CN108727471A - 一种脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物及其制备方法和应用 - Google Patents
一种脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物及其制备方法和应用 Download PDFInfo
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- CN108727471A CN108727471A CN201810573603.9A CN201810573603A CN108727471A CN 108727471 A CN108727471 A CN 108727471A CN 201810573603 A CN201810573603 A CN 201810573603A CN 108727471 A CN108727471 A CN 108727471A
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Classifications
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- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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Abstract
本发明公开了一种脂肪组织靶向性多肽‑毛蕊花苷‑纳米金颗粒衍生物的制备方法:将脂肪组织靶向性多肽C端的半胱氨酸残基的羧基活化生成酰氯;将毛蕊花苷和氢氧化钠反应得到酚钠;酰氯和酚钠发生酯化反应生成脂肪组织靶向性多肽‑毛蕊花苷衍生物;将脂肪组织靶向性多肽‑毛蕊花苷衍生物和PEG修饰的纳米金颗粒反应;还公开了脂肪组织靶向性多肽‑毛蕊花苷‑纳米金颗粒衍生物及其在制备治疗肥胖疾病的药物中的应用。本发明的脂肪组织靶向性多肽‑毛蕊花苷‑纳米金颗粒衍生物,具有良好的生物相容性,可携带药物靶向进入脂肪细胞,大大增强了药物的可利用率,从而显著提高了药物的靶向抗肥胖活性。
Description
技术领域
本发明涉及靶向性多肽,具体涉及一种脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物及其制备方法和应用。
背景技术
近年来,由于膳食结构的改变,久坐的工作模式,运动量减少,生活方式逐渐西方化等因素导致能量过度摄入,使肥胖患者的数量在我国迅速增加。肥胖是由于能量摄入大于消耗导致白色脂肪(包括内脏脂肪、皮下脂肪)在体内过度堆积而形成的一种慢性代谢性疾病,它可分为中心性肥胖(也称腹型肥胖,主要表现为内脏脂肪堆积)和单纯性肥胖(主要表现为皮下脂肪堆积)两大类。大量研究发现,白色脂肪增多导致的肥胖是促进胰岛素抵抗、2型糖尿病、高血脂症、高血压等代谢性疾病发生的主要原因。此外,肥胖除与代谢性疾病有关外,还与多种肿瘤的发生和进展有着紧密的关系。因此,针对肥胖尤其是靶向白色脂肪的干预治疗是预防和治疗肥胖相关疾病的重要措施。
目前,对于肥胖症的治疗主要有饮食行为疗法、外科手术和药物治疗。对于大多数肥胖患者来说,减少能量的摄入并增加运动量可以起到减肥效果,但当停止减肥体重会反弹回去,甚至超过了减肥前的体重。而外科手术(如:缩胃术、胃旁路手术、胃束带手术)风险太大。因此,许多肥胖患者把药物治疗作为首选,美国FDA批准了两种可长期应用的减肥药,分别为西布曲明(Sibutramine)和奥利司他(Orlistat)。但长期使用后,前者可引发高血压、失眠等,后者会造成严重的胃肠道副作用,如腹泻、排泄失禁等,导致用药受到限制。因此,在参与代谢综合症相关的器官中,如何使得药物能够仅仅作用于脂肪组织,却对其他脏器和组织不造成影响,从而达到不改变人体免疫系统的基础上能更高效治疗代谢综合症的目的,成为现在肥胖治疗面临的重要问题和研究重点。
