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 ∼1900 cisPt were loaded per TMV-cisPt with biphasic release profiles characterized by a fast half-life (t₁) of ∼1 h and slow half-life (t₂) of ∼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.

中文翻译：

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烟草花叶病毒提供的顺铂恢复抗铂的卵巢癌细胞的功效。

卵巢癌中的铂耐药性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，或者对铂类化学疗法产生反应。由于对替代化学疗法的反应较差并且缺乏靶向疗法，因此迫切需要一种新的治疗铂耐药性（PR）卵巢癌的方法。纳米级递送系统具有克服阻力机制的潜力。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-顺铂偶联物（TMV-cisPt）是使用电荷驱动反应合成的，该反应类似于经典的点击反应，对于大规模生产而言简单而可靠。大约1小时的t ₁）和大约12小时的慢半衰期（t ₂），与pH无关。当与卵巢癌细胞一起孵育时，观察到TMV的有效细胞摄取，并且与游离顺铂相比，TMV-cisPt在铂敏感（PS）和PR癌细胞中显示出优异的细胞毒性和DNA双链断裂（DSB）。PR卵巢癌细胞的细胞毒性和总体较低的有效剂量需求使TMV-cisPt成为改善卵巢癌治疗策略的有力候选者。