CN117414442A - 金属多酚网络重组高密度脂蛋白的纳米递药系统及其制备方法和应用 - Google Patents
金属多酚网络重组高密度脂蛋白的纳米递药系统及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种金属多酚网络重组高密度脂蛋白纳米递药系统及其制备方法和应用,其中递药系统由药物内核和仿生外壳组成,载药内核为丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A与铁离子配位自组装形成的金属多酚网络;仿生外壳为装载有丹参酮IIA的重组高密度脂蛋白,其表面修饰有apoA‑I,其通过物理包埋的方式包载药物内核后形成金属多酚网络重组高密度脂蛋白纳米递药系统。该纳米递药系统有助于提高药物的生物利用度和靶向动脉粥样硬化斑块的能力。
Description
技术领域
本发明属于药物化学技术和药物递送系统技术领域,更具体地涉及一种金属多酚网络重组高密度脂蛋白的纳米递药系统及其制备方法和应用。
背景技术
动脉粥样硬化是一种慢性炎症性血管疾病,作为许多心血管疾病的发病基础,如冠心病、动脉疾病、急性心肌梗死等。脂质代谢障碍为动脉粥样硬化的病变基础,其特点是受累动脉病变从内膜开始,一般先有脂质和复合糖类积聚、出血及血栓形成,进而纤维组织增生及钙质沉着,并有动脉中层的逐渐蜕变和钙化,导致动脉壁增厚变硬、血管腔狭窄。病变常累及大中肌性动脉,一旦发展到足以阻塞动脉腔,则该动脉所供应的组织或器官将缺血或坏死。
目前临床上常用的治疗动脉粥样硬化的药物主要为他汀类药物,其可通过降低血脂水平来减缓动脉粥样硬化的发病进展,从而降低心血管事件的发生风险。但是他汀类药物在临床上治疗动脉粥样硬化患者过程中也存在一定的问题,主要体现在可能造成横纹肌、需要长期用药、无法逆转已经生成的粥样斑块等问题。
所以,提供一种新型的治疗动脉粥样硬化的药物是很有必要的。
发明内容
本发明的目的是提供一种金属多酚网络重组高密度脂蛋白的纳米递药系统及其制备方法和应用。本发明以丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A,金属多酚网络作为药物内核、装载有丹参酮IIA的重组高密度脂蛋白为载药外壳,构建一种新型治疗动脉粥样硬化的纳米粒,该纳米递药系统提高了在体内的循环时间并且具有良好的靶向性。
为解决上述问题,本发明采用如下技术方案:
本发明第一方面提供金属多酚网络重组高密度脂蛋白的纳米递药系统,该递药系统包括药物内核和药物载体;其中,所述药物内核包括铁离子、丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A;所述药物载体为重组高密度脂蛋白。
进一步的,所述重组高密度脂蛋白包括磷脂、胆固醇、胆酸钠,载脂蛋白和丹参酮IIA。
进一步的,所述磷脂为大豆卵磷脂;所述载脂蛋白为apoA-I。
本发明第二方面提供金属多酚网络重组载脂蛋白的纳米递药系统的制备方法,其特征在于,该方法包括:以铁离子与丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A配位聚合而成,得到所述药物内核,记为SSPH-MPN;将所述SSPH-MPN被装载有的脂质体囊泡包载后,再通过apoA-I进行修饰,以使所述SSPH-MPN的表面形成重组高密度脂蛋白,得到所述金属多酚网络重组载脂蛋白的纳米递药系统,记为SSPH-MPN@rHDL。
进一步的,该方法具体包括,
