负载雷公藤红素/丙戊酸的透明质酸主动靶向性纳米材料的构建及联合抗骨肉瘤机制的研究

Recently, drug combination and construction of targeting carrier have become the research hotspots in the treatment of osteosarcoma. Celastrol has a wide range of antitumor effects. However, the clinical application has been limited owing to its poor water solubility and multiple biotoxicity. Valproic acid could enhance efficacy of other drugs by inducing epigenetic alterations in tumor, but whether it could enhance the antitumor effect of celastrol is still unexplored. Chitosan nanomaterials are widely used as drug carriers, but it lacks the ability of actively targeting tumors. CD44, the receptor of hyaluronic acid, is highly expressed in a variety of tumors. It could improve the targeting ability by specific binding of CD44 and hyaluronic acid. The results of our previous study revealed that celastrol had the inhibitory effect of osteosarcoma by inducing ROS, but also upregulated the activity of Nrf2/Keap1-mediated antioxidase. Combination of celastrol and valproic acid had synergistic antitumor effects and drug-loaded nanoparticle preliminarily constructed displayed good performance. We also found high expression of CD44 in osteosarcoma. In this study, we plan to conduct celastrol and valproic acid loaded nanomaterial of active targeting mediated by hyaluronic acid. The inhibitory effect of osteosarcoma and security of this drug-loaded nanoparticle are to be evaluated by experiments in vivo and vitro. The correlations of the Nrf2/Keap1 axis or epigenetics with combination mechanism are also to be explored. This study will provide scientific basis for combination and targeting therapy of osteosarcoma.

联合用药及构建靶向载体是近些年来治疗骨肉瘤的研究热点。雷公藤红素具有广泛抗肿瘤活性，但其较差的水溶性和多重生物毒性限制了临床应用。丙戊酸能够通过改变肿瘤表观遗传而增强药物作用，能否增强雷公藤红素抗肿瘤作用尚无报道。壳聚糖纳米材料被广泛用作药物载体，但其缺乏对肿瘤的主动靶向能力。透明质酸受体CD44在多种肿瘤中高表达，利用透明质酸/CD44特异性作用可提高药物靶向性。我们在前期研究中发现雷公藤红素通过激活ROS杀伤骨肉瘤，但上调了Nrf2/Keap1介导的抗氧化酶水平；两药联合具有协同抗肿瘤作用；初步构建的载药粒子显示出良好的性能表征。我们还检测到CD44在骨肉瘤中表达升高。本项目拟构建负载雷公藤红素和丙戊酸的透明质酸主动靶向性纳米材料，通过体内外实验评价载药粒子对骨肉瘤的抑制效果和安全性，探索联合作用机制与Nrf2/Keap1轴和表观遗传学的相关性，最终为联合靶向治疗骨肉瘤提供科学依据。

骨肉瘤是最常见的原发性恶性骨肿瘤。尽管新辅助化疗结合手术已可将骨肉瘤患者的5年生存率提高到60-80％，但近30年来患者的生存率始终没有进一步的提高。寻找一种新型有效、安全的治疗方法，是目前亟需解决的关键问题。联合用药及构建靶向载体是近些年来治疗骨肉瘤的研究热点。雷公藤红素具有广泛抗肿瘤活性，但其较差的水溶性和多重生物毒性限制了临床应用。丙戊酸能够通过改变肿瘤表观遗传而增强药物作用，能否增强雷公藤红素抗肿瘤作用尚无报道。壳聚糖纳米材料被广泛用作药物载体，但其缺乏对肿瘤的主动靶向能力。透明质酸受体CD44在多种肿瘤中高表达，利用透明质酸/CD44特异性作用可提高药物靶向性。本项目构建了负载雷公藤红素的透明质酸主动靶向性壳聚糖纳米材料，通过体内外实验和对临床样本研究，我们发现其联合丙戊酸能够显著增强对骨肉瘤的周期阻滞、凋亡等增殖抑制效应，在探索联合作用机制时发现与下调Nrf2/Keap1介导的抗氧化酶水平而导致的ROS蓄积，以及进一步增强p-JNK表达相关。该项目的研究结果能够为联合靶向治疗骨肉瘤提供科学依据，为肿瘤联合治疗机制的探索提供新思维。