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

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 antitumor 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.