2004年,著名的科学杂志“Nature Medcine”报道发现一多肽能特异性地和白色脂肪组织血管的内皮细胞受体结合,其氨基酸序列为CKGGRAKDC。中国专利CN102120755A公开了一种棕色脂肪组织靶向性多肽及其应用,公开了多肽可以与具有生物药理活性的物质相连接,能够靶向性运送治疗性药物到达棕色脂肪组织,发挥药理学效应,从而达到靶向治疗的目的,侧重于报道一种棕色脂肪组织靶向性治疗的多肽载体,但该靶向性多肽载体的生物兼容性及所载药物的疗效如何还需要进一步验证。
发明内容
发明目的:为了解决靶向治疗肥胖的问题,本发明第一方面提供了一种脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的制备方法,本发明第二方面提供了一种脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物,本发明第三方面提供了脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物在制备治疗肥胖疾病的药物中的应用。
技术方案:本发明所述一种脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的制备方法,包括以下步骤:
(1)将脂肪组织靶向性多肽C端的半胱氨酸残基的羧基活化生成酰氯,所述脂肪组织靶向性多肽的氨基酸序列为CKGGRAKDC;
(2)将毛蕊花苷和氢氧化钠反应得到酚钠;
(3)将步骤(1)得到的酰氯和步骤(2)得到的酚钠发生酯化反应生成脂肪组织靶向性多肽-毛蕊花苷衍生物;
(4)纳米金颗粒进行PEG修饰,将步骤(3)得到的脂肪组织靶向性多肽-毛蕊花苷衍生物和PEG修饰的纳米金颗粒混合反应,其中脂肪组织靶向性多肽C端的半胱氨酸残基的巯基和纳米金通过Au-S键连接。
步骤(1)中,脂肪组织靶向性多肽的氨基酸序列中各个字母符号所代表的氨基酸残基的定义如下:C为半胱氨酸,K为赖氨酸,G为甘氨酸,R为精氨酸,A为丙氨酸,D为天冬氨酸;所述脂肪组织靶向性多肽的第2位和第7位氨基酸残基的侧链连接有氨基保护基,第5位氨基酸残基(精氨酸)连接有胍基保护基,第8位氨基酸残基连接有羧基保护基,N端氨基酸残基连接有巯基保护基,N端氨基被苄氧甲酰基保护。优选地,所述氨基保护基为9-芴甲氧羰基(Fmoc),所述胍基保护基为金刚烷氧羰基(Adoc),羧基保护基为甲酯,巯基保护基为三苯甲基。
步骤(1)中,将多肽CKGGRAKDC用DMSO溶解,然后将多肽溶液加入到三颈瓶内,滴加N,N-二甲基甲酰胺(DMF)和二氯亚砜,搅拌均匀,70-75℃反应1-2h,获得酰氯。
优选地,10mg多肽CKGGRAKDC(氨基、侧链羧基、N端巯基已保护)用1mL DMSO溶解,加入到三颈瓶内,滴加2-5滴的DMF,观察温度计使瓶内温度控制在25℃以下,缓慢滴加3-5mL二氯亚砜,搅拌均匀。随后缓慢升温,于70-75℃反应1-2h,冷却,获得酰氯,密封备用。
步骤(2)中,将毛蕊花苷与氢氧化钠分别用甲醇溶解,将彻底溶解的两种溶液混合,室温反应,生成酚钠。其中,毛蕊花苷的化学结构式见式Ⅰ,毛蕊花苷和氢氧化钠的摩尔比为1:4,即NaOH的量足以和毛蕊花苷的4个酚羟基都发生反应。
优选地,将0.1mol毛蕊花苷和0.4mol氢氧化钠放入20mL的甲醇中,充分搅拌均匀至完全溶解。随后,将两种溶液等体积、室温充分混合反应。
步骤(3)中,将步骤(2)得到的酚钠溶解在去离子水中,充分搅拌,然后在低温下缓慢均匀滴加步骤(1)获得的酰氯,于10-15℃搅拌反应1.5-2h,反应完全后,清洗、抽滤、压干,获得脂肪组织靶向性多肽-毛蕊花苷衍生物。优选地,步骤(1)中所述脂肪组织靶向性多肽和步骤(2)中所述毛蕊花苷的摩尔比为1-5:1。
