Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy
Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy
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DOI：
10.1016/j.biomaterials.2016.07.036
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发表时间：
2016-10-01
期刊：
影响因子：
14
通讯作者：
Haam, Seungjoo
中科院分区：
文献类型：
--
作者：
Jang, Eunji;Kim, Eunjung;Haam, Seungjoo
癌症干细胞（CSC）假说假定过表达CD 44的癌细胞被标记为引起肿瘤发生和复发的CSC。这一假设表明，CD 44是一个潜在的治疗靶点，可以干扰CSC的质量。MicroRNA-34 a（miR-34 a）是基于CD 44抑制的癌症治疗的有希望的候选物，因为已经报道其抑制CD 44阳性CSC 5的增殖、转移和存活。在这里，我们使用含有PLI/miR复合物（NVs/miR）的纳米囊泡来全身递送miR-34 a并在裸鼠原位和皮下植入的肿瘤中诱导miR-34 a触发的CD 44抑制。聚（L-赖氨酸-接枝-咪唑）（PLI）缩合miR，并且在功能上被修饰以通过咪唑残基在内体pH下的缓冲作用将miR递送至作用位点。事实上，由包封PLI/miR复合物的PEG化脂质组成的NV/miR通过补偿其表面电荷而大大降低了聚阳离子的不可避免的毒性，并且与PLI/miR复合物相比，显著改善了其体内稳定性和对肿瘤组织的积累。我们的NV介导的miR-3/4a递送系统特异性地增加内源性靶miR水平，从而通过抑制CD 44的表达并降低Bcl-2、Oct 3/4和Nanog基因的水平来减弱胃癌细胞的增殖和迁移。我们的策略导致了比基于顺铂的递送更好的治疗结果，具有高度选择性的肿瘤细胞死亡，并显著延迟了CD 44阳性荷瘤小鼠模型中的肿瘤生长，从而为CSC 5提供了基本的治疗窗口。(C)2016爱思唯尔有限公司版权所有
The cancer stem cell (CSC) hypothesis postulates that cancer cells overexpressing CD44 are marked as CSCs that cause tumorigenesis and recurrence. This hypothesis suggests that CD44 is a potential therapeutic target that can interfere with CSCs qualities. MicroRNA-34a (miR-34a) is a promising candidate for CD44 repression-based cancer therapy as it has been reported to inhibit proliferation, metastasis, and survival of CD44-positive CSC5. Here, we used nanovesicles containing PLI/miR complexes (NVs/miR) to systemically deliver miR-34a and induce miR-34a-triggered CD44 suppression in orthotopically and subcutaneously implanted tumors in nude mice. Poly(L-lysine-graft-imidazole) (PLI) condenses miRs and is functionally modified to deliver miRs to the site of action by buffering effect of imidazole residues under endosomal pH. Indeed, NVs/miR consisting of PEGylated lipids enveloping PLI/miR complexes greatly reduced inevitable toxicity of polycations by compensating their surface charge and markedly improved their in vivo stability and accumulation to tumor tissue compared to PLI/miR polyplexes. Our NVs-mediated miR-34a delivery system specifically increased endogenous target miR levels, thereby attenuating proliferation and migration of gastric cancer cells by repressing the expression of CD44 with decreased levels of Bcl-2, Oct 3/4 and Nanog genes. Our strategy led to a greater therapeutic outcome than PLI-based delivery with highly selective tumor cell death and significantly delayed tumor growth in CD44-positive tumor-bearing mouse models, thus providing a fundamental therapeutic window for CSC5. (C) 2016 Elsevier Ltd. All rights reserved.