High capacity nanoporous silicon carrier for systemic delivery of gene silencing therapeutics.
High capacity nanoporous silicon carrier for systemic delivery of gene silencing therapeutics.
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用于基因沉默治疗药物全身递送的高容量纳米多孔硅载体
DOI：
10.1021/nn4035316
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发表时间：
2013-11-26
期刊：
影响因子：
17.1
通讯作者：
Shen, Haifa
中科院分区：
文献类型：
--
作者：
Shen, Jianliang;Xu, Rong;Mai, Junhua;Kim, Han-Cheon;Guo, Xiaojing;Qin, Guoting;Yang, Yong;Wolfram, Joy;Mu, Chaofeng;Xia, Xiaojun;Gu, Jianhua;Liu, Xuewu;Mao, Zong-Wan;Ferrari, Mauro;Shen, Haifa
基因沉默剂如小干扰RNA（siRNA）和microRNA提供了调节几乎每个基因的表达以治疗包括癌症在内的人类疾病的希望。然而，缺乏用于有效全身递送至疾病器官的载体极大地限制了它们在体内的应用。在这项研究中，我们开发了一种高容量的聚阳离子功能化的纳米多孔硅（PCPS）平台，包括纳米多孔硅微粒功能化的甘氨酸-聚乙烯亚胺内的纳米孔的基因沉默剂的有效交付。MDA-MB-231人乳腺癌细胞与负载有STAT 3 siRNA（PCPS/STAT 3）或GRP 78 siRNA（PCPS/GRP 78）的PCPS孵育导致体外STAT 3和GRP 78基因表达降低91%和83%。用PCPS中的microRNA-18 a模拟物（PCPS/miR-18）处理细胞，可使microRNA-18 a靶基因ATM的表达降低90%。PCPS/STAT 3 siRNA在MDA-MB-231乳腺癌小鼠模型中的全身递送在肿瘤组织中富集颗粒并降低癌细胞中的STAT 3表达，导致残留肿瘤组织中的癌症干细胞显著减少。在治疗剂量下，PCPS/STAT 3 siRNA未引发FVB小鼠的急性免疫应答，包括血清细胞因子、趋化因子和集落刺激因子的变化。此外，基于体重、血液学、血液化学和主要器官组织学的变化，每周给药PCPS/STAT 3 siRNA持续四周未引起亚急性毒性的迹象。总的来说，结果表明，我们已经开发出一种安全的载体，有效地传递基因沉默剂。
Gene silencing agents such as small interfering RNA (siRNA) and microRNA offer the promise to modulate expression of almost every gene for the treatment of human diseases including cancer. However, lack of vehicles for effective systemic delivery to the disease organs has greatly limited their in vivo applications. In this study, we developed a high capacity polycation-functionalized nanoporous silicon (PCPS) platform comprised of nanoporous silicon microparticles functionalized with arginine-polyethyleneimine inside the nanopores for effective delivery of gene silencing agents. Incubation of MDA-MB-231 human breast cancer cells with PCPS loaded with STAT3 siRNA (PCPS/STAT3) or GRP78 siRNA (PCPS/GRP78) resulted in 91% and 83% reduction of STAT3 and GRP78 gene expression in vitro. Treatment of cells with a microRNA-18a mimic in PCPS (PCPS/miR-18) knocked down 90% expression of the microRNA-18a target gene ATM. Systemic delivery of PCPS/STAT3 siRNA in murine model of MDA-MB-231 breast cancer enriched particles in tumor tissues and reduced STAT3 expression in cancer cells, causing significant reduction of cancer stem cells in the residual tumor tissue. At the therapeutic dosage, PCPS/STAT3 siRNA did not trigger acute immune response in FVB mice, including changes in serum cytokines, chemokines and colony-stimulating factors. In addition, weekly dosing of PCPS/STAT3 siRNA for four weeks did not cause signs of sub-acute toxicity based on changes in body weight, hematology, blood chemistry, and major organ histology. Collectively, the results suggest that we have developed a safe vehicle for effective delivery of gene silencing agents.
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