Tobacco Mosaic Virus-Delivered Cisplatin Restores Efficacy in Platinum-Resistant Ovarian Cancer Cells
Tobacco Mosaic Virus-Delivered Cisplatin Restores Efficacy in Platinum-Resistant Ovarian Cancer Cells
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DOI：
10.1021/acs.molpharmaceut.7b00466
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发表时间：
2018-08-01
影响因子：
4.9
通讯作者：
Steinmetz, Nicole F.
中科院分区：
文献类型：
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作者：
Franke, Christina E.;Czapar, Anna E.;Steinmetz, Nicole F.
卵巢癌的铂耐药是疾病预后的主要决定因素。耐药性可能首先在疾病发作时出现，或在以铂为基础的化疗反应中发展。由于对替代化疗的不良反应和缺乏靶向治疗，临床上迫切需要一种新的途径来治疗铂耐药(PR)卵巢癌。纳米级的递送系统具有克服耐药性机制的潜力。在这项工作中，我们提出了烟草花叶病毒(TMV)作为顺铂的纳米载体用于治疗PR卵巢癌细胞。TMV-顺铂偶合物(TMV-cispt)是通过电荷驱动反应合成的，与经典的点击反应一样，该反应简单可靠，可用于大规模生产。每个TMV-cispt的载药量接近1900个，具有与pH无关的快半衰期(t(1))接近1h和慢半衰期(t(2))接近12h的两相释放特征。与卵巢癌细胞孵育时，细胞对TMV的摄取效率较高，与游离顺铂相比，TMV-cispt对铂敏感(PS)和PR癌细胞显示出更好的细胞毒性和DNA双链断裂(DSB)。TMV-cispt对PR卵巢癌细胞的细胞毒性和总体较低的有效剂量要求使其成为改进卵巢癌治疗策略的有力候选者。
Platinum resistance in ovarian cancer is the major determinant of disease prognosis. Resistance can first appear at the onset of disease or develop in response to platinum-based chemotherapy. Due to poor response to alternate chemotherapies and lack of targeted therapies, there is an urgent clinical need for a new avenue toward treatment of platinum-resistant (PR) ovarian cancer. Nanoscale delivery systems hold potential to overcome resistance mechanisms. In this work, we present tobacco mosaic virus (TMV) as a nanocarrier for cisplatin for treatment of PR ovarian cancer cells. The TMV-cisplatin conjugate (TMV-cisPt) was synthesized using a charge-driven reaction that, like a classic click reaction, is simple and reliable for large-scale production. Up to similar to 1900 cisPt were loaded per TMV-cisPt with biphasic release profiles characterized by a fast half-life (t(1)) of similar to 1 h and slow half-life (t(2)) of similar to 12 h independent of pH. Efficient cell uptake of TMV was observed when incubated with ovarian cancer cells, and TMV-cisPt demonstrated superior cytotoxicity and DNA double strand breakage (DSB) in platinum-sensitive (PS) and PR cancer cells when compared to free cisplatin. The cytotoxicity in PR ovarian cancer cells and overall lower effective dosage requirement makes TMV-cisPt a powerful candidate for improved ovarian cancer treatment strategies.