文献：Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening

文献链接：https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/advs.202001914

作者：Fangyuan Shao, Xueying Lyu, Kai Miao, Lisi Xie, Haitao Wang, Hao Xiao, Jie Li,Qiang Chen, Renbo Ding, Ping Chen, Fuqiang Xing, Xu Zhang, Guang-Hui Luo,Wenli Zhu, Gregory Cheng, Ng Wai Lon, Scott E. Martin, Guanyu Wang, Guokai Chen,Yunlu Dai, and Chu-Xia Deng

相关产品：mPEG-PLGA（甲氧基聚乙二醇-聚乳酸-羟基乙酸共聚物）

原文摘要：

Resistance to therapeutic drugs occurs in virtually all types of cancers, and the tolerance to one drug frequently becomes broad therapy resistance; however,the underlying mechanism remains elusive. Combining a whole whole-genome-wide RNA interference screening and an evolutionary drug pressure model with MDA-MB-231 cells, it is found that enhanced protein damage clearance and reduced mitochondrial respiratory activity are responsible for cisplatin resistance. Screening drug-resistant cancer cells and human patient-derived organoids for breast and colon cancers with many anticancer drugs indicates that activation of mitochondrion protein import surveillance system enhances proteasome activity and minimizes caspase activation, leading to broad drug resistance that can be overcome by co-treatment with a proteasome inhibitor, bortezomib. It is further demonstrated that cisplatin and bortezomib encapsulated into nanoparticle further enhance their therapeutic efficacy and alleviate side effects induced by drug combination treatment. These data demonstrate a feasibility for eliminating broad drug resistance by targeting its common mechanism to achieve effective therapy for multiple cancers.   

mPEG-PLGA：mPEG 是甲氧基聚乙二醇。聚乙二醇（PEG）是一种具有良好水溶性和生物相容性的聚合物，其一端的羟基被甲氧基取代后，形成 mPEG，甲氧基的存在可以防止聚合物两端都发生不必要的反应。PLGA 是聚乳酸 - 羟基乙酸共聚物（Poly (lactic - co - glycolic acid)）的缩写。它是由乳酸（Lactic acid）和羟基乙酸（Glycolic acid）聚合而成的。mPEG - PLGA 是将 mPEG 和 PLGA 通过化学键连接在一起形成的嵌段共聚物。这种结构使得聚合物兼具了 mPEG 和 PLGA 的性质。如，mPEG 链段可以提供良好的亲水性和空间位阻效应，减少蛋白质吸附，而 PLGA 链段则具有可生物降解性和一定的化合物负载能力。基于mPEG-PLGA的性能，制药mPEG-PLGA NPs合成如下：

图：mPEG-PLGA结构式

载药mPEG-PLGA NPs的制备：

将mPEG5000-PLGA、硼替佐米和顺铂粉分别在 THF中完全溶解。然后，将mPEG-PLGA和化合物以一定的喂养比在THF中充分混合。然后将溶液快速滴入水溶液中，超声处理。将得到的混合物在空气中搅拌过夜，蒸发THF并封装化合物。接下来，用Amicon Ultra-4过滤器过滤纯化NPs。获得的产品用去离子水洗涤，以去除非封装的化合物。最后，将载药的mPEG-PLGA NPs进行冻干以供进一步使用。

图：不同负载的电镜图像

结论：

该文献成功制备出基于mPEG-PLGA合成的载物mPEG-PLGA NPs。数据显示，顺铂和硼替佐米包裹纳米颗粒能够提高其效果，缓解化合物联合引起的副作用，数据表明，通过靶向其共同机制来实现对多种cancer的效果，从而消除wide-ranging的耐药性的可行性。