Delivery of platinum (II) drugs with bulky ligands in trans-geometry for overcoming cisplatin drug resistance
Delivery of platinum (II) drugs with bulky ligands in trans-geometry for overcoming cisplatin drug resistance
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以跨几何结构输送具有大配体的铂 (II) 药物以克服顺铂耐药性
DOI：
10.1016/j.msec.2018.10.092
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发表时间：
2019-03-01
影响因子：
7.9
通讯作者：
Qiu, Yongming
中科院分区：
文献类型：
--
作者：
Yang, Xi;Yu, Yingjie;Qiu, Yongming
由增加细胞内解毒剂水平诱导的对常规铂（II）药物如金属硫蛋白（MT）和谷胱甘肽（GSH）的耐药性是广泛使用的基于铂的化学治疗癌症的主要障碍。在这里，我们开发了具有空间位阻大体积配体PyPt的反式几何铂（II）药物，其能够阻碍铂药物的GSH攻击以克服顺铂抗性。此外，PyPt可以与可生物降解的共聚物mPEG-PGA自组装成均匀的纳米颗粒，其中PyPt药物在聚合物核中，PEG作为外壳，进一步保护PyPt免于GSH解毒，以进一步减缓与GSH的体内反应速率。这种策略的开发带来的好处不仅增加了空间位阻铂类药物的溶解度，而且还打击顺铂耐药性。在肿瘤微环境中，M（PyPt）表现出环境控制的Pt释放，抑制了肿瘤细胞的分裂。此外，由于纳米颗粒包封的PyPt的溶解度增加，通过分别用流式细胞术和MTT法评估，与顺铂和PyPt相比，M（PyPt）对两种癌症抗性细胞的细胞摄取和细胞毒性增强。因此，可以得出结论，M（PyPt）能够成功克服耐药细胞系中的顺铂耐药性，表明其在治疗具有强顺铂耐药性的临床癌症中的潜在应用。因此，M（PyPt）策略可能代表一种有前途的新型药物递送系统，用于耐药性癌症的局部治疗。
Drug resistance induced by increasing intracellular levels of detoxifying agents for conventional platinum(II) drugs such as metallothioneins (MTs) and glutathione (GSH) are the major obstacles for widely used platinum-based chemotherapeutic cancer treatment. Here, we developed trans-geometry platinum (II) drugs with sterically hindered bulky ligands PyPt which is able to hind the GSH attack of platinum drug to overcome cisplatin resistance. Moreover, the PyPt can self-assemble with biodegradable copolymer mPEG-PGA into uniform nanoparticles with PyPt drugs in the polymeric core and PEG as the shell, further protecting PyPt from GSH detoxification to further slow the reaction rate with GSH in vivo. This strategy was developed to bring benefit of not only increasing the solubility of sterically hindered platinum drugs but also combating cisplatin resistance. The M(PyPt) exhibited environment controlled releasing of Pt in tumor micro-environment which prohibited the division of cancer cells. Furthermore, due to the increasing solubility of nanoparticle encapsulated PyPt, the cellular uptake and cytotoxicity of M(PyPt) against both cancer resistance cells was enhanced compared to the cisplatin and PyPt through evaluating with flow cytometry and MTT, respectively. Thus, it was concluded that the M(PyPt) was capable to successfully overcome the cisplatin resistance in the drug-resistant cell line, indicating its potential application in the treatment of clinical cancers with strong cisplatin resistance. Hence the M(PyPt) strategy may represent a promising novel drug delivery system for the local treatment of drug resistance cancer.