步骤(4)中,所述纳米金颗粒进行PEG修饰的步骤如下:将纳米金颗粒与2mM SH-mPEG-COOH(分子量5000)溶液于20-25℃混合,搅拌孵育12-24h,随后经离心、洗涤3次将未反应的SH-mPEG-COOH清除,所得沉淀溶于去离子水中备用;所述脂肪组织靶向性多肽-毛蕊花苷衍生物和PEG修饰的纳米金颗粒的摩尔比为106:9-5(摩尔比以毛蕊花苷和纳米金的摩尔量确定),反应条件为避光过夜摇匀,摇床转速200-250rpm,温度20-25℃。其中纳米金具有抑制肥胖和提高衍生物的生物兼容性的作用。
本发明第二方面提供上述制备方法制备得到的脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物。
本发明第三方面提供所述脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物在制备治疗肥胖疾病的药物中的应用。优选地,所述药物为注射剂。
有益效果:(1)本发明提供的脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物,具有良好的生物相容性,可携带药物靶向进入脂肪细胞,大大增强了药物的可利用率,从而显著提高了药物的靶向抗肥胖活性,适用于不同给药方法如静脉注射的靶向作用、腹腔、肌肉和皮下注射的缓控释作用;(2)本发明所用的材料成本低廉、便于获取,制备过程简单快捷,且为常规反应,未破坏药物本身的性质;且本法制备的脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物性质稳定,便于保存。
附图说明
图1为TEM检测脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的大小,图片由左到右依次代表:纳米金颗粒的大小;脂肪组织靶向性多肽-毛蕊花苷衍生物与纳米金的体积比为1:9时获得的脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的大小;
图2为1DLS检测脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的大小,图片由上到下依次代表:纳米金颗粒的大小;脂肪组织靶向性多肽-毛蕊花苷衍生物与纳米金的体积比为1:9时获得的脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的大小;
图3为高脂喂养肥胖小鼠,造模过程中两组小鼠体重变化;
图4为H-E染色检测各组小鼠肝脏和肾脏的病理变化。
具体实施方式
实施例1脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的制备
实验药品:多肽由南京金斯瑞生物科技有限公司合成并进行侧链保护,纳米金颗粒购于Sigma公司,毛蕊花苷购自中科院西北高原生物研究所。
实验步骤:
1)称量10mg化学合成的多肽CKGGRAKDC(氨基、侧链羧基、N端巯基已保护)用1mLDMSO溶解,加入到含有温度计、冷凝管的三颈瓶内,滴加2-5滴的DMF,观察温度计使瓶内温度控制在25℃以下,缓慢滴加3-5mL二氯亚砜,搅拌均匀。随后缓慢升温,于70-75℃反应1-2h,冷却,获得酰氯,密封备用;
2)分别将0.1mol毛蕊花苷和0.4mol氢氧化钠放入各含有20mL甲醇的两个100mL圆底烧瓶内,充分搅拌均匀至完全溶解。随后,将两种溶液等体积、室温充分混合反应。电磁搅拌(200r/min)的同时,毛细管通入氩气鼓泡,水泵减压缓慢蒸出甲醇,冷却沉淀至室温,磨碎,真空干燥过夜,生成的酚钠于干燥器中保存备用;
3)称取10mg酚钠放入含有温度计、搅拌器的300mL三颈瓶内,加水30mL,充分搅拌后冷却至0-5℃,缓慢均匀滴加酰氯(按酚钠与酰氯的摩尔比1:1.5的量滴加酰氯,其中酚钠的分子量为712.59),半小时完毕,密闭静置,于10-15℃搅拌反应1.5-2h。反应完全后,反应液过滤,用10-15mL去离子水清洗、抽滤得到的滤饼,反复3次后,压干,获得脂肪组织靶向性多肽-毛蕊花苷衍生物粗品。随后将得到的粗品及10倍量的无水乙醇放入300mL圆底烧瓶中,加热回流让其彻底溶解,冷却后加入适量活性炭,继续加热回流20min。趁热过滤,滤液放置析出晶体,获得纯的脂肪组织靶向性多肽-毛蕊花苷衍生物,保存备用;
