Abstract：
Cisplatin alone or in combination with 5FU and docetaxel is the preferred chemotherapy regimen for advanced-stage OSCC patients. However, its use has been linked to recurrence and metastasis due to the development of drug resistance. Therefore, sensitization of cancer cells to conventional chemotherapeutics can be an effective strategy to overcome drug resistance. Piperlongumine (PL), an alkaloid, have shown anticancer properties and sensitizes numerous neoplasms, but its effect on OSCC has not been explored. However, low aqueous solubility and poor pharmacokinetics limit its clinical application. Therefore, to improve its therapeutic efficacy, we developed piperlongumine-loaded PLGA-based smart nanoparticles (smart PL-NPs) that can rapidly release PL in an acidic environment of cancer cells and provide optimum drug concentrations to overcome chemoresistance. Our results revealed that smart PL-NPs has high cellular uptake in acidic environment, facilitating the intracellular delivery of PL and sensitizing cancer cells to cisplatin, resulting in synergistic anticancer activity in vitro by increasing DNA damage, apoptosis, and inhibiting drug efflux. Further, we have mechanistically explored the Hippo-YAP signaling pathway, which is the critical mediator of chemoresistance, and investigated the chemosensitizing effect of PL in OSCC. We observed that PL alone and in combination with cisplatin significantly inhibits the activation of YAP and its downstream target genes and proteins. In addition, the combination of cisplatin with smart PL-NPs significantly inhibited tumor growth in two preclinical models (patient-derived cell based nude mice and zebrafish xenograft). Taken together, our findings suggest that smart PL-NPs with cisplatin will be a novel formulation to reverse cisplatin resistance in patients with advanced OSCC.
摘要：
顺铂单独或与5FU和多西他赛联合是晚期OSCC患者的首选化疗方案。然而,由于耐药性的发展，它的使用与复发和转移有关。因此,癌细胞对常规化疗药物的致敏可能是克服耐药性的有效策略。胡椒长胺,一种生物碱,已经显示出抗癌特性并对许多肿瘤敏感，但其对OSCC的影响尚未被探索。然而,低水溶性和差的药代动力学限制了其临床应用。因此,为了提高其治疗效果，我们开发了基于Pierlongumine的基于PLGA的智能纳米颗粒（智能PL-NP），该纳米颗粒可以在癌细胞的酸性环境中快速释放PL，并提供最佳的药物浓度以克服化学耐药性。我们的结果表明，智能PL-NP在酸性环境中具有较高的细胞摄取，促进PL的细胞内递送和使癌细胞对顺铂敏感，通过增加DNA损伤在体外产生协同抗癌活性，凋亡，并抑制药物外排。Further,我们已经从机制上探索了Hippo-YAP信号通路，这是化学抗性的关键介质，并研究了PL在OSCC中的化学增敏作用。我们观察到PL单独和与顺铂组合显著抑制YAP及其下游靶基因和蛋白质的激活。此外,在两种临床前模型(基于患者来源的裸鼠和斑马鱼异种移植物)中,顺铂与智能PL-NP的组合显著抑制肿瘤生长.一起来看,我们的研究结果表明,智能PL-NP联合顺铂将是逆转晚期OSCC患者顺铂耐药的新制剂.
