Integrated Combination Treatment Using a "Smart" Chemotherapy and MicroRNA Delivery System Improves Outcomes in an Orthotopic Colorectal Cancer Model
Integrated Combination Treatment Using a "Smart" Chemotherapy and MicroRNA Delivery System Improves Outcomes in an Orthotopic Colorectal Cancer Model
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使用“智能”化疗和 MicroRNA 递送系统的综合联合治疗可改善原位结直肠癌模型的结果
DOI：
10.1002/adfm.201801118
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发表时间：
2018-07-11
影响因子：
19
通讯作者：
Fang, Chao
中科院分区：
文献类型：
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作者：
Liu, Hai-Jun;Luan, Xin;Fang, Chao
介孔二氧化硅纳米粒子 (MSN) 可以负载和递送潜在的协同抗癌药物，例如小分子细胞毒素（如阿霉素、DOX）和核酸（如 microRNA、miRNA）。然而，这些货物具有不同的基本化学性质，因此克服各自的细胞内递送障碍是一个关键考虑因素。从 MSN 传递 DOX 的策略经常采用 pH 驱动的机制，这些机制仅限于溶酶体的酸性环境。相反，递送 miRNA 的策略利用故意损害溶酶体膜完整性的方法，以实现有效负载的胞质递送。为了协调这两种需求（DOX 的溶酶体递送和 miRNA 的细胞内递送），开发了一种新方法，通过二硫键在 MSN 表面“编织”聚乙烯亚胺，以实现化疗 (DOX) 和 miRNA 治疗（使用 miRNA-145）的卓越递送。此外，还开发了一种基于对葡萄糖调节蛋白 78（GRP78）（一种在结直肠癌中过度表达的细胞表面蛋白）具有亲和力的肽配体的主动靶向策略。主动靶向方法可在结直肠癌原位小鼠模型中增强体外和体内的协同抗肿瘤作用。总而言之，这项工作展示了“智能”MSN 递送系统将抗癌药物适当递送至目标癌细胞的能力和优势。
Mesoporous silica nanoparticles (MSN) can load and deliver potentially synergistic anticancer agents such as small molecule cytotoxics (like doxorubicin, DOX) and nucleic acids (like microRNA, miRNA). However, these cargos have different underlying chemical properties so overcoming respective intracellular delivery barriers is a key consideration. Strategies to deliver DOX from MSN frequently employ pH-driven mechanisms that are restricted to the acidic environment of lysosomes. Conversely, strategies to deliver miRNA make use of approaches that deliberately compromise lysosomal membrane integrity to enable cytosolic delivery of the payload. To reconcile these two needs (lysosomal delivery of DOX and intracellular delivery of miRNA), a new methodology by "weaving" polyethylenimine on the MSN surface through disulfide bonds to achieve superior delivery of chemotherapy (DOX) and miRNA therapy (using miRNA-145) is developed. Furthermore, an active targeting strategy based on a peptide ligand with affinity to glucose-regulated protein 78 (GRP78), a cell surface protein overexpressed in colorectal carcinoma, is developed. The active targeting approach results in enhanced synergistic antitumor effect both in vitro and in vivo in an orthotopic murine model of colorectal cancer. Taken together, this work demonstrates the capability and advantages of "smart" MSN delivery systems to deliver anticancer cargo appropriately to targeted cancer cells.