4)将2×1010粒径为20nm的纳米金颗粒与5mL SH-mPEG-COOH溶液(浓度为2mM)25℃混合,搅拌孵育12h,随后经离心、洗涤3次将未经反应的SH-mPEG-COOH清除,所得沉淀为PEG修饰的纳米金颗粒,溶于去离子水中备用;
5)向10mL PEG修饰的粒径为20nm的纳米金颗粒溶液中滴加浓度为10wt.%的碳酸钾水溶液,调节pH值至7;然后将DMSO溶解的浓度为1mM脂肪组织靶向性多肽-毛蕊花苷衍生物溶液(以毛蕊花苷的摩尔量计算,10μL)与1nM纳米金溶液(90μL)以体积比1:9的比例混合(取出的纳米金加完碳酸钾后需立即加入脂肪组织靶向性多肽-毛蕊花苷衍生物以免纳米金聚团),包锡箔纸避光过夜摇匀,摇床转速200rpm,温度25℃;
6)次日向每管加PBS定容到1mL,然后移到1.5mL的离心管,于4℃、14000rpm离心30min,后用无菌PBS洗3次(4℃、14000rpm、5min),随后再加100μLPBS重悬衍生物;
7)TEM检测:配制2%的磷戊酸:称取0.02g的磷戊酸用1mL水溶解,超声振荡后用氢氧化钠将pH调到6-7之间。取3个铜网,将样品分别滴于铜网上,5min后用滤纸吸干水分后,用2%的磷戊酸复染两分钟。最后吸干水分,置于滤纸上干燥以备拍摄。在40000-50000放大倍数下保证比例尺为100nm,曝光时间2-3s下拍摄;
8)动态光散射(DLS)检测:将样品加超纯水稀释至1mL,吹打混匀后做上机检测大小。
TEM检测结果如图1所示,同单纯的纳米金颗粒相比,脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的纳米金颗粒表面有一层脂肪组织靶向性多肽-毛蕊花苷衍生物的富集(黑色箭头所示,一层半透明的圆环围绕),且经DLS检测(如图2)进一步分析发现,脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物同单纯的纳米金颗粒相比,粒径峰有了明显的偏移,说明脂肪组织靶向性多肽-毛蕊花苷衍生物有效结合到了纳米金颗粒的表面,明显增加了纳米金颗粒大小。这些都说明脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物已构建成功。
实施例2脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的制备
制备方法同实施例1,不同的是步骤3)中酚钠与酰氯的摩尔比1:5,步骤5)中脂肪组织靶向性多肽-毛蕊花苷衍生物(以毛蕊花苷的摩尔量计算)与纳米金的体积比为1:5(10μL:50μL)。
实施例3脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物可有效抑制高脂喂养小鼠的体重增加
实验动物:3-4周龄雄性小鼠及饲料,由南京医科大学实验动物中心提供,许可证号:SCXK(苏)2011-0003。动物随机分笼饲养,食水自由。
实验药品:实验组为实施例1制备的(脂肪组织靶向性)多肽-毛蕊花苷-纳米金颗粒衍生物、多肽-毛蕊花苷衍生物、多肽-纳米金衍生物、毛蕊花苷-纳米金衍生物,阴性对照为生理盐水。
实验步骤:
1)制备多肽-毛蕊花苷衍生物、多肽-纳米金衍生物及毛蕊花苷-纳米金衍生物
a:多肽-毛蕊花苷衍生物的制备:按照实施例1中的步骤制备多肽-毛蕊花苷衍生物;
