CN116813709A - 一种pH值响应性生物活性短肽及其制药用途 - Google Patents
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Abstract
本发明属于生物制药领域,具体的公开了一种pH值响应性生物活性短肽及其制药用途;所述短肽由以下步骤制备:1)将氨基酸序列如SEQ ID NO.1所述的短肽ELA‑11与单端醛基的mPEG在室温下溶于二甲基亚砜中反应;2)步骤1)反应完成后,将上述溶液用超纯水稀释,进行自组装;3)自组装完成后进行透析纯化,得到纯的mPEG@ELA‑11组装体,即为所述的pH值响应性生物活性短肽。本发明公开的上述短肽可延长ELA‑11的体内半衰期,又能实现在不稳定斑块的低pH微环境下mPEG@ELA‑11降解为ELA‑11原药,被动靶向聚集在动脉粥样硬化斑块区域,达到抑制巨噬细胞泡沫化、提高斑块稳定性的治疗效果,具有良好的成药前景。
Description
技术领域
本发明属于生物制药领域,具体的公开了一种pH值响应性生物活性短肽及其制药用途。
背景技术
动脉粥样硬化(AS)是一种慢性炎症性疾病,是冠心病、脑梗死、外周血管病的主要原因。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。由于在动脉内膜积聚的脂质外观呈黄色粥样,因此称为动脉粥样硬化。动脉粥样硬化是缩短人类寿命的重大疾病。
动脉粥样硬化的用药主要包括两大方面,一个是阿司匹林等抗血小板聚集的药物,另外一个是他汀类调脂药。但是上述药物均无靶向性,目前运用纳米递药系统对动脉粥样硬化进行治疗成为研究的热点,但传统的纳米递药系统存在循环寿命短、缺乏特异靶向性、药物释放可控性差等问题。
发明内容
为解决上述问题,本发明公开了一种pH值响应性生物活性短肽及其制药用途,申请人研究发现,巨噬细胞吞噬ox-LDL形成泡沫细胞,脂质过载迫使巨噬细胞切换到厌氧糖酵解来产生能量,导致乳酸盐的积累和斑块微环境pH值的下降,导致斑块的微环境为弱酸性(pH值6.0-6.8),富含活性氧(ROS)、脂类和酶,且巨噬细胞溶酶体的pH值为高酸性(pH值4.5-5.5),因此申请人研发了一种根据环境pH特点可被动靶向聚集在动脉粥样硬化斑块区域,达到抑制巨噬细胞泡沫化、提高斑块稳定性的治疗效果的短肽。
为实现上述目的,本发明采用如下技术方案:
一方面,本发明公开了一种pH值响应性生物活性短肽,由以下步骤制备:
1)将氨基酸序列如SEQ ID NO.1=CMPLHSRVPFP的所示的短肽ELA-11与单端醛基的mPEG在室温下溶于二甲基亚砜中反应;
2)步骤1)反应完成后,将上述溶液用超纯水稀释,进行自组装;
3)自组装完成后进行透析纯化,得到纯的mPEG@ELA-11组装体,即为所述的pH值响应性生物活性短肽。
进一步的,上述一种pH值响应性生物活性短肽,所述步骤1)中,短肽ELA-11与mPEG的摩尔比为0.5:1-1:2,反应时间12-36h;优选的,短肽ELA-11与mPEG的摩尔比为1:1,反应时间24h。
进一步的,上述一种pH值响应性生物活性短肽,所述步骤2)中,超纯水稀释倍数为5-20倍,自组装时间1-5h;优选的,超纯水稀释倍数为10倍,自组装时间3h。
进一步的,上述一种pH值响应性生物活性短肽,所述步骤3)中透析纯化的时间为24-120h,透析袋截留分子量小于等于2kDa,透析缓冲液为PBS缓冲液;优选的,透析纯化的时间为72h,透析袋截留分子量等于2kDa。
进一步的,上述一种pH值响应性生物活性短肽,所述pH值响应性生物活性短肽在弱酸性环境下的释放速度快于在中性或者碱性环境中;在一些实施例中,mPEG@ELA-11在体外pH为5.5时快速释放91.2%,而pH为7.4时为38.7%。
