克服肿瘤乏氧的超分子纳米粒的制备及其增强光动力疗效  

Preparation and enhanced photodynamic therapy of supramolecular nanoparticles to overcome tumor hypoxia

作　　者：杨雪晗 林娇 张雪婷 徐航 张佳良 宋洪涛 YANG Xue-han;LIN Jiao;ZHANG Xue-ting;XU Hang;ZHANG Jia-liang;SONG Hong-tao(School of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350108,China;900 Hospital of the Joint Logistics Team,Fuzhou 350025,China)

机构地区：[1]福建中医药大学药学院,福建福州350108 [2]中国人民解放军联勤保障部队第九〇〇医院,福建福州350025

出　　处：《药学学报》2021年第2期593-603,共11页Acta Pharmaceutica Sinica

基　　金：福建省自然科学基金资助项目(2018J01343)。

摘　　要：肿瘤乏氧的微环境使光动力治疗的疗效降低,抑制肿瘤细胞自身呼吸耗氧比增加氧供给更能有效地克服肿瘤乏氧,提高光动力治疗疗效。为了实现这一策略,本研究采用纳米沉淀法制备了装载光敏剂维替泊芬(verteporfin,VER)、耗氧抑制剂阿托伐醌(atovaquone,ATO)及稳定剂聚乙烯吡咯烷酮(PVP)-K30的超分子纳米粒(VER-ATOsupramolecular nanoparticles,VER-ATO-SMN)。以粒径作为评价指标,采用单因素实验确定VER-ATO-SMN的最佳处方为:VER∶ATO(w/w)=1∶1,PVP-K30用量100 mg,N,N-二甲基甲酰胺∶水(v/v)=1∶10;对超分子纳米粒的形态、大小、粒径分布及包封率等进行表征。结果显示,所制得超分子纳米粒为规则球形,分散性良好,水合动力学直径为101.21±4.30 nm,VER和ATO的包封率分别为70.86%和77.52%;纳米粒光稳定性良好,且在模拟生理条件溶液中稳定。与游离VER和VER脂质体相比,VER-ATO-SMN在细胞水平上表现出更强的治疗效果,其机制是能够更有效地进入肿瘤细胞,并通过降低细胞的呼吸耗氧,提高细胞内的氧浓度,从而增加了VER介导的光动力治疗产生的活性氧的数量。本文还建立了4T1荷瘤小鼠模型(动物实验符合中国实验动物护理和使用准则,并经联勤保障部队第九〇〇医院实验动物伦理委员会批准)进行体内药效实验。结果表明,VER-ATO-SMN可有效抑制肿瘤生长甚至完全消融肿瘤。The therapeutic effect of tumor photodynamic therapy is severely limited by the hypoxic tumor microenvironment.Inhibiting tumor celloxygen consumption is a more effective way than increasing its oxygen supply to overcome the tumor hypoxia and enhance photodynamic therapy.To carry out this strategy,the supramolecular nanoparticles VER-ATO-SMN loaded with photosensitizer verteporfin(VER),oxygen-consuming inhibitor atovaquone(ATO),and stabilizer polyvinylpyrrolidone(PVP)-K30 were prepared by the nanoprecipitation method,and the optimal prescription was screened and optimized by single factor experiments.The results showed that the optimal prescription for VER-ATO-SMN was ATO∶VER(w/w)=1∶1,PVP-K30=100 mg,N,N-dimethylformamide∶water(v/v)=1∶10.The morphology,particle size,particle dispersion index and encapsulation efficiency of supramolecular nanoparticles were characterized.The VER-ATO-SMN showed a spherical morphology and was well dispersed.The hydrodynamic size of VER-ATO-SMN was 101.21±4.30 nm as determined by dynamic light scattering(DLS).The encapsulation efficiencies of VER and ATO in VER-ATO-SMN prepared with the optimal prescription were 70.86%and 77.52%,respectively.The VER-ATO-SMN exhibited good laser stability and also showed high stability in conditions which simulated the physiological solution.Compared with free VER and VER liposome,VER-ATO-SMN performed enhanced therapeutic effect at the cell level.The mechanism was that VERATO-SMN could effectively incorporate into cells and improving the intracellular oxygen concentration by reducing the oxygen consumption of tumor cells could increase the amount of reactive oxygen species generated by VER mediated photodynamic therapy.The in vivo anticancer efficacy results of tumor-bearing mice suggested that VER-ATO-SMN could effectively inhibit the tumor growth or even completely eliminate the tumor.All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of 900 Hospital of the Joint

关 键 词：维替泊芬 阿托伐醌 光动力治疗 肿瘤乏氧 细胞呼吸抑制 超分子纳米粒 

分 类 号：R943[医药卫生—药剂学]