b:多肽-纳米金衍生物的制备:按实施例1步骤4)的方法对纳米颗粒进行PEG修饰,取底部沉淀,用等体积的5mL去离子水稀释;将5mL 1nM 20nm PEG修饰的纳米金溶液用浓度为10wt.%的碳酸钾水溶液调节pH值为7,随后取10μL 1mM多肽溶液与90μL 1nM纳米金溶液以体积比1:9的比例室温混合;避光,25℃、200rpm过夜摇匀;次日加PBS定容到1mL,于4℃、14000rpm离心30min,后用无菌PBS洗3次(4度、14000rpm、5min);完毕后,获得沉淀,即为多肽-纳米金衍生物;
c:毛蕊花苷-纳米金衍生物的制备:按实施例1步骤4)的方法对纳米颗粒进行PEG修饰,取底部沉淀,用等体积的5mL去离子水稀释;用浓度为10wt.%的碳酸钾水溶液调pH为8,加热到60℃,随后,加入2mL 1M的毛蕊花糖苷(VB)溶液,进行酯化反应。反应2h后,离心取底部沉淀,即为金纳米颗粒共价键修饰毛蕊花糖苷的衍生物——毛蕊花苷-纳米金衍生物。
2)6周龄60只雄性小鼠在南京医科大学实验动物中心清洁环境中饲养,温度(21±2)℃,湿度(35±2)%,12h:12h昼夜间断照明,自由进食饮水,饮用水为实验动物中心制备的蒸馏水;
3)经适应性饲养2-3天后,随机取10只作为空白对照组给予常规饲料,其余50只给予高脂饲料(胆固醇1wt.%,猪油20wt.%,胆盐0.2wt.%,常规饲料78.8wt.%),每隔2周测定一次各组小鼠的体重。所得数据进行统计学处理,结果如图3所示,其中*P<0.05,**P<0.01,***P<0.001表示与正常饲料喂养的空白对照组比较;
4)选取高脂饲料喂养的肥胖小鼠随机分组,每组10只,分别于每天上午9:30注射(以腹腔注射为例说明)生理盐水(0.03mL/30g体重,模型对照组)、多肽-毛蕊花苷衍生物(15mg/kg体重,溶于DMSO中)、多肽-纳米金衍生物(15mg/kg体重,溶于DMSO中)、毛蕊花苷-纳米金衍生物(15mg/kg体重,溶于DMSO中)和多肽-毛蕊花苷-纳米金颗粒衍生物(15mg/kg体重,溶于DMSO中)(注:这四种衍生物注射动物的剂量保持一致,以便排除总量的不同导致对动物毒性上的不同,从而对比哪一种衍生物更有效)。除空白对照组外,其余5组均继续给予高脂饲料。分别于给药后6周、12周,称重,所得数据进行统计学处理。结果见表1所示。
表1 脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物对小鼠体重升高的抑制作用n=10
注:**P<0.01,表示与空白对照组比较;#P<0.05,表示与模型对照组比较;$$P<0.01,表示与另外3组(多肽-毛蕊花苷组、多肽-纳米金组、毛蕊花苷-纳米金组)比较。
从图3可以看出,经8周高脂饲料喂养,小鼠体重增加快于空白对照组,差异有统计学意义(**p<0.01),标志肥胖模型成功。随后经多肽-毛蕊花苷衍生物、多肽-纳米金衍生物、毛蕊花苷-纳米金衍生物及多肽-毛蕊花苷-纳米金颗粒衍生物治疗6周后,小鼠体重增加明显受到抑制,与模型对照组比较,差异显著(#p<0.05)。重要的是,同多肽-毛蕊花苷衍生物、多肽-纳米金衍生物及毛蕊花苷-纳米金衍生物实验组相比,多肽-毛蕊花苷-纳米金颗粒衍生物可更高效(双重载药)的将毛蕊花苷及纳米金颗粒投递到脂肪靶组织中,起到更加显著的减肥作用($$p<0.01),在给药12周时,脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物给药组小鼠平均体重为30.2g,而肥胖模型组平均体重达到40.7g,二者与空白对照组比较,差值分别为2g和11.5g,体重抑制达到(11.5-2)÷11.5×100%=82.6%,说明脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物抑制体重增加作用显著(见表1)。
实施例4脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物可显著抑制高脂喂养小鼠的内脏脂肪和皮下脂肪的储存
1)根据实施例3的实验步骤给高脂喂养的肥胖小鼠腹腔注射给药12周;