步骤一、SSPH-MPN的制备:将丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A共同溶解于水中,加入聚乙烯吡咯烷酮水溶液,得到药物溶液;将三氯化铁溶液和聚乙烯吡咯烷酮水溶液混合,得到金属离子溶液;将所述金属离子溶液逐滴加入药物溶液中,室温条件下磁力搅拌24小时,使用针式过滤器过滤两次,得到SSPH-MPN;
步骤二、SSPH-MPN@rHDL的制备:将磷脂、胆固醇、胆酸钠溶于有机溶剂中得到料A,丹参酮IIA溶于甲醇溶液得到料B;将所述料B缓慢滴加入料A中,然后在水浴下减压旋蒸至形成均匀的脂质油膜后,置于真空干燥箱中40℃干燥2小时,挥去溶剂,得到料C;将SSPH-MPN加入所述料C中,超声水浴辅助两者混合,然后进行探头超声处理,随后进行过滤得到料D;往所述料D中加入载脂蛋白apoA-I,搅拌过夜,然后使用挤出仪挤出10~15次,得到SSPH-MPN@rHDL。
进一步的,步骤一中,所述丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A的质量比为1:1:1:1;丹参素和三氯化铁的摩尔比为1:3~1:6,丹参素和聚乙烯吡咯烷酮的质量比为1:20~1:30;步骤二中,所述磷脂与胆固醇的质量比为1:1~2:3,磷脂与胆酸钠的质量比为1:1~2:3;磷脂与丹参酮IIA的质量比为15:1~20:1,磷脂与载脂蛋白的质量比为10:1。
进一步的,步骤二中,所述有机溶剂体积比为1:1~1:2的甲醇和氯仿混合而成;所述探头超声处理的工作参数具体为:超声探头功率为150瓦,超声功率为10%~30%,工作2~5秒,间歇1~3秒,超声总时间为10~30分钟;所述挤出仪为含有孔径为200纳米的聚酯碳酸脂膜的挤出仪。
本发明第三方面提供如上述的金属多酚网络重组高密度脂蛋白的纳米递药系统在治疗动脉粥样硬化领域中的应用。
与现有的技术相比,本发明具有如下优点:
本发明将重组高密度脂蛋白和金属-多酚网络结合,形成了一种新型的仿生纳米靶向制剂,利用重组高密度脂蛋白本身与内源性脂蛋白相似的特性,将金属多酚网络装载于重组高密度脂蛋白中,同时因为重组高密度脂蛋白的磷脂双分子层内部亲脂性的特性,在制备载体的过程中将丹参酮IIA这一亲脂性的成分装载于仿生外壳中,从而完善基于丹参-红花药对的“药辅合一”型纳米药物递送系统构建,达到安全高效的协同抗动脉粥样硬化的作用,体现了中药多成分共递送载体的设计,在一定程度上解决中药多成分药物共递送的瓶颈问题。
本发明采用的药物为丹参素、原儿茶醛、丹酚酸B、羟基红花黄色素A和丹参酮IIA,是中药丹参和红花中主要的活性成分,丹参-红花作为中药中常用于治疗动脉粥样硬化的药对已被广泛使用,具有抗氧化、抗炎、抑制血小板凝聚、促进血管舒张和调节血脂等多种疗效,可通过“多点、多通路、多环节”发挥治疗动脉粥样硬化的作用,但是丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A水溶性较强,药物容易在体内降解,导致生物利用度低,临床使用受限。为使这些药物在治疗动脉粥样硬化做发挥更大的疗效,将这些药物与铁离子自组装形成金属-多酚网络结构,在不影响药物本身疗效发挥的基础上,提高药物的生物利用度。
附图说明
图1为实施例1中SSPH-MPN和SSPH-MPN@rHDL的透射电镜图;
图2为实施例1中SSPH-MPN和SSPH-MPN@rHDL的粒径图和电位图;
图3为实施例1中体外抗氧化活性的实验结果图;
图4为实施例2中SSPH-MPN和SSPH-MPN@rHDL的体内靶向性实验结果图;
