• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文会议>World biomaterials congress >A theranostic gemcitabine prodrug with AIE-based intracellular light-up characteristics for selective suppression of pancreatic cancer cells
【24h】

A theranostic gemcitabine prodrug with AIE-based intracellular light-up characteristics for selective suppression of pancreatic cancer cells

机译：具有基于AIE的细胞内点亮特性的治疗性吉西他滨前药，可选择性抑制胰腺癌细胞

获取原文
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Pancreatic cancer is one of the most lethal malignancies with a 5 year survival rate of 5%. Gemcitabine (GEM) is currently trie first line drug available for treatment of pancreatic cancer. Unfortunately, the clinical application of GEM is severely limited since it can undergo rapid deamination into inactive metabolite. Meanwhile, in the clinical management of pancreatic cancer patients, timely assessment of therapeutic response to a given therapy is critical for making treatment decisions. A new class of fluorescent probes with aggregation-induced emission (AIE) behaviours was reported as a powerful tool in biosensing and bioimaging . In this research, we designed a novel theranostic tetraphenylene (TPE)-containing gemcitabine prodrug TPE-GEM-RGD, which can be used for targeted light-up imaging and selective release of GEM under intracellular reductive environment (Figure 1). Figure 1. TPE-GEM-RGD for cathepsin β-responsive fluorescence light up and reduction-responsive drug release. In order to evaluate the light-up capability of TPE-GEM-RGD prodrug, the fluorescent spectra of TPE-GEM-RGD incubated with cathepsin B were recorded. The fluorescence intensity of TPE-GEM-RGD increased steadily with time in the presence of cathepsin B, which might be ascribed to the cleavage of GFLG sequence by cathepsin B. The reduction-responsive GEM release was studied by incubating TPE-GEM-RGD prodrug with 10 mM of GSH. According to HPLC analysis, upon treating with GSH, GEM was released owing to the appearance of the peak at 4.3 min, which was the characteristic peak of free GEM. Therefore, GEM can be released upon treating with GSH. Since cathepsin B is overexpressed in pancreatic cancer cells, the capability of TPE-GEM-RGD as cancer cell specific fluorescent light-up probe was studied for live cell imaging . As shown in Figure 2, strong blue fluorescence was observed after BxPC-3 cells were incubated with 50 μM TPE-GEM-RGD. However, when BxPC-3 cells were pretreated with cathepsin B inhibitor CA-074-Me, only very weak blue fluorescence was observed. Moreover, TPE-GEM-RDG prodrug without RGD targeting was used as a negative control. The fluorescent intensity of BxPC-3 cells incubated with TPE-GEM-RDG was much weaker than that incubated with TPE-GEM-RGD. These results demonstrated that the intracellular fluorescence light-up can be achieved. Figure 2. Fluorescent microscopy images of BxPC-3 cells (a) incubated with TPE-GEM-RGD; (b) pretreated with CA-074-Me and incubated with TPE-GEM-RGD; (c) incubated with TPE-GEM-RDG. In order to identify the reduction-responsive release of GEM, the in vitro cell proliferation inhibition behavior was studied by MTT. The GSH level in BxPC-3 cells can be enhanced or inhibited by pretreating the cells with GSH promoterGSH-OEt or GSH inhibitor BSO . As shown in Figure 3,the BxPC-3 cells pretreated with GSH-OEt or BSO exhibited lowest or highest cell viability, which proved the GSH-responsive behavior of TPE-GEM-RGD prodrug. Figure 3. Cell viability of BxPC-3 cells incubated with TPE-GEM-RGD prodrug. BxPC-3 cells were pretreated with BSO or GSH-OEt. In summary, we have successfully synthesized a theranostic TPE-GEM-RGD prodrug with AlE-based intracellular light-up properties. The TPE-GEM-RGD prodrug was used for targeted light-up imaging and selective inhibition of the proliferation of pancreatic cancer cells.
机译：胰腺癌是最致命的恶性肿瘤之一，其5年生存率为5％。吉西他滨（GEM）目前是可用于治疗胰腺癌的第一线药物。不幸的是，GEM的临床应用受到严重限制，因为它会快速脱氨成无活性的代谢产物。同时，在胰腺癌患者的临床管理中，及时评估对给定疗法的治疗反应对于制定治疗决策至关重要。据报道，具有聚集诱导发射（AIE）行为的新型荧光探针是生物传感和生物成像的有力工具。在这项研究中，我们设计了一种新型的含治疗性四苯并苯（TPE）的吉西他滨前药TPE-GEM-RGD，可用于细胞内还原环境下的靶向光成像和GEM的选择性释放（图1）。图1. TPE-GEM-RGD用于组织蛋白酶β反应性荧光增强和还原反应性药物释放。为了评估TPE-GEM-RGD前药的发光能力，记录了与组织蛋白酶B孵育的TPE-GEM-RGD的荧光光谱。在组织蛋白酶B存在下，TPE-GEM-RGD的荧光强度随时间稳定增加，这可能归因于组织蛋白酶B对GFLG序列的裂解。含10 mM的GSH。根据HPLC分析，经GSH处理后，由于出现了4.3分钟的峰，该峰是游离GEM的特征峰，因此释放了GEM。因此，GEM可以在用GSH治疗后释放。由于组织蛋白酶B在胰腺癌细胞中过表达，因此对TPE-GEM-RGD作为癌细胞特异性荧光发光探针的能力进行了活细胞成像研究。如图2所示，将BxPC-3细胞与50μMTPE-GEM-RGD孵育后，观察到强烈的蓝色荧光。但是，当用组织蛋白酶B抑制剂CA-074-Me预处理BxPC-3细胞时，仅观察到非常弱的蓝色荧光。此外，将没有RGD靶向的TPE-GEM-RDG前药用作阴性对照。用TPE-GEM-RDG孵育的BxPC-3细胞的荧光强度比用TPE-GEM-RGD孵育的荧光强度弱得多。这些结果证明可以实现细胞内荧光点亮。图2. BxPC-3细胞的荧光显微镜图像（a）与TPE-GEM-RGD孵育; （b）用CA-074-Me预处理并与TPE-GEM-RGD一起孵育; （c）与TPE-GEM-RDG一起孵育。为了鉴定GEM的还原反应性释放，MTT研究了体外细胞增殖抑制行为。 BxPC-3细胞中的GSH水平可以通过用GSH启动子GSH-OEt或GSH抑制剂BSO预处理来增强或抑制。如图3所示，用GSH-OEt或BSO预处理的BxPC-3细胞表现出最低或最高的细胞活力，这证明了TPE-GEM-RGD前药的GSH响应行为。图3.用TPE-GEM-RGD前药孵育的BxPC-3细胞的细胞活力。 BxPC-3细胞用BSO或GSH-OEt预处理。总之，我们已经成功合成了具有AlE基细胞内发光特性的治疗性TPE-GEM-RGD前药。 TPE-GEM-RGD前药用于靶向光成像和选择性抑制胰腺癌细胞的增殖。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号