2)各组小鼠禁食12h,以3%戊巴比妥钠,45mg/kg腹腔注射麻醉后,准确称重;
3)常规消毒开腹,迅速摘取肾脏周围脂肪组织、肠系膜周围脂肪组织、附睾周围脂肪组织以及腹部皮下脂肪组织称取湿重(其中,腹部皮下脂肪组织范围:肋弓以下、腹股沟以上的腹部,两侧以腋中线为界);
4)按如下公式计算,即:腹腔脂肪湿重;脂肪垫总重(g)=肾脏周围脂肪组织+附睾周围脂肪组织;体脂含量=脂肪垫总重(g)/尸重(g);
5)所得数据进行统计学处理,结果见表2、表3和表4所示。
表2 脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物对小鼠内脏脂肪的储存的抑制作用n=10
注:**P<0.01,表示与空白对照组比较;#P<0.05,表示与模型对照组比较;$$P<0.01,表示与另外3组(多肽-毛蕊花苷组、多肽-纳米金组、毛蕊花苷-纳米金组)比较。
表3 脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物对小鼠体脂指数的抑制作用n=10
注:**P<0.01,表示与空白对照组比较;#P<0.05,表示与模型对照组比较;$$P<0.01,表示与另外3组(多肽-毛蕊花苷组、多肽-纳米金组、毛蕊花苷-纳米金组)比较。脂肪垫总重=肾脏周围脂肪组织+附睾周围脂肪组织;体脂指数=脂肪垫总重(g)/体重(g)
表4 脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物对小鼠皮下脂肪储存的抑制作用n=10
注:**P<0.01,表示与空白对照组比较;#P<0.05,表示与模型对照组比较;$$P<0.01,表示与另外3组(多肽-毛蕊花苷组、多肽-纳米金组、毛蕊花苷-纳米金组)比较。
从表2可以看出,高脂饲料喂养的模型对照组小鼠的内脏脂肪,如附睾脂肪,肾脏周围、网膜及肠系膜周围的脂肪较空白对照组明显增加,差异存在统计学意义(**p<0.01),说明肥胖引起了大量内脏脂肪的储存。而经多肽-毛蕊花苷衍生物、多肽-纳米金衍生物、毛蕊花苷-纳米金衍生物及多肽-毛蕊花苷-纳米金颗粒衍生物治疗后,小鼠内脏脂肪组织湿重明显降低,与模型对照组比较,差异显著(#p<0.05)。重要的是,同多肽-毛蕊花苷衍生物、多肽-纳米金衍生物及毛蕊花苷-纳米金衍生物实验组相比,多肽-毛蕊花苷-纳米金颗粒衍生物更加明显抑制了高脂喂养小鼠内脏脂肪的储存($$p<0.01)。脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物给药前后高脂喂养小鼠体脂指数(F-IDX)的变化结果见表3所示,模型对照组小鼠的体脂含量较空白对照组明显升高(**p<0.01)。腹腔注射脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物治疗后,同多肽-毛蕊花苷衍生物、多肽-纳米金衍生物及毛蕊花苷-纳米金衍生物治疗处理组相比,小鼠的体脂指数明显降低,差异明显($$p<0.01),更进一步说明多肽-毛蕊花苷-纳米金颗粒衍生物能显著抑制高脂喂养小鼠内脏脂肪的增加。如表4所示,同多肽-毛蕊花苷衍生物、多肽-纳米金衍生物及毛蕊花苷-纳米金衍生物处理组相比,脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的处理不仅降低了高脂喂养小鼠内脏脂肪的储存,还减轻了高脂喂养小鼠皮下脂肪的重量,降低了皮下脂肪占体重的比例,差异显著($$p<0.01)。总之,以上的结果都表明同空白对照组相比,高脂喂养小鼠的腹腔内脏脂肪和腹部皮下脂肪明显增加,经脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的治疗后,不论是同模型组相比,还是同多肽-毛蕊花苷衍生物、多肽-纳米金衍生物及毛蕊花苷-纳米金衍生物处理组相比,高脂喂养小鼠的腹腔内脏脂肪和腹部皮下脂肪湿重都有显著的降低。结合实施例3的结果,更进一步的说明脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物具有更为显著的抑制肥胖的作用,即其可携带药物(毛蕊花苷、纳米金)靶向进入脂肪细胞,大大增强了药物的可利用率,从而显著提高了毛蕊花苷、纳米金的靶向抗肥胖活性。
