文献：Toward targeted therapy in chemotherapy-resistant pancreatic cancer with a smart triptolide nanomedicine

文献链接：https://pubmed.ncbi.nlm.nih.gov/26840019/

作者：Cheng Wang, Biao Liu, Xuelian Xu, Bo Zhuang, Hongxia Li, Jiaqi Yin, Mengyi Cong, Wei Xu, Aiping Lu

相关产品：

HOOC-PEG-PDLLA

原文摘要：Chemoresistance is the major impediment for treating pancreatic cancer.Herbderived compound triptolide (TP) can inhibit proliferation of chemo-resistant pancreatic cancer (CPC) cell lines through multiple mechanisms, which exhibited superior anticancer efficacy compared with gemcitabine. However, toxicity due to non-specific exposure to healthy tissues hindered its clinical translation. Herein we successfully achieved targeting CPC cells and avoiding exposure to healthy tissues for TP by nucleolin-specific aptamer (AS1411) mediated polymeric nanocarrier. We conjugated AS1411 aptamer to carboxy terminated poly(ethylene glycol)–block–poly(d, l-lactide) (HOOC-PEG-PDLLA), then prepared AS1411-PEG-PDLLA micelle loading TP (AS-PPT) through solid dispersion technique. AS-PPT showed more antitumor activity than TP and equivalent specific binding ability with gemcitabine-resistant human pancreatic cancer cell (MIA PaCa-2) to AS1411 aptamer in vitro. Furthermore, we studied the distribution of AS-PPT (Cy3-labed TP) at tissue and cellular levels using biophotonic imaging technology. The results showed AS1411 facilitated TP selectively accumulating in tumor tissues and targeting CPC cells. The lifetime of the MIA PaCa-2 cell-bearing mice administrated with AS-PPT was efficiently prolonged than that of the mice subjected to the clinical anticancer drug Gemzar® in vivo. Such work provides a new strategy for overcoming the drug resistance of pancreatic cancer.

雷公藤甲素（TP）可通过多种机制Inhibition of chemotherapy resistant pancreatic cancer细胞系的增殖，较吉西他滨具有良好的抗cancer效果。通过核仁特异性适配体（AS1411）介导的聚合物纳米载体实现了靶向CPC细胞，并避免了暴露于健康组织中的TP。将AS1411适配体结合到羧基端聚（乙二醇）-块聚（d，l-乳酸）（HOOC-PEG-PDLLA)上，通过固体分散技术制备AS1411-PEG-PDLLA胶束（AS-PPT）。

具体制备方法：将AS1411适配体结合到羧基端聚HOOC-PEG-PDLLA上，通过固体分散技术制备AS1411-PEG-PDLLA胶束（AS-PPT）。AS-PPT比TP具有更高的抗tumour活性，并在体外与MIA PaCa-2和AS1411适配体具有同等的特异性结合能力。利用生物光子成像技术研究了AS-PPT（cy3标记的TP）在组织和细胞水平上的分布。

图为：合成AS1411-PEG-PDLLA和制备选择性靶向CPC细胞

AS1411聚合物的合成：

AS1411-PEG2000-PDLLA6000聚合物由EDC/NHS技术简单合成，一些HOOC- PEG2000-PDLLA6000聚合物悬浮在DNase/无核水与L EDC和L NHS在室温下轻轻摇晃。NHS活化的纳米粒子与3‘-氨基rna适配体反应。在室温下持续混合，反应持续。然后用离心滤管与水纯化AS1411- PEG2000-PDLLA6000聚合物（AS-PP）。将AS-PP聚合物在无DNase/rnase的水中重悬，然后冻干成干粉以供进一步使用。

图为：HOOC-PEG-PDLLA聚合物材料的1H NMR谱。

结论：通过AS1411介导的聚合物纳米载体实现了靶向CPC细胞，并避免了暴露于健康组织中的TP。将AS1411适配体结合到HOOC-PEG-PDLLA，通过固体分散技术制备AS1411-PEG-PDLLA胶束（AS-PPT）。AS-PPT比TP具有更高的抗tumor活性，结果表明，AS1411促进了TP的选择性。