淫羊藿素与焦脱镁叶绿酸-a自组装纳米药物通过诱导细胞自噬促进肿瘤光动力疗效的研究  

Icaritin and pyropheophorbide-a self-assembled nanomedicine for enhanced the efficacy of photodynamic tumor therapy by increase the cell autophagy

作　　者：关润钿 郑蓉蓉 杨妮 饶小娜 李仕颖 GUAN Run-tian;ZHENG Rong-rong;YANG Ni;RAO Xiao-na;LI Shi-ying(School of Pharmacy,Guangzhou Medical University,Guangzhou 511436,China;School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou 510006,China)

机构地区：[1]广州医科大学药学院,广东广州511436 [2]广东药科大学药学院,广东广州510006

出　　处：《药学学报》2023年第8期2483-2493,共11页Acta Pharmaceutica Sinica

基　　金：国家重点研发计划项目(2021YFD1800600);广东省基础与应用基础项目(2021B1515020043)。

摘　　要：自噬(autophagy)经常发生在细胞遭受氧化应激(oxidative stress)后,通过吞噬受损结构并降解成营养物质,从而降低氧化损伤,促进癌细胞存活并降低光动力治疗(photodynamic therapy,PDT)的治疗效果。然而过度激活自噬能促进细胞发生凋亡,本研究使用光敏剂焦脱镁叶绿酸-a(pyropheophorbide-a,Ppa)产生大量的活性氧(reactive oxygen species,ROS)达到杀伤癌细胞的效果,同时通过联用自噬诱导剂淫羊藿素(icaritin,Ica)过度激活自噬,使其对癌细胞的保护转变为促进癌细胞凋亡的作用,进而达到提高PDT的效果。本研究利用Ica与Ppa间的相互作用力,成功构建了具有稳定性好、载药量高等特点的自组装纳米药物IP。其中,该纳米药物合成方法简单,通过药物自身作为载体,将Ica与Ppa的载药量(loading capacity,LA)分别提升至83.53%和16.45%,且不引入纳米载体潜在的生物安全性隐患。与游离Ppa相比,自组装纳米药物IP在细胞摄取和ROS产生等方面展现出优越性能。此外,自组装纳米药物IP能通过激活肿瘤细胞发生自噬,进而逆转PDT诱发的保护性自噬并促进细胞凋亡和抗肿瘤协同,显著提高PDT的抗肿瘤活性。Autophagy often occurs after cells are attacked by oxidative stress,where damaged structures are phagocytic and degraded into nutrients,thereby reducing oxidative damage,promoting the survival of cancer cells and reducing the therapeutic effect of photodynamic therapy(PDT).However,excessive activation of autophagy can promote cell apoptosis.In this paper,the photosensitizer pyropheophorbide-a(Ppa)was used to produce a large amount of reactive oxygen species(ROS)to achieve the effect of killing cancer cells.At the same time,icaritin(Ica),an autophagy inducer,was used to over-activate autophagy,which transformed the protection of cancer cells into the promotion of cancer cell apoptosis,so as to improve the effect of photodynamic therapy.In this study,the interaction force between Ica and Ppa was exploited to successfully construct a self-assembled nanomedicine IP with good stability and high drug load.The synthesis method is simple,through using the drug itself as a carrier,and the loading capacity(LA)of Ica and Ppa can be increased to 83.53%and 16.45%without introducing potential biosafety risks of nanocarriers.Compared with free Ppa,self-assembled nanomedicine IP showed superior performance in cellular uptake and reactive oxygen species production.In addition,the self-assembled nanomedicine IP can reverse the protective autophagy induced by PDT by activating the autophagy of tumor cells,and facilitate apoptosis and antitumor coordination,which significantly improves the antitumor activity of PDT.

关 键 词：光动力治疗 自噬 自组装 纳米药物 癌症 

分 类 号：R945[医药卫生—微生物与生化药学]