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烟草花叶病毒递送顺铂恢复铂耐药卵巢癌细胞的疗效。

Tobacco Mosaic Virus-Delivered Cisplatin Restores Efficacy in Platinum-Resistant Ovarian Cancer Cells.

出版信息

Mol Pharm. 2018 Aug 6;15(8):2922-2931. doi: 10.1021/acs.molpharmaceut.7b00466. Epub 2017 Sep 19.

Abstract

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 ( t) of ∼1 h and slow half-life ( t) 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.

摘要

铂耐药性是卵巢癌主要的预后决定因素。耐药性可能在疾病开始时首次出现,也可能对铂类化疗产生反应。由于对替代化疗反应不佳且缺乏靶向治疗,因此迫切需要一种新的方法来治疗铂耐药(PR)卵巢癌。纳米递药系统具有克服耐药机制的潜力。在这项工作中,我们提出烟草花叶病毒(TMV)作为顺铂的纳米载体,用于治疗 PR 卵巢癌细胞。TMV-顺铂缀合物(TMV-cisPt)是使用电荷驱动反应合成的,该反应与经典点击反应一样,简单可靠,适合大规模生产。每个 TMV-cisPt 可负载多达约 1900 个 cisPt,具有双相释放曲线特征,半衰期( t)约为 1 小时,半衰期( t)约为 12 小时,与 pH 无关。当与卵巢癌细胞孵育时,观察到 TMV 的有效细胞摄取,与游离顺铂相比,TMV-cisPt 在铂敏感(PS)和 PR 癌细胞中表现出更高的细胞毒性和 DNA 双链断裂(DSB)。在 PR 卵巢癌细胞中的细胞毒性和总体较低的有效剂量要求使 TMV-cisPt 成为改善卵巢癌治疗策略的有力候选药物。

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