实施例5脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物无明显的生物学毒性
1)根据实施例3的实验步骤给正常喂养的小鼠腹腔注射给药12周,空白对照组注射生理盐水(0.03ml/30g体重),实验组注射脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物(30mg/kg体重,实验组;溶于DMSO中)。
2)各组小鼠禁食12小时,以3%戊巴比妥钠,45mg/kg腹腔注射麻醉后,常规消毒开腹,迅速摘取肝脏、肾脏组织,进行H-E染色观察,所得结果见图4所示。
从图4(200×)可以看出,同空白对照组相比,腹腔注射脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的小鼠肝脏和肾脏组织没有明显的病理改变,说明新型脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物对小鼠无明显的毒副作用,即其具有良好的生物相容性。
Claims (9)
1.一种脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物的制备方法,其特征在于,包括以下步骤:
(1)将脂肪组织靶向性多肽C端的半胱氨酸残基的羧基活化生成酰氯,所述脂肪组织靶向性多肽的氨基酸序列为CKGGRAKDC;
(2)将毛蕊花苷和氢氧化钠反应得到酚钠;
(3)将步骤(1)得到的酰氯和步骤(2)得到的酚钠发生酯化反应生成脂肪组织靶向性多肽-毛蕊花苷衍生物;
(4)将纳米金颗粒进行PEG修饰,将步骤(3)得到的脂肪组织靶向性多肽-毛蕊花苷衍生物和PEG修饰的纳米金颗粒混合反应,其中脂肪组织靶向性多肽C端的半胱氨酸残基的巯基和纳米金通过Au-S键连接。
2.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述脂肪组织靶向性多肽的第2位和第7位氨基酸残基的侧链连接有氨基保护基,第5位精氨酸残基连接有胍基保护基,第8位氨基酸残基连接有羧基保护基,N端氨基酸残基连接有巯基保护基。
3.根据权利要求2所述的制备方法,其特征在于,所述氨基保护基为9-芴甲氧羰基,所述胍基保护基为金刚烷氧羰基,所述羧基保护基为甲酯,所述巯基保护基为三苯甲基。
4.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述脂肪组织靶向性多肽和步骤(2)中所述毛蕊花苷的摩尔比为1-5:1。
5.根据权利要求1所述的制备方法,其特征在于,步骤(4)中所述纳米金颗粒进行PEG修饰的步骤如下:将纳米金颗粒与SH-mPEG-COOH于20-25℃混合,搅拌孵育12-24h,经离心、洗涤后将未反应的SH-mPEG-COOH清除,得到的沉淀即为PEG修饰的纳米金颗粒。
6.根据权利要求1所述的制备方法,其特征在于,步骤(4)中所述脂肪组织靶向性多肽-毛蕊花苷衍生物和PEG修饰的纳米金颗粒的摩尔比为106:9-5。
7.权利要求1-6任意一项所述的制备方法制备得到的脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物。
8.权利要求7所述脂肪组织靶向性多肽-毛蕊花苷-纳米金颗粒衍生物在制备治疗肥胖疾病的药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述药物剂型为注射剂。
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