Bioreducible Polymeric Nanoparticles Containing Multiplexed Cancer Stem Cell Regulating miRNAs Inhibit Glioblastoma Growth and Prolong Survival.
Bioreducible Polymeric Nanoparticles Containing Multiplexed Cancer Stem Cell Regulating miRNAs Inhibit Glioblastoma Growth and Prolong Survival.
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DOI：
10.1021/acs.nanolett.8b00390
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发表时间：
2018-07-11
期刊：
影响因子：
10.8
通讯作者：
Green JJ
中科院分区：
文献类型：
--
作者：
Lopez-Bertoni H;Kozielski KL;Rui Y;Lal B;Vaughan H;Wilson DR;Mihelson N;Eberhart CG;Laterra J;Green JJ
尽管我们对胶质母细胞瘤（GBM）的分子认识不断增加，但治疗方式仍然有限。细胞命运调控机制和纳米医学的最新发展为通过分子治疗药物的递送来治疗和管理脑肿瘤提供了新的途径。在这里，我们已经开发了生物可还原的聚（β-氨基酯）纳米颗粒，其表现出高细胞内递送功效、低细胞毒性、从内体逃逸以及促进细胞溶质靶向的环境触发的货物释放，用于将miRNA递送至肿瘤增殖的人类癌症干细胞。在这份报告中，我们将这种纳米生物技术与新发现的癌症干细胞抑制miRNA相结合，开发了自组装的含miRNA的聚合物纳米颗粒（nano-miRs）来治疗胶质瘤。我们表明，这些纳米miR有效地在细胞内递送单个和组合miRNA模拟物，其在体外抑制人GBM细胞的干细胞表型。在直接肿瘤内输注后，发现这些纳米miR分布在整个肿瘤中，抑制已建立的原位人GBM异种移植物的生长，并协同增强对标准护理γ辐射的应答。在生物可还原的纳米-miR颗粒内共递送两种miRNA，miR-148 a和miR-296- 5 p，使得能够在小鼠中从GBM长期存活。
Despite our growing molecular understanding of glioblastoma (GBM), treatment modalities remain limited. Recent developments in mechanisms of cell fate regulation and nanomedicine provide new avenues to treat and manage brain tumors via delivery of molecular therapeutics. Here we have developed bioreducible poly(beta-amino ester) nanoparticles that demonstrate high intracellular delivery efficacy, low cytotoxicity, escape from endosomes, and promotion of cytosol-targeted environmentally-triggered cargo release for miRNA delivery to tumor-propagating human cancer stem cells. In this report, we combined this nanobiotechnology with newly discovered cancer stem cell inhibiting miRNAs to develop self-assembled miRNA-containing polymeric nanoparticles (nano-miRs) to treat gliomas. We show that these nano-miRs effectively intracellularly deliver single and combination miRNA mimics that inhibit the stem cell phenotype of human GBM cells in vitro. Following direct intratumoral infusion, these nano-miRs were found to distribute through the tumors, inhibit the growth of established orthotopic human GBM xenografts, and cooperatively enhance response to standard-of-care γ–radiation. Co-delivery of two miRNAs, miR-148a and miR-296-5p, within the bioreducible nano-miR particles enabled long-term survival from GBM in mice.
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影响因子：
25
作者：
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