Li Min, Zhang Ling'e, Xuan Yang, Zhi Defu, Wang Wei, Zhang Wenjun, Zhao Yinan, Zhang Shufen, Zhang Shubiao
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, PR China; Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, PR China.
Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, PR China.
Int J Biol Macromol. 2022 May 1;206:489-500. doi: 10.1016/j.ijbiomac.2022.02.131. Epub 2022 Feb 28.
Although many chemotherapy prodrugs have been developed for tumor therapy, non-targeted delivery, uncontrolled release and tedious construction procedure of prodrugs still limit their clinical application in tumor treatment. In this work, hyaluronic acid (HA) which has tumor-targeting ability was used to conjugate to antitumor drug podophyllotoxin (PPT) to construct a pH-sensitive prodrug named HA-CO-O-PPT just via a one-step esterification reaction. The HA-CO-O-PPT spontaneously assembled into nano spherical micelles in aqueous medium, which had outstanding serum stability and blood compatibility. The obtained prodrug micelles (named HP micelles) exhibited a pH-responsive drug release mode with cumulative release reaching 81.2% due to their dissociation in response to acid stimulus, and had a high cellular uptake efficiency beyond 97% owing to HA receptor-mediated targeting. Furthermore, it was found that the prodrug micelles showed excellent antitumor activities in vivo with the tumor inhibition ratio up to 85% and negligible systemic toxicity. Accordingly, the pH-responsive HP micelles constructed by a simple one-step reaction, could be a promising candidate as a chemotherapeutic agent for cancer therapy.
尽管已经开发了许多化疗前药用于肿瘤治疗，但前药的非靶向递送、释放不受控制以及构建过程繁琐等问题仍然限制了它们在肿瘤治疗中的临床应用。在这项工作中，具有肿瘤靶向能力的透明质酸（HA）通过一步酯化反应与抗肿瘤药物鬼臼毒素（PPT）缀合，构建了一种pH敏感前药，命名为HA-CO-O-PPT。HA-CO-O-PPT在水性介质中自发组装成纳米球形胶束，具有出色的血清稳定性和血液相容性。所得到的前药胶束（命名为HP胶束）表现出pH响应性药物释放模式，由于其在酸刺激下解离，累积释放率达到81.2%，并且由于HA受体介导的靶向作用，具有超过97%的高细胞摄取效率。此外，发现前药胶束在体内表现出优异的抗肿瘤活性，肿瘤抑制率高达85%，全身毒性可忽略不计。因此，通过简单的一步反应构建的pH响应性HP胶束有望成为一种用于癌症治疗的化疗药物。
