Roberts Cai M, Shahin Sophia Allaf, Wen Wei, Finlay James B, Dong Juyao, Wang Ruining, Dellinger Thanh H, Zink Jeffrey I, Tamanoi Fuyuhiko, Glackin Carlotta A
Irell & Manella Graduate School of Biological Sciences, City of Hope-Beckman Research Institute, Duarte, California, USA; Department of Stem Cell and Developmental Biology, City of Hope-Beckman Research Institute Duarte, California, USA.
Department of Chemistry and Biochemistry, Jonsson Comprehensive Cancer Center, California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA.
Nanomedicine. 2017 Apr;13(3):965-976. doi: 10.1016/j.nano.2016.11.010. Epub 2016 Nov 25.
Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers.
上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤，因其诊断时已处于晚期且耐药复发频繁。迫切需要新的疗法来克服这些障碍。TWIST是一种在癌症中重新激活的发育转录因子，与血管生成、转移、癌症干细胞表型和耐药性有关，使其成为一个有前景的治疗靶点。在这项研究中，我们证明了TWIST siRNA（siTWIST）和两种纳米颗粒递送平台在EOC模型中逆转化疗耐药性的功效。聚酰胺胺树枝状大分子和介孔二氧化硅纳米颗粒（MSN）将siTWIST携带到靶细胞中，并在体外导致TWIST的持续敲低。用顺铂加MSN-siTWIST治疗的小鼠比单独用顺铂治疗的小鼠肿瘤负担更低，大部分效果来自于播散性肿瘤的减少。该平台在克服EOC和其他TWIST过表达癌症的转移和化疗耐药性的临床挑战方面具有潜在应用价值。