另一方面,本发明公开了上述pH值响应性生物活性短肽在制备靶向治疗动脉粥样硬化的药物中的应用。
进一步的,所述药物为静脉注射剂,单次剂量0.1-2mg.kg-1;优选的,单次剂量1mg.kg-1。
进一步的,所述动脉粥样硬化由高脂饮食造成。
另一方面,本发明公开了一种靶向治疗动脉粥样硬化的药物组合物,包含上述的pH值响应性生物活性短肽。
本发明具有以下有益效果:本发明公开了一种pH值响应性生物活性短肽,亲水性聚乙二醇单甲醚(mPEG)@ELA-11,将单端羟基的mPEG氧化为单端醛基的mPEG,与ELA-11上的氨基反应,形成带有席夫碱结构的mPEG@ELA-11,并通过亲疏水自组装制备对应的组装体。mPEG@ELA-11在体外pH为5.5时快速释放91.2%,而pH为7.4时为38.7%。这种设计即可延长ELA-11的体内半衰期,又能实现在不稳定斑块的低pH微环境下mPEG@ELA-11降解为ELA-11原药,被动靶向聚集在动脉粥样硬化斑块区域,达到抑制巨噬细胞泡沫化、提高斑块稳定性的治疗效果。
附图说明
图1为mPEG@ELA-11的制备及降解粥样硬化斑块示意图;
图2为mPEG@ELA-11红外图谱分析;
图3为mPEG@ELA-11水合粒径分析;
图4为透射电子显微镜下mPEG@ELA-11的形态,(比例尺=100nm);
图5为mPEG-CHO,ELA-11和mPEG@ELA-11的核磁分析图;
图6为组装体在不同环境的胶体稳定性;
图7为mPEG@ELA-11在不同pH值PBS中的体外释放曲线;
图8为Cy5-ELA-11和Cy5-mPEG@ELA-11体内代谢时间曲线;
图9为mPEG@ELA-11改善AS小鼠炎症情况,观察不同剂型(生理盐水、ELA-11、mPEG@ELA-11对AS小鼠血清血脂(a-d)、肝肾功(e-h)和炎症因子IL-1β、IL-6和TNF-α(i-k)水平的影响(n=8);不同剂型对AS小鼠体重(l)的影响(n=8);所有数据均以平均值±标准差表示,统计分析采用单因素方差分析(*P≤0.05);
图10为小鼠心脏和主动脉ICG荧光信号体外成像(激发/发射波长为788/808nm);
图11为小鼠主要脏器ICG荧光信号体外成像(激发/发射波长为788/808nm);
图12为mPEG@ELA-11对ApoE小鼠动脉粥样硬化模型的靶向治疗效果;A:ELA-11和mPEG@ELA-11处理后,ApoE小鼠主动脉ORO染色,n=8,标尺:5mm;B-C:ApoE小鼠主动脉HE、α-SMA抗体染色的主动脉根部切片的代表性照片,n=8,标尺:500μm;
图13为mPEG@ELA-11对ApoE小鼠动脉粥样硬化模型的靶向治疗效果(续),D和E分别为MASSON、CD31抗体染色的主动脉根部切片的代表性照片,n=8,标尺:500μm;
图14为定量分析主动脉组织平滑肌面积(F)和胶原面积(G),(n=8),所有数据均以平均值±标准差表示,统计分析采用单因素方差分析。*:P≤0.05、**:P≤0.01。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
本发明实施例中使用的试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规试剂产品。
主要实验原料见表1,主要实验仪器见表2。
表1主要实验原料
。
表2主要实验仪器设备
。
实施例1
一种pH值响应性生物活性短肽的制备和检测。
一:实验内容
(1)mPEG@ELA-11组装体的制备