图5为实施例3中SSPH-MPN@rHDL治疗动脉粥样硬化模型动物的主动脉瓣苏木精-伊红染色图;
图6为实施例3中SSPH-MPN@rHDL治疗动脉粥样硬化模型动物的主动脉瓣免疫组化染色图。
具体实施方式
发明人发现,中药治疗动脉粥样硬化的体现在综合疗效的方面,体现在其具有潜在的抗炎、抗氧化和心血管保护作用。丹参-红花作为中药中常用于治疗动脉粥样硬化的药对被广泛使用,其有效成分(丹酚酸B、丹参素、原儿茶醛、羟基红花黄色素A、丹参酮IIA)可通过“多点、多通路、多环节”发挥治疗作用。
丹参素作为一种从丹参中提取的有效成分,具有多重功效,包括抗氧化、抗炎、抑制血栓形成、血管扩张和调节血脂等作用,其原理主要在于通过减轻氧化应激和炎症、抑制血栓形成以及改善血管功能等多种途径,降低动脉粥样硬化的风险和进展,为心血管健康提供潜在的保护。丹酚酸B是从丹参中提取的活性成分,具有多重功效,包括抗氧化、抗炎、抑制血栓形成、促进血管舒张和调节血脂代谢等作用。其抗动脉粥样硬化原理主要在于通过减少氧化应激和炎症、抑制血小板凝聚、增强一氧化氮的释放,以及降低胆固醇水平等多种途径,减缓动脉粥样硬化的发展进程,减少心血管事件的风险。原儿茶醛具有抗氧化和抗炎特性,可通过减少氧化应激和炎症反应、抑制血管内胆固醇的氧化以及改善内皮功能等多重机制,有望减缓动脉粥样硬化的进展,降低心血管疾病风险,为心血管健康提供潜在保护作用。然而,目前还需要进一步研究和临床验证其在动脉粥样硬化治疗中的确切效益。羟基红花黄色素A是从红花中提取的化合物,具有多种生物活性,包括抗氧化、抗炎、抑制血小板凝聚和促进血管舒张等作用。其抗动脉粥样硬化原理主要在于通过减少氧化应激和炎症、抑制血栓形成、促进一氧化氮(NO)的释放以及改善血管内皮功能等多种途径,有望减缓动脉粥样硬化的发展,改善心血管健康,降低心脏疾病和中风等心血管事件的风险。然而,其具体效益需要进一步的研究和临床验证。然而,这些成分均为多酚类的水溶性成分,体内代谢较快,加之动脉粥样硬化斑块形态不规则,呈弥散性分布,使用传统的用药方式会导致各成分难以共递送至病灶区域,影响药物疗效的发挥。
近年来的研究表明,通过金属-多酚网络结构的形成可以增强多酚类药物体内的稳定性,从而改善药物的体内效应。发明人在前期的研究中发现这4种成分可与铁离子自组装形成金属多酚网络。为了实现更好的治疗效果,利用重组高密度脂蛋白本身与内源性脂蛋白相似的特性,将金属多酚网络装载于重组高密度脂蛋白中,同时利用重组高密度脂蛋白存在疏水性空腔的特性,在制备载体的过程中将丹参酮IIA这一亲脂性的成分装载于仿生外壳内,从而完善基于丹参-红花药对“药辅合一”型纳米药物递送系统的构建。因此,基于金属-多酚网络改善丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A的生物利用度,通过和装载有丹参酮IIA的重组高密度脂蛋白载体结合,可以提高药物的靶向性,最终提高药物抗动脉粥样硬化的疗效。
综上所述,本发明以丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A与铁离子形成的金属多酚网络为药物内核,以装载丹参酮IIA的重组高密度脂蛋白作为仿生外壳,构建一种新型治疗动脉粥样硬化的纳米粒,改仿生靶向纳米递药系统可解决的问题:(1)解决了水溶性药物给药后生物利用度低的缺陷,将水溶性药物形成金属多酚网络能够更好的发挥药物的治疗作用;(2)采用重组高密度脂蛋白作为药物载体,并将亲脂性的成分装载于载体中,载体本身具有与内源性脂蛋白相似的抗动脉粥样硬化的作用;使用它作为药物载体,具有提高药物生物相容性和体内靶向性的能力,避免被免疫系统清除、达到长循环效果。
