白文静, 夏春玉, 李曼, 卢正则, 何勤*. 共递送IR-780及18β-甘草次酸的还原敏感胶束型纳米粒的构建及其抗肿瘤效果评价J. 药学学报, 2022,57(1): 211-221. doi: 10.16438/j.0513-4870.2021-1235
引用本文: 白文静, 夏春玉, 李曼, 卢正则, 何勤*. 共递送IR-780及18β-甘草次酸的还原敏感胶束型纳米粒的构建及其抗肿瘤效果评价J. 药学学报, 2022,57(1): 211-221. doi: 10.16438/j.0513-4870.2021-1235
BAI Wen-jing, XIA Chun-yu, LI Man, LU Zheng-ze, HE Qin*. Construction and anti-tumor efficiency evaluation of redox-responsive micelles for the co-delivery of IR-780 and 18β-glycyrrhetinic acidJ. Acta Pharmaceutica Sinica, 2022,57(1): 211-221. doi: 10.16438/j.0513-4870.2021-1235
Citation: BAI Wen-jing, XIA Chun-yu, LI Man, LU Zheng-ze, HE Qin*. Construction and anti-tumor efficiency evaluation of redox-responsive micelles for the co-delivery of IR-780 and 18β-glycyrrhetinic acidJ. Acta Pharmaceutica Sinica, 2022,57(1): 211-221. doi: 10.16438/j.0513-4870.2021-1235

共递送IR-780及18β-甘草次酸的还原敏感胶束型纳米粒的构建及其抗肿瘤效果评价

Construction and anti-tumor efficiency evaluation of redox-responsive micelles for the co-delivery of IR-780 and 18β-glycyrrhetinic acid

  • 摘要: 光热治疗(photothermal therapy,PTT)是一种高效的抗肿瘤手段,但在激光照射消融肿瘤的同时,通常会引发一系列炎性反应,促进肿瘤的进一步发展,影响肿瘤治疗效果。因此,在肿瘤光热治疗的同时,实现对抗炎药物的肿瘤精准靶向递送,抑制光热治疗引发的炎性反应,是提高抗肿瘤效果的有效手段。为此,本课题以还原敏感连接物3,3'-二硫代二丙酸(DA)键合疏水段抗炎药物18β-甘草次酸(18β-GA)和亲水段甲氧基-聚乙二醇-氨基(mPEG-NH2)得到还原敏感的两亲性聚合物PEG-DA-GA,并包载光热剂IR-780,制备得到还原敏感胶束型纳米粒PDG/IR-780 NPs。PDG/IR-780 NPs的粒径均一,为80.2±5.3 nm,多分散指数(PDI)为0.215±0.079。所有动物实验遵循四川大学伦理委员会制定的伦理学要求。结果表明,与非还原敏感的对照纳米粒PSG/IR-780 NPs相比,PDG/IR-780 NPs可响应肿瘤细胞内高表达的谷胱甘肽,促进纳米粒解体,有效释放出18β-GA,对4T1细胞的杀伤效率显著提升。肿瘤组织的冰冻切片实验结果表明,与游离药物组相比,所设计的PDG NPs可提高药物在肿瘤的分布。最后,PDG/IR-780 NPs在小鼠4T1三阴性原位乳腺癌模型中表现出显著的抗肿瘤疗效,为肿瘤光热治疗提供了新的思路。

     

    Abstract: Photothermal therapy (PTT) is a highly effective anti-tumor method. However, when laser radiation was used to ablate tumors, it usually triggers a series of inflammatory reactions, promoting the further development of tumors and affecting the effect of anti-tumor therapy. Therefore, it is an effective method to improve the anti-tumor effect by suppressing the inflammatory response through the precise targeted delivery of anti-inflammatory drug while realizing the photothermal treatment of tumors. To this end, the redox-responsive linker 3,3'-dithiodipropionic acid was used to bond the classic hydrophobic anti-inflammatory drug 18β-glycyrrhetinic acid (18β-GA) and the hydrophilic fragment methoxy-polyethylene glycol (mPEG-NH2) to obtain redox-responsive amphiphilic polymer PEG-DA-GA in this study. Then, photothermal agent IR-780 was encapsulated to prepare redox-responsive polymer micelle PDG/IR-780 NPs. The PDG/IR-780 NPs exhibited uniform particle size of 80.2±5.3 nm and the polydispersity index (PDI) was 0.215±0.079. All animal experiments followed the ethical requirements formulated by the Ethics Committee of Sichuan University. The results showed that PDG/IR-780 NPs could respond to the abundant glutathione (GSH) in tumor cells to promote the disintegration of nanoparticle and the release of 18β-GA, thus significantly improved the killing efficiency on 4T1 cells, when compared with the non-redox-responsive control PSG/IR-780 NPs. When the concentration of 18β-GA was 50 μg·mL-1, the cell viability of 4T1 cells in the PDG/IR-780 NPs group was only (19.29±1.80)%, which was significantly lower than the result of in PSG/IR-780 NPs group (29.30±1.37)%. The results of frozen sections of tumor tissues showed that the designed PDG NPs can promote the tumor-targeted distribution of drugs compared with the free drug group. Eventually, PDG/IR-780 NPs achieved wonderful anti-tumor efficacy on 4T1 triple-negative breast cancer model, revealing the new possibility of the combined therapy strategy of photothermal and anti-inflammatory therapy.

     

/

返回文章
返回