Abstract:
BRAF-V600E mutation is regarded as the source of lung cancer resistance to trametinib (Tr), and no solution available for completely addressing this intractable resistance has emerged yet. Herein, the combination of ultrasonic (US) propelled folic acid (FA)-modified liposomes strategy and BRAF-driven gene silencing program is proposed to effectively reverse Tr\'s resistance to lung cancer. Meanwhile, the prepared cationic nanoliposomes can assist Tr drug and BRAF siRNA to escape lysosome disposal, thereby avoiding Tr drug pumping out or siRNA degradation. More significantly, loaded BRAF siRNA is designed to silence BRAF-V600E mutation genes via modulating BRAF-ERK-pathway and remarkably reverse the PC9R resistance to Tr. Systematic experiments validate that these cooperatively sensitize PC9R cells to Tr and shrink resistant NSCLC in vivo, especially after combining with FA-mediated targeting and US-enhanced permeability that permits more intratumoral accumulations of Tr. Such a biocompatible targeting drug-resistance liberation agent and its underlying design strategy lay a foundation avenue to completely reverse tumor resistance, which is preferable to treat BRAF mutation-arised resistance of various tumors, holding high clinical translation potentials.
摘要:
BRAF-V600E突变被认为是肺癌对曲美替尼(Tr)耐药的来源,目前还没有完全解决这种棘手的耐药性的解决方案。在这里,超声(US)推动叶酸(FA)修饰的脂质体策略和BRAF驱动的基因沉默程序相结合,可有效逆转Tr对肺癌的耐药性。同时,制备的阳离子纳米脂质体可以帮助Tr药物和BRAFsiRNA逃避溶酶体处理,从而避免Tr药物抽出或siRNA降解。更重要的是,加载的BRAFsiRNA旨在通过调节BRAF-ERK途径沉默BRAF-V600E突变基因,并显着逆转PC9R对Tr的抗性。系统实验验证了这些协同作用使PC9R细胞在体内对Tr和收缩抗性NSCLC敏感,特别是在结合FA介导的靶向和US增强的通透性后,允许肿瘤内积累更多的Tr。这种生物相容性靶向耐药释放剂及其潜在的设计策略为完全逆转肿瘤耐药奠定了基础。优选治疗各种肿瘤的BRAF突变产生的耐药性,具有很高的临床翻译潜力。