本发明第一方面提供金属多酚网络重组高密度脂蛋白的纳米递药系统,该递药系统包括药物内核和药物载体;其中,所述药物内核包括铁离子、丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A;所述药物载体为重组高密度脂蛋白。
发明原理为:本发明提供的重组高密度脂蛋白的纳米递药系统静脉注射进入体内后,可利用重组高密度脂蛋白的特性将纳米载体靶向递送至动脉粥样硬化斑块部位,因该纳米载体具有生物降解性,因此可以将药物内核和装载药物释放;由于药物内核中金属-多酚网络结构可在动脉粥样硬化斑块区偏酸微环境下释放药物,从而达到丹参-红花多成分药物的协同增效作用,最终提高治疗效果。
本发明第二方面提供金属多酚网络重组载脂蛋白的纳米递药系统的制备方法,其特征在于,该方法包括:以铁离子与丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A配位聚合而成,得到所述药物内核,记为SSPH-MPN;将所述SSPH-MPN被装载有的脂质体包载后,再通过apoA-I进行修饰,以使所述SSPH-MPN的表面形成重组高密度脂蛋白,得到所述金属多酚网络重组载脂蛋白的纳米递药系统,记为SSPH-MPN@rHDL。
下面结合具体实施方式,进一步阐述本发明。
实施例1
(1)金属多酚网络重组载脂蛋白的纳米递药系统制备
分别称取丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A溶解于2mL水中,加入2mL浓度为100mg/mL的聚乙烯吡咯烷酮(polyvinyl pyrrolidone,PVP)水溶液,组成药物相,其中丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A的质量比为1:1:1:1,四种药物总量不低于1mg/mL。将浓度为10mg/mL的FeCl3溶液和2mL浓度为100mg/mL的PVP水溶液组成金属离子相,按照丹参素和三氯化铁的摩尔比为1:3~1:6计算FeCl3溶液用量,溶液配制完成后保持两相溶液体积比为1:1~1:1.5。将金属离子相逐滴加入含药相中,室温条件下磁力搅拌12~24小时后,使用0.22μm微孔滤膜过滤两次,制得SSHP-MPN。
分别称取大豆卵磷脂、胆固醇、胆酸钠溶解于有机溶剂中(甲醇:氯仿=1:1~1:5),加入浓度为1mg/mL丹参酮IIA甲醇溶液,其中磷脂与胆固醇的质量比为1:1~2:3,磷脂与胆酸钠的质量比为1:1~2:3;磷脂与丹参酮IIA的质量比为15:1~20:1,磷脂与有机溶剂的质量/体积比为6:5~2:1(mg:mL)。溶液40℃水浴减压蒸发形成一层均匀光滑的脂质薄膜。加入与上述有机溶剂同体积的SSHP-MPN溶液,水浴超声辅助溶解脂质膜,形成乳状混悬液,随后使用超声探头超声处理(超声探头功率为150瓦,超声功率为10%~30%,工作2~5秒,间歇1~3秒,超声总时间为10~30分钟),然后使用孔径为0.22μm的过滤器过滤,使用含有孔径为200纳米的聚酯碳酸脂膜的挤出仪挤出10~15次,制得中间体,记为SSPH-MPN@liposome。然后在SSPH-MPN@liposome中加入载脂蛋白apoA-I,按照磷脂与载脂蛋白的质量比为10:1~15:1计算载脂蛋白用量。搅拌过夜,使用含有孔径为200纳米的聚酯碳酸脂膜的挤出仪挤出10~15次,制得金属多酚网络重组载脂蛋白的纳米递药系统,记为SSPH-MPN@rHDL。
