Cellular Fas-associated protein with death domain-like interleukin-1β-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.

中文翻译：

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聚氨基酸层（LbL）构造的二氧化硅支持的介孔二氧化钛纳米载体的刺激响应传递的microRNA 708和紫杉醇的联合化学疗法。

细胞Fas相关蛋白与死亡域样白介素1β转换酶抑制蛋白（c-FLIP）经常在多种癌症中强烈表达，在阻止细胞凋亡和诱导癌症的化疗耐药性中起着关键作用。将化学疗法与抑制c-FLIP水平结合起来的综合方法可能在治疗c-FLIP过表达的癌症中被证明是至关重要的。在这项研究中，我们利用二氧化硅支持的中孔二氧化钛纳米颗粒（MTNst）的聚合物逐层组装（LbL）共同递送紫杉醇（PTX）和microRNA 708（miR708），以同时进行化疗和c-FLIP抑制大肠癌。所得的LbL miR708 / PTX-MTNst在HCT-116和DLD-1大肠癌细胞系中表现出剂量依赖性的细胞毒性，它明显优于免费的PTX或LbL PTX-MTNst。LbL miR708 / PTX-MTNst强烈抑制c-FLIP表达，并导致凋亡蛋白的表达增加。在带有DLD-1异种移植瘤的小鼠中，纳米粒子在肿瘤中积累，导致明显的肿瘤消退，其中载有PTX和miR708的纳米粒子比游离的PTX或载有PTX的纳米粒子表现出明显更大的抑制作用。肿瘤的免疫组织化学分析进一步证实了纳米颗粒具有显着的凋亡和抗增殖作用，而器官组织学则增强了该系统的生物相容性。因此，LbL miR708 / PTX-MTNst系统由于能够将化疗药物和抑制性miRNA传递到肿瘤部位，