一氧化氮和光动力协同治疗的自组装纳米粒的制备及其药效学评价  

Preparation and Pharmacodynamics Evaluation of Self-Assembled Nanoparticles for Synergistic Treatment of NO and Photodynamic Therapy

作　　者：卡迪热娅·艾克拉木 白静雅 仲春红 张倩[1] 苏文君 王梅[1] Kadireya·Aikelamu;BAI Jingya;ZHONG Chunhong;ZHANG Qian;SU Wenjun;WANG Mei(College of Pharmacy,Xinjiang Medical University,Engineering Research Center of Xinjiang and Central Asian Medicine Resources,Ministry of Education,Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology,Urumqi 830017,China)

机构地区：[1]新疆医科大学药学院,教育部工程研究中心新疆及中亚特色医药资源教育部工程研究中心,新疆天然药物活性组分与释药技术重点实验室,乌鲁木齐830017

出　　处：《中国药学杂志》2025年第1期55-65,共11页Chinese Pharmaceutical Journal

基　　金：新疆维吾尔自治区研究生科研创新项目资助(XJ2023G197);新疆天然活性组分和释药技术重点实验室项目资助(XJDX1713)。

摘　　要：目的合成及制备一氧化氮供体-酞菁硅偶联前药自组装纳米粒(NO-SiPc-NO@NPs),并对纳米粒的制剂学特性和药效学进行初步评价。方法通过化学反应合成了氧化呋咱类NO供体-酞菁硅光敏剂偶联物。采用纳米沉淀法制备NO-SiPc-NO@NPs,并以粒径、多分散系数(PDI)和Zeta电位为评价指标,考察NO-SiPc-NO的浓度、水相转速、有机相与水相体积比以及稳定剂DSPE-PEG2K含量等因素的影响;分别用Griess法和化学探针法检测纳米粒的体外NO和活性氧(ROS)产生以及光稳定性;在此基础上,考察NO-SiPc-NO@NPs的贮存稳定性及在不同pH的磷酸缓冲盐溶液中的体外解聚情况;最后,采用CCK-8法检测纳米粒光动力效果,通过荧光探针观察自组装纳米粒对细胞内NO的影响。结果^(1)H-NMR结果显示,NO-SiPc-NO被成功合成。最佳制备工艺条件为:NO-SiPc-NO质量浓度为2.5 mg·mL^(-1)、转速为1000 r·min^(-1)、有机相与水相体积比为1∶3和稳定剂含量为40%;所制备的自组装纳米粒粒径、PDI和电位分别为(111.467±3.365)nm,(0.123±0.035)和(-11.433±0.850)mV;透射电镜下纳米粒呈球形或类球形,形态较为完整,分布均匀;NO与ROS释放结果表明,纳米粒在溶液中能释放NO和ROS,并具有良好的光稳定性;NO-SiPc-NO@NPs在两种条件下稳定性较好,其粒径、电位、PDI、NO-SiPc-NO的包封率和载药量均无明显变化;体外纳米粒解聚实验结果表明,NO-SiPc-NO@NPs具有缓释性,并且其遵循一级动力学模型;CCK-8实验结果显示纳米粒组均呈现出剂量依赖性细胞毒性,且光照后的NO-SiPc-NO@NPs对MCF-7细胞具有更强的光动力效果;在NO测定实验中,NO-SiPc-NO@NPs在胞内能产生大量的NO。结论成功制备NO-SiPc-NO@NPs,所制备的自组装纳米粒具有良好的光动力活性,并实现了NO的有效递送,为气体疗法和光动力疗法的协同治疗奠定了理论基础。OBJECTIVE To synthesize and prepare nitric oxide donor(NODonor)-silicon phthalocyanine(SiPc)conjugated prodrug self-assembled nanoparticles(NO-SiPc-NO@NPs)and preliminarily evaluatetheir formulating properties and pharmacodynamics.METHODS Furoxan NO donor-phthalocyanine silicon photosensitizer couplings were synthesized by chemical reactions.The NO-SiPc-NO@NPs were prepared using a nanoprecipitation method,and the effects of different concentrations of NO-SiPc-NO,rotational speed,the volume ratio of the organic phase to the aqueous phase,and the content of the stabilizer DSPE-PEG2K on particle sizes,polydispersity index(PDI),and Zeta potential of NO-SiPc-NO@NPs were investigated to obtain the better prescriptions.The release of NO and reactive oxygen species(ROS)yields as well as the photostability of NO-SiPc-NO were detected by the Griess method and the chemical probe method,respectively.On this basis,the storage stability and in vitro release of NO-SiPc-NO@NPs in phosphate buffer salt solutions of different pH were investigated.Finally,the photodynamic effect of nanoparticles was detected by CCK-8 method,and the effect of self-assembled nanoparticles on intracellular NO was observed by fluorescent probe.RESULTS The^(1)H-NMR results showed that NO-SiPc-NO was successfully synthesized.The optimal preparation process conditions were:NO-SiPc-NO concentration of 2.5 mg·mL^(-1),rotational speed of 1000 r·min^(-1),organic phase to aqueous phase volume ratio of 1∶3 and stabilizer content of 40%.The prepared self-assembled nanoparticles were(111.467±3.365)nm,(0.123±0.035)and(-11.433±0.850)mV in particle size,PDI and Zeta potential,respectively.The nanoparticles in transmission electron microscopy were spherical or spheroidal in shape,with a more intact morphology and homogeneous distribution.The results of NO and ROS release showed that the nanoparticles could release NO and ROS in solution with good photostability.NO-SiPc-NO@NPs were stable under both conditions,and there was no significant change in particle si

关 键 词：一氧化氮供体-酞菁硅偶联前药自组装纳米粒 一氧化氮 光敏剂 自组装纳米粒 偶联物 MCF-7细胞 

分 类 号：R944[医药卫生—药剂学]