(2)金属多酚网络重组载脂蛋白的纳米递药系统表征
使用透射电镜观察纳米粒的形态和粒径分布,如图1所示,SSPH-MPN为具有明显壳核结构的类球形粒径分布均一。使用动态光散射(Dynamic Light Scattering,DLS)粒径电位仪检测纳米粒的平均粒径和电位,如图2所示,其中图2的左图为SSPH-MPN与SSPH-MPN@rHDL的粒径图,右图为SSPH-MPN与SSPH-MPN@rHDL的电位图。从图2中可以看出,SSPH-MPN粒径为162.7±2.7nm,电位为-5.81±0.3mV;SSPH-MPN@rHDL粒径为240.6±7.9nm,电位为-4.94±1.2mV。
(3)金属多酚网络重组载脂蛋白的体外抗氧化活性评价
采用1,1-二苯基-2-三硝基苯肼(1,1-diphenyl-2-picrylhydrazyl,DDPH)自由基清除率实验检测评价纳米粒的体外抗氧化活性,具体实验方法为:将1.4mL的DPPH乙醇溶液(40μg/mL)与等体积的不同浓度(0.1、0.2、0.5、1.0、2.0mg/mL)的SSPH-MPN、SSPH-MPN@liposome和SSPH-MPN@rHDL样品混合,避光孵育30min后,使用紫外-可见分光光度计测量每个样品在517nm处的吸光度。阴性对照为样品加入等体积的乙醇溶液,阳性对照为DPPH加入等体积的水。DPPH自由基清除率计算如下方程所示:
采用超氧阴离子清除率检测评价纳米粒的体外抗氧化活性,具体实验方法为:1.65mL三(羟甲基)氨基甲烷盐酸(Tris-HCl)缓冲溶液、0.25mL烟酰胺腺嘌呤二核苷酸(Nicotinamide Adenine Dinucleotide,NADH)(156μM)和0.2mL氯化硝基四氮唑蓝(Nitro-tetrazolium Chloride Blue,NBT)(150μM)与0.2mL不同浓度(0.1、0.2、0.5、1.0、2.0mg/mL)的SSPH-MPN、SSPH-MPN@liposome和SSPH-MPN@rHDL混合,然后加入0.2mL吩嗪甲基硫酸盐(Phenazine Methyl Sulfate,PMS)(450μM),并让其反应5min。使用紫外-可见分光光度计在560nm处测量了每个样品的吸光度。实验过程中不加入PMS的实验组作为相应药物的阴性对照组,不加入各组样品的实验组作为阳性对照组。超氧阴离子清除率的计算如下方程所示:
如图3所示,其中图3的左图为SSPH-MPN、SSPH-MPN@liposome与SSPH-MPN@rHDL的DPPH自由基清除率的结果图,右图为SSPH-MPN、SSPH-MPN@liposome与SSPH-MPN@rHDL的DPPH的超氧阴离子清除率的结果图。从图3中可以看出,SSPH-MPN、SSPH-MPN@liposome和SSPH-MPN@rHDL纳米粒随着浓度的升高,其体外抗氧化活性也逐步升高,总体呈现出一个较好的抗氧化活性水平,说明将四种药物进行配位组装,不会显著影响药物本身的抗氧化能力。
实施例2
(1)装载DiR的荧光探针的金属多酚网络重组载脂蛋白的纳米递药系统制备
将按照实施例1中所述方法制得的1mL SSHP-MPN中加入0.1mL浓度为1mg/mL的DiR甲醇溶液,在4~10℃的避光条件下孵育2h,得到DiR-SSHP-MPN;将按照实施例1中所述方法制得的1mL SSHP-MPN@rHDL中加入0.1mL浓度为1mg/mL的DiR甲醇溶液,在4~10℃的避光条件下孵育2h,得到DiR-SSHP-MPN@rHDL。
