如何解决顺铂(CDDP)的耐药性一直是临床挑战。铂类药物的耐药机制非常复杂,包括核DNA损伤修复,凋亡逃逸,和肿瘤代谢重编程。肿瘤细胞可以在线粒体氧化磷酸化(OXPHOS)和糖酵解之间切换,并通过代谢变异性对化疗药物产生耐药性。此外,由于缺乏组蛋白保护和相对较弱的损伤修复能力,线粒体DNA(mtDNA)更容易受到损伤,这反过来又会影响线粒体OXPHOS,并可能成为铂类药物的潜在靶标。因此,线粒体,作为抗癌药物的靶标,已成为肿瘤耐药研究的热点。本研究构建了自组装纳米靶向药物递送系统LND-SS-Pt-TPP/HA-CD。β-环糊精接枝的水合酸(HA-CD)包封的前药纳米颗粒可以靶向肿瘤表面上的CD44,并进一步通过三苯基膦基团(TPP+)将前药递送至胞内线粒体。二硫化物键可以被线粒体中的谷胱甘肽(GSH)选择性降解,释放lonidamine(LND)和顺铂前药(Pt(IV))。在GSH和抗坏血酸的作用下,Pt(IV)进一步还原成顺铂(Pt(II))。顺铂可引起mtDNA损伤,诱导线粒体功能障碍和线粒体自噬,然后影响线粒体OXPHOS。同时,LND可以降低己糖激酶II(HKII)水平,诱导线粒体的破坏,并通过糖酵解抑制阻断能量供应。最终,这种自组装的纳米靶向递送系统可以协同杀死顺铂耐药的肺癌细胞,通过破坏线粒体疗法提供克服顺铂耐药性的选择。
How to address the resistance of cisplatin (CDDP) has always been a clinical challenge. The resistance mechanism of platinum-based drugs is very complex, including nuclear DNA damage repair, apoptosis escape, and tumor metabolism reprogramming. Tumor cells can switch between
mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis and develop resistance to chemotherapy drugs through metabolic variability. In addition, due to the lack of histone protection and a relatively weak damage repair ability,
mitochondrial DNA (mtDNA) is more susceptible to damage, which in turn affects
mitochondrial OXPHOS and can become a potential target for platinum-based drugs. Therefore, mitochondria, as targets of anticancer drugs, have become a hot topic in tumor resistance research. This study constructed a self-assembled nanotargeted drug delivery system LND-SS-Pt-TPP/HA-CD. β-Cyclodextrin-grafted hydronic acid (HA-CD)-encapsulated prodrug nanoparticles can target CD44 on the tumor surface and further deliver the prodrug to intracellular mitochondria through a triphenylphosphine group (TPP+). Disulfide bonds can be selectively degraded by glutathione (GSH) in mitochondria, releasing lonidamine (LND) and the cisplatin prodrug (Pt(IV)). Under the action of GSH and ascorbic acid, Pt(IV) is further reduced to cisplatin (Pt(II)). Cisplatin can cause mtDNA damage, induce
mitochondrial dysfunction and mitophagy, and then affect
mitochondrial OXPHOS. Meanwhile, LND can reduce the hexokinase II (HK II) level, induce destruction of mitochondria, and block energy supply by glycolysis inhibition. Ultimately, this self-assembled nano targeted delivery system can synergistically kill cisplatin-resistant lung cancer cells, which supplies an overcome cisplatin resistance choice via the disrupt mitochondria therapy.