Aminoglucose-functionalized, redox-responsive polymer nanomicelles for overcoming chemoresistance in lung cancer cells.
Aminoglucose-functionalized, redox-responsive polymer nanomicelles for overcoming chemoresistance in lung cancer cells.
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氨基葡萄糖功能化、氧化还原响应聚合物纳米胶束用于克服肺癌细胞的化疗耐药性
DOI：
10.1186/s12951-017-0316-z
复制
发表时间：
2017-11-28
影响因子：
10.2
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Zhou Y;Wen H;Gu L;Fu J;Guo J;Du L;Zhou X;Yu X;Huang Y;Wang H
用于癌症治疗的化疗药物经常遇到多重耐药（MDR）。靶向肿瘤并在细胞内积聚和释放药物的纳米级载体具有克服耐多药的最大潜力。利用癌细胞中葡萄糖转运蛋白-1 （GLUT-1）和谷胱甘肽（GSH）的过表达，从聚乙二醇和聚乳酸的单二硫键桥接嵌段聚合物（AG- peg - ss - pla）组装氨基葡萄糖（AG）偶联的氧化还原反应纳米胶束。然而，这种双重功能载体能否克服肺癌的耐多药耐药尚不清楚。本实验成功合成了AG-PEG-SS-PLA，紫杉醇（PTX）负载的AG-PEG-SS-PLA （AG-PEG-SS-PLA/PTX）纳米胶束表现出优异的物理性能。这些纳米胶束在耐多药癌细胞中表现出增强的肿瘤靶向性以及药物积累和保留。依赖于小泡蛋白的内吞作用主要负责纳米微粒的内化。内化后，AG-PEG-SS-PLA的二硫键在细胞内高水平谷胱甘肽的存在下被切割，导致疏水核心成为极性水溶液，随后导致纳米束分解和被封装的PTX的快速释放。体外观察到癌细胞的耐药性降低。AG-PEG-SS-PLA/PTX纳米胶束通过上调促凋亡蛋白Bax和Bid，抑制抗凋亡蛋白Bcl-2，激活caspase-9和caspase-3级联，从而增加细胞凋亡。此外，通过尾部注射AG-PEG-SS-PLA/PTX纳米胶束可显著增强携带A549/ADR异种移植肿瘤的裸鼠的肿瘤生长抑制作用。这些有希望的结果表明AG-PEG-SS-PLA/PTX纳米胶束可以为耐多药癌症治疗的范式转变提供基础。本文的在线版本（10.1186/s12951-017-0316-z）包含补充内容，仅供授权用户使用。
Chemotherapeutic drugs used for cancer therapy frequently encounter multiple-drug resistance (MDR). Nanoscale carriers that can target tumors to accumulate and release drugs intracellularly have the greatest potential for overcoming MDR. Glucose transporter-1 (GLUT-1) and glutathione (GSH) overexpression in cancer cells was exploited to assemble aminoglucose (AG)-conjugated, redox-responsive nanomicelles from a single disulfide bond-bridged block polymer of polyethylene glycol and polylactic acid (AG-PEG-SS-PLA). However, whether this dual functional vector can overcome MDR in lung cancer is unknown. In this experiment, AG-PEG-SS-PLA was synthetized successfully, and paclitaxel (PTX)-loaded AG-PEG-SS-PLA (AG-PEG-SS-PLA/PTX) nanomicelles exhibited excellent physical properties. These nanomicelles show enhanced tumor targeting as well as drug accumulation and retention in MDR cancer cells. Caveolin-dependent endocytosis is mainly responsible for nanomicelle internalization. After internalization, the disulfide bond of AG-PEG-SS-PLA is cleaved in the presence of high intracellular glutathione levels, causing the hydrophobic core to become a polar aqueous solution, which subsequently results in nanomicelle disassembly and the rapid release of encapsulated PTX. Reduced drug resistance was observed in cancer cells in vitro. The caspase-9 and caspase-3 cascade was activated by the AG-PEG-SS-PLA/PTX nanomicelles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the anti-apoptotic protein Bcl-2, thereby increasing apoptosis. Furthermore, significantly enhanced tumor growth inhibition was observed in nude mice bearing A549/ADR xenograft tumors after the administration of AG-PEG-SS-PLA/PTX nanomicelles via tail injection. These promising results indicate that AG-PEG-SS-PLA/PTX nanomicelles could provide the foundation for a paradigm shift in MDR cancer therapy. The online version of this article (10.1186/s12951-017-0316-z) contains supplementary material, which is available to authorized users.
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DOI：
10.5402/2012/623139
发表时间：
2012
期刊：
ISRN pharmacology
影响因子：
--
作者：
Surapaneni MS;Das SK;Das NG
通讯作者：
Das NG
DOI：
10.1016/j.aanat.2010.03.001
发表时间：
2010-05-20
期刊：
Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft
影响因子：
--
作者：
Airley R;Evans A;Mobasheri A;Hewitt SM
通讯作者：
Hewitt SM
DOI：
10.2174/1872213x113079990016
发表时间：
2013-01-01
影响因子：
4.2
作者：
Naik, Suresh R.;Desai, Sandhya K.;Wala, Santosh M.
通讯作者：
Wala, Santosh M.
影响因子：
10
作者：
Sun, Chun-Yang;Dou, Shuang;Wang, Jun
通讯作者：
Wang, Jun
影响因子：
4.9
作者：
Liu, Pengxing;Lu, Yanhui;Gao, Qingzhi
通讯作者：
Gao, Qingzhi