Oxali(IV)Fluors: Fluorescence Responsive Oxaliplatin(IV) Complexes Identify a Hypoxia-Dependent Reduction in Cancer Cells.
Oxali(IV)Fluors: Fluorescence Responsive Oxaliplatin(IV) Complexes Identify a Hypoxia-Dependent Reduction in Cancer Cells.
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DOI：
10.1021/jacs.3c03320
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发表时间：
2023-06-21
影响因子：
15
通讯作者：
Sedgwick, Adam C.
中科院分区：
文献类型：
--
作者：
Boulet, Marie H. C.;Bolland, Hannah R.;Hammond, Ester M.;Sedgwick, Adam C.
铂(IV)抗癌药物已显示出克服广泛使用的铂(II)化疗药物、顺铂、卡铂和奥沙利铂相关限制的潜力。为了确定可以应用这种类型的化疗的治疗方案，需要更好地了解铂(IV)络合物的细胞内还原。在这里，我们报道了两个荧光响应性的草酸铂(IV)(Oxpt)配合物的合成，OxaliRes和OxaliNap。抗坏血酸钠(NaAsc)能降低每个OxPt(IV)络合物的荧光强度，使其在585和545 nm处的荧光发射强度增加。每个Ox铂(IV)络合物与结直肠癌细胞系孵育后，各自的荧光发射强度变化很小。相反，NaAsc处理的这些细胞显示出剂量依赖性的荧光发射强度增加。有了这些知识，我们测试了肿瘤缺氧的还原潜力，其中观察到每个OxPT(IV)络合物的氧依赖生物还原，其中-lt；0.1%O2提供最大的荧光信号。克隆细胞存活分析与这些观察结果相关联，表明低氧(<；0.1%O2)和常氧(21%O2)的毒性存在显著差异。据我们所知，这是第一个显示氨基甲酸酯功能化的OxPT(IV)配合物作为潜在的低氧激活前药的报告。
Platinum(IV) anticancer agents have demonstrated the potential to overcome the limitations associated with the widely used Pt(II) chemotherapeutics, cisplatin, carboplatin, and oxaliplatin. In order to identify therapeutic scenarios where this type of chemotherapy can be applied, an improved understanding on the intracellular reduction of Pt(IV) complexes is needed. Here, we report the synthesis of two fluorescence responsive oxaliplatin(IV)(OxPt) complexes, OxaliRes and OxaliNap. Sodium ascorbate (NaAsc) was shown to reduce each OxPt(IV) complex resulting in increases in their respective fluorescence emission intensities at 585 and 545 nm. The incubation of each OxPt(IV) complex with a colorectal cancer cell line resulted in minimal changes to the respective fluorescence emission intensities. In contrast, the treatment of these cells with NaAsc showed a dose-dependent increase in fluorescence emission intensity. With this knowledge in hand, we tested the reducing potential of tumor hypoxia, where an oxygen-dependent bioreduction was observed for each OxPt(IV) complex with <0.1% O2 providing the greatest fluorescence signal. Clonogenic cell survival assays correlated with these observations demonstrating significant differences in toxicity between hypoxia (<0.1% O2) and normoxia (21% O2). To the best of our knowledge, this is the first report showing carbamate-functionalized OxPt(IV) complexes as potential hypoxia-activated prodrugs.
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影响因子：
15
作者：
Guisan-Ceinos, Santiago;Rivero, Alexandra R.;Romeo-Gella, Fernando;Simon-Fuente, Silvia;Gomez-Pastor, Silvia;Calvo, Natalia;Orrego, Alejandro H.;Manuel Guisan, Jose;Corral, Ines;Sanz-Rodriguez, Francisco;Ribagorda, Maria
通讯作者：
Ribagorda, Maria
影响因子：
4.2
作者：
Wu, GY;Fang, YZ;Turner, ND
通讯作者：
Turner, ND
影响因子：
4
作者：
Yao, Houzong;Zhu, Guangyu
通讯作者：
Zhu, Guangyu
影响因子：
3.4
作者：
Hammond, E. M.;Asselin, M. -C.;Williams, K. J.
通讯作者：
Williams, K. J.
影响因子：
4.6
作者：
Spector, Daniil, V;Erofeev, Alexander S.;Krasnovskaya, Olga O.
通讯作者：
Krasnovskaya, Olga O.