进行化疗和c-flip抑制。LBLmiR708/PTX-MTNst对HCT-116和DLD-1结直肠癌细胞的杀伤作用呈剂量依赖性，明显优于游离PTX或LBLPTX-MTNst。LBLmiR708/PTX-MTNst强烈抑制c-flip的表达，并导致促凋亡蛋白的表达增加。在DLD-1移植瘤小鼠中，纳米粒在肿瘤内积聚，导致显著的肿瘤消退，其中载PTX和miR708纳米粒的抑制作用明显强于游离的PTX或PTX载纳米粒。对肿瘤的免疫组织化学分析进一步证实了纳米颗粒显著的凋亡和抗增殖作用，而器官组织学则加强了该系统的生物相容性。因此，LBLmiR708/PTX-MTNst系统，由于其能够将化疗药物和抑制miRNA输送到肿瘤部位，在临床治疗结直肠癌方面显示出巨大的潜力。
Cellular Fas-associated protein with death domain-like interleukin-1 beta-converting enzyme-inhibitory protein (c-FLIP), often strongly expressed in numerous cancers, plays a pivotal role in thwarting apoptosis and inducing chemotherapy resistance in cancer. An integrated approach combining chemotherapy with suppression of c-FLIP levels could prove paramount in the treatment of cancers with c-FLIP overexpression. In this study, we utilized a polymeric layer-by-layer (LbL) assembly of silica-supported mesoporous titania nanoparticles (MTNst) to co-deliver paclitaxel (PTX) and microRNA 708 (miR708) for simultaneous chemotherapy and c-FLIP suppression in colorectal carcinoma. The resulting LbL miR708/PTX-MTNst showed dose-dependent cytotoxicity in HCT-116 and DLD-1 colorectal carcinoma cell lines, which was remarkably superior to that of free PTX or LbL PTX-MTNst. LbL miR708/PTX-MTNst strongly inhibited c-FLIP expression and resulted in increased expression of proapoptotic proteins. In DLD-1 xenograft tumor-bearing mice, the nanoparticles accumulated in the tumor, resulting in remarkable tumor regression, with the PTX and miR708-loaded nanoparticles showing significantly greater inhibitory effects than the free PTX or PTX-loaded nanoparticles. Immunohistochemical analyses of the tumors further confirmed the remarkable apoptotic and antiproliferative effects of the nanoparticles, whereas organ histology reinforced the biocompatibility of the system. Therefore, the LbL miR708/PTX-MTNst system, owing to its ability to deliver both chemotherapeutic drug and inhibitory miRNA to the tumor site, shows great potential to treat colorectal carcinoma in clinical settings.