(2)金属多酚网络重组载脂蛋白的纳米递药系统靶向性评价
采用活体成像仪对给药4h后的小鼠的各个器官的药物分布进行定量。具体实验方法如下:按每只小鼠0.2mL的药物剂量进行尾静脉注射,对照组的注射剂量与给药组的DiR浓度一致。注射后4h处死小鼠,取心、肝、脾、肺、肾和主动脉在小动物成像系统中进行定量和计算。如图4所示,相较于对照组,SSPH-MPN和SSPH-MPN@rHDL在体内循环的时间明显延长;相较于SSPH-MPN,SSPH-MPN@rHDL的主动脉靶向性有显著性的提升,说明金属多酚网络重组载脂蛋白的纳米递药系统有效延长了药物在体内的循环时间并且提高了药物对于主动脉的靶向能力。
实施例3
(1)动物给药制剂制备
按照实施例1中所述方法的基础上,为满足动物实验剂量要求,使药物内核浓度提高10倍。具体制备方法如下:分别称取12mg的丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A溶解于5.4mL水中,加入0.6mL浓度为100mg/mL的PVP水溶液,混合均匀,组成药物相。精密量取1.384mL的浓度为50mg/mL的FeCl3溶液和0.6mL浓度为100mg/mL的PVP水溶液加入到2.076mL的水中,混合均匀,组成金属离子相。将金属离子相逐滴加入药物相中,室温下搅拌24h后使用0.22μm过滤器过滤3次,使用含有孔径为200纳米的聚酯碳酸脂膜的挤出仪挤出10-15次,制得动物给药制剂SSHP-MPN。
分别称取20mg大豆卵磷脂、25mg胆固醇、20mg胆酸钠溶解于12mL有机溶剂中(甲醇:氯仿=1:1),加入1mL浓度为1mg/mL丹参酮IIA甲醇溶液,溶液40℃水浴减压蒸发形成一层均匀的油膜。加入12mL动物给药制剂SSHP-MPN,水浴超声辅助溶解油膜,形成乳状混悬液,然后使用超声探头处理(功率为150瓦,工作2秒,间歇1秒,时间为20min),然后使用孔径为0.22μm的过滤器过滤3次,使用含有孔径为200纳米的聚酯碳酸脂膜的挤出仪挤出10~15次,制得中间体(SSPH-MPN@liposome)。然后再每1mL SSPH-MPN@liposome中加入2mg载脂蛋白apoA-I,搅拌过夜,使用含有孔径为200纳米的聚酯碳酸脂膜的挤出仪挤出10-15次,制得动物给药制剂SSHP-MPN@rHDL。
(2)金属多酚网络重组载脂蛋白的纳米递药系统抗动脉粥样硬化疗效评价
适应性喂养一周后,将18只6周龄雄性ApoE-/-小鼠随机分为3组,每组6只:对照组、模型组和SSHP-MPN@rHDL给药组。小鼠高脂饲养12周后,停喂高脂饲料,改为标准饲料。对照组和SSHP-MPN@rHDL分别静脉注射0.2mL生理盐水和SSHP-MPN@rHDL,给药组注射剂量为20mg/kg的药物浓度,每周3次,模型组小鼠不做任何处理,给药8周后,处死小鼠以获取心脏和主动脉用于苏木精-伊红染色和免疫组化染色切片的制作。
如图5所示,相较于模型组,给药组的动脉粥样硬化病灶区域有明显减少。如图6所示,相较于模型组,给药组在CD68和NF-κb的表达有较为明显的下降现象。表明纳米粒具有减少动脉粥样硬化斑块区域脂质累积和降低局部炎症反应的作用,从而发挥出抗动脉粥样硬化的疗效。
本领域的普通技术人员可以理解,上述各实施方式是实现本申请的具体实施例,而在实际应用中,可以在形式上和细节上对其作各种改变,而不偏离本申请的精神和范围。任何本领域技术人员,在不脱离本申请的精神和范围内,均可作各自更动与修改,因此本申请的保护范围应当以权利要求限定的范围为准。
