Combinational siRNA delivery using hyaluronic acid modified amphiphilic polyplexes against cell cycle and phosphatase proteins to inhibit growth and migration of triple-negative breast cancer cells
Combinational siRNA delivery using hyaluronic acid modified amphiphilic polyplexes against cell cycle and phosphatase proteins to inhibit growth and migration of triple-negative breast cancer cells
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DOI：
10.1016/j.actbio.2017.11.036
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发表时间：
2018-01-15
影响因子：
9.7
通讯作者：
Uludag, Hasan
中科院分区：
文献类型：
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作者：
Parmar, Manoj B.;Sundaram, Daniel Nisakar Meenakshi;Uludag, Hasan
三阴性乳腺癌是一种侵袭性乳腺癌，如果在辅助化疗后复发，则几乎没有治疗选择。RNA干扰可能是转移性乳腺癌的替代疗法，其中小干扰RNA（siRNA）可以沉默对恶性细胞的生长和迁移至关重要的异常基因的表达。在这里，我们制定了一个siRNA的递送系统，使用脂质取代的聚乙烯亚胺（PEI）和透明质酸（HA），并表征了纳米颗粒递送系统的大小，zeta电位和细胞摄取。定制的PEI/HA制剂对siRNA的更高细胞摄取表明，由于载体和HA结合CD 44受体的改善的物理化学特性，复合物与乳腺癌细胞的相互作用更好。然后使用针对267种蛋白酪氨酸磷酸酶的文库筛选来鉴定针对抑制MDA-MB-231细胞迁移的特异性磷酸酶的siRNA，并进一步验证抑制细胞迁移的siRNA。然后，我们评估了针对CDC 20的siRNA减少细胞生长和针对几种磷酸酶的siRNA减少乳腺癌细胞迁移的组合递送。针对CDC 20和鉴定的磷酸酶PPP 1 R7、PTPN 1、PTPN 22、LHPP、PPP 1 R12 A和DUPD 1的组合siRNA疗法分别成功地抑制细胞生长和迁移，而不干扰共递送的siRNA的功能效应。所鉴定的磷酸酶可作为抑制高度侵袭性转移性乳腺癌细胞迁移的潜在靶点。组合siRNA交付对细胞周期和磷酸酶可能是一个有前途的战略，以抑制生长和迁移的转移性乳腺癌细胞，并可能其他类型的转移cancer.Statement的SignificanceThe手稿调查的疗效定制的聚合物siRNA交付系统的配方以及组合siRNA治疗转移性乳腺癌细胞，以抑制恶性细胞的生长和迁移。siRNA递送通过非病毒手段用PEI/HA进行。我们鉴定了六种磷酸酶，它们可能是抑制高度侵袭性转移性乳腺癌细胞迁移的关键靶点。我们进一步报告了特异性靶向细胞周期和磷酸酶蛋白，以同时减少恶性细胞的生长和迁移。临床基因治疗转移性乳腺癌的有效和安全的传递系统是迫切需要实现的潜力，分子医学在这种致命的疾病，我们的研究在这篇手稿的目的是促进这一奋进。(C)2017 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Triple-negative breast cancer is an aggressive form of breast cancer with few therapeutic options if it recurs after adjuvant chemotherapy. RNA interference could be an alternative therapy for metastatic breast cancer, where small interfering RNA (siRNA) can silence the expression of aberrant genes critical for growth and migration of malignant cells. Here, we formulated a siRNA delivery system using lipid substituted polyethylenimine (PEI) and hyaluronic acid (HA), and characterized the size, zeta-potential and cellular uptake of the nanoparticulate delivery system. Higher cellular uptake of siRNA by the tailored PEI/HA formulation suggested better interaction of complexes with breast cancer cells due to improved physicochemical characteristics of carrier and HA-binding CD44 receptors. The siRNAs against specific phosphatases that inhibited migration of MDA-MB-231 cells were then identified using library screen against 267 protein-tyrosine phosphatases, and siRNAs to inhibit cell migration were further validated. We then assessed the combinational delivery of a siRNA against CDC20 to decrease cell growth and a siRNA against several phosphatases shown to decrease migration of breast cancer cells. Combinational siRNA therapy against CDC20 and identified phosphatases PPP1R7, PTPN1, PTPN22, LHPP, PPP1R12A and DUPD1 successfully inhibited cell growth and migration, respectively, without interfering the functional effect of the co-delivered siRNA. The identified phosphatases could serve as potential targets to inhibit migration of highly aggressive metastatic breast cancer cells. Combinational siRNA delivery against cell cycle and phosphatases could be a promising strategy to inhibit both growth and migration of metastatic breast cancer cells, and potentially other types of metastatic cancer.Statement of SignificanceThe manuscript investigated the efficacy of a tailored polymeric siRNA delivery system formulation as well as combinational siRNA therapy in metastatic breast cancer cells to inhibit malignant cell growth and migration. The siRNA delivery was undertaken by non-viral means with PEI/HA. We identified six phosphatases that could be critical targets to inhibit migration of highly aggressive metastatic breast cancer cells. We further report on specifically targeting cell cycle and phosphatase proteins to decrease both malignant cell growth and migration simultaneously. Clinical gene therapy against metastatic breast cancer with effective and safe delivery systems is urgently needed to realize the potential of molecular medicine in this deadly disease and our studies in this manuscript is intended to facilitate this endeavor. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.