Concurrent silencing of TBCE and drug delivery to overcome platinum-based resistance in liver cancer  

作　　者：Senlin Li Siyu Chen Zhihui Dong Xingdong Song Xiuling Li Ziqi Huang Huiru Li Linzhuo Huang Ganyuan Zhuang Ran Lan Mingyan Guo Wende Li Phei Er Saw Lei Zhang 

机构地区：[1]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation,Guangdong-Hong Kong Joint Laboratory for RNA Medicine,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,510120,China [2]Department of Hepatobiliary Surgery,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China [3]Guangdong Laboratory Animals Monitoring Institute,Guangdong Key Laboratory of Laboratory Animals,Guangzhou,510663,China [4]Department of Anesthesiology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,510120,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第3期967-981,共15页药学学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (81874226 and 81803020);the “Three Million for Three Years” Project of the High-Level Talent Special Funding Scheme of Sun Yat-sen Memorial Hospital;the Guangdong Natural Science Foundation (2016A030313834and 2017A030313871,China)

摘　　要：Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma(HCC).Herein,RNAseq analysis revealed that elevated tubulin folding cofactor E(TBCE)expression is associated with platinum-based chemotherapy resistance.High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients.Mechanistically,TBCE silencing significantly affects cytoskeleton rearrangement,which in turn increases cisplatin-induced cycle arrest and apoptosis.To develop these findings into potential therapeutic drugs,endosomal pH-responsive nanoparticles(NPs)were developed to simultaneously encapsulate TBCE siRNA and cisplatin(DDP)to reverse this phenomena.NPs(siTBCE+DDP)concurrently silenced TBCE expression,increased cell sensitivity to platinum treatment,and subsequently resulted in superior anti-tumor effects both in vitro and in vivo in orthotopic and patient-derived xenograft(PDX)models.Taken together,NP-mediated delivery and the co-treatment of siTBCE+DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.

关 键 词：Hepatocellular carcinoma Tubulin folding cofactor E CHEMORESISTANCE siRNA delivery RNA interference Nanoparticle Combination therapy NANOMEDICINE 

分 类 号：R735.7[医药卫生—肿瘤]