Claims (8)
1.金属多酚网络重组高密度脂蛋白的纳米递药系统,其特征在于,该递药系统包括药物内核和药物载体;
其中,所述药物内核包括铁离子、丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A;所述药物载体为重组高密度脂蛋白。
2.根据权利要求1所述的金属多酚网络重组载脂蛋白的纳米递药系统,其特征在于,所述重组高密度脂蛋白包括磷脂、胆固醇、胆酸钠,载脂蛋白和丹参酮IIA。
3.根据权利要求2所述的金属多酚网络重组载脂蛋白的纳米递药系统,其特征在于,所述磷脂为大豆卵磷脂;所述载脂蛋白为apoA-I。
4.根据权利要求1至3中任一项所述的金属多酚网络重组载脂蛋白的纳米递药系统的制备方法,其特征在于,该方法包括:
以铁离子与丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A配位聚合而成,得到所述药物内核,记为SSPH-MPN;
将所述SSPH-MPN被装载有的脂质体囊泡包载后,再通过apoA-I进行修饰,以使所述SSPH-MPN的表面形成重组高密度脂蛋白,得到所述金属多酚网络重组载脂蛋白的纳米递药系统,记为SSPH-MPN@rHDL。
5.根据权利要求4所述的金属多酚网络重组高密度脂蛋白的纳米递药系统的制备方法,其特征在于,该方法具体包括,
步骤一、SSPH-MPN的制备:
将丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A共同溶解于水中,加入聚乙烯吡咯烷酮水溶液,得到药物溶液;
将三氯化铁溶液和聚乙烯吡咯烷酮水溶液混合,得到金属离子溶液;
将所述金属离子溶液逐滴加入药物溶液中,室温条件下磁力搅拌24小时,使用针式过滤器过滤两次,得到SSPH-MPN;
步骤二、SSPH-MPN@rHDL的制备:
将磷脂、胆固醇、胆酸钠溶于有机溶剂中得到料A,丹参酮IIA溶于甲醇溶液得到料B;
将所述料B缓慢滴加入料A中,然后在水浴下减压旋蒸至形成均匀的脂质油膜后,置于真空干燥箱中40℃干燥2小时,挥去溶剂,得到料C;
将SSPH-MPN加入所述料C中,超声水浴辅助两者混合,然后进行探头超声处理,随后进行过滤得到料D;
往所述料D中加入载脂蛋白apoA-I,搅拌过夜,然后使用挤出仪挤出10-15次,得到SSPH-MPN@rHDL。
6.根据权利要求5所述的金属多酚网络重组高密度脂蛋白的纳米递药系统的制备方法,其特征在于,步骤一中,所述丹参素、原儿茶醛、丹酚酸B和羟基红花黄色素A的质量比为1:1:1:1;丹参素和三氯化铁的摩尔比为1:3~1:6,丹参素和聚乙烯吡咯烷酮的质量比为1:20~1:30;
步骤二中,所述磷脂与胆固醇的质量比为1:1~2:3,磷脂与胆酸钠的质量比为1:1~2:3;磷脂与丹参酮IIA的质量比为15:1~20:1,磷脂与载脂蛋白的质量比为10:1。
7.根据权利要求5所述的金属多酚网络重组高密度脂蛋白的纳米递药系统的制备方法,其特征在于,步骤二中,所述有机溶剂为体积比为1:1~1:2的甲醇和氯仿混合而成;所述探头超声处理的工作参数具体为:超声探头功率为150瓦,超声功率为10%~30%,工作2~5秒,间歇1~3秒,超声总时间为10~30分钟;所述挤出仪为含有孔径为200纳米的聚酯碳酸脂膜的挤出仪。
8.如权利要求1至3中任一项所述的金属多酚网络重组高密度脂蛋白的纳米递药系统在治疗动脉粥样硬化领域中的应用。
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