将100mg ELA-11(氨基酸序列:CMPLHSRVPFP,上海科肽生物科技有限公司,NO.PO21031711)与78mg单端醛基的mPEG(Sigma-Aldrich,NO.202487,摩尔量1:1)溶解于2ml二甲基亚砜中,室温下搅拌充分反应24h,得到mPEG@ELA-11。取上述mPEG@ELA-11溶液2ml加至20ml超纯水中自组装,搅拌3h,透析3天纯化mPEG@ELA-11,得到纯净的mPEG@ELA-11组装体,其主要流程见图1。
(2)荧光标记mPEG@ELA-11组装体的制备
取步骤1制得mPEG@ELA-11组装体悬浮溶液2ml,用锡箔纸包住避光条件下分别加入40μl溶于二甲基亚砜(1mg/ml)的异硫氰酸荧光素(FITC),吲哚箐绿(ICG)和花青素荧光染料(CY5),搅拌1h,8000转离心洗涤5分钟,重复3次来去除没有包载的荧光染料,分别得到标记异硫氰酸荧光素,吲哚箐绿和花青素荧光染料的mPEG@ELA-11组装体。
(3)mPEG@ELA-11组装体的红外表征
首先,将2.0mg制备的mPEG@ELA-11冻干粉末与购买的mPEG-CHO(Sigma-Aldrich,JKA3039)和多肽ELA-11单体粉末、溴化钾晶体一起研磨压片,使用美国瓦里安公司(Varian)600IR光谱仪在室温下进行红外光谱分析,验证组装体mPEG-CHO和药物多肽ELA-11的特征化学官能团以及组装后新的特征结构。
(4)动态光散射(DLS)
称取制备的mPEG@ELA-11约5mg均匀分散在超纯水中,使用涡旋仪充分振荡1分钟,然后加入超纯水稀释至组装体的浓度为1mg/ml。取1ml悬浮液加入测试皿中检测其粒径分布Zeta电位和流体力学直径(Dh)。组装体的粒径信息是使用Nano-ZS 90Nanosizer(Malvern Instruments Ltd.,Worcestershire,UK)分析的,其中包括测量流体力学直径、尺寸分布和Zeta电位。Dh是使用斯托克斯-爱因斯坦方程中的扩散系数计算出来的。每个报告的测量都进行了三次。
(5)透射式电子显微镜(TEM)
用配备了Gatan 894Ultrascan 1k CCD相机的日本电子公司JEOL JEM-2100在200千伏的条件下观察并采集TEM图像。具体样品制备过程为首先称取2mg组装的mPEG@ELA-11,溶于5ml超纯水中,超声振荡1分钟充分分散,稀释至0.1mg/ml。用等离子体处理铜网,取10μl悬浮液小心滴加在处理干燥后的铜网上,覆盖培养皿,静置12h风干后置于透射电子显微镜中观察其形貌和尺寸。
(6)核磁共振波普分析(NMR)
分别取5mg制备的mPEG@ELA-11,mPEG-CHO和多肽药物ELA-11用氘代溶剂溶解,并稀释至相同的浓度做核磁分析,通过特征官能团的验证和消失来确定多肽与聚乙二醇的成功反应以及反应物多肽和聚乙二醇的结构。核磁共振图谱是在室温下用布鲁克AV 400MHz光谱仪以TMS为标准记录的。
(7)生理稳定性检测
用不同生理环境的模拟溶液来分析纳米凝胶的生理稳定性。称量10mg的mPEG@ELA-11组装体。将组装体悬浮在磷酸盐缓冲溶液、胎牛血清或细胞培养液中,稀释至1mg/ml,每天通过粒径检测仪检测水合动力学粒径,持续检测五天后,最后监测其平均水合粒径和尺寸分布的变化。每个实验数据均独立检测三次。
(8)组装体pH响应降解检测
称取5mg包裹荧光物质的组装体,将组装体溶解于1ml PBS缓冲液中,使用涡旋仪充分振荡,均匀分散,装于透析袋(MWCO 2kDa,D8812)分别置于pH5.5、pH6.5、pH7.4的PBS缓冲液中,缓冲液体积为9ml,间隔一段时间1ml的取透析液,取出液体后加入等量的同pH缓冲液,维持液体总体积不变,通过检测释放到缓冲液的荧光物质强度荧来检测组装体的pH响应的降解性能。
二:结果分析:
1.红外分析
傅里叶变换红外(FT-IR)可用于表征材料的化学组成和特征官能基团。如图2所示,mPEG曲线中,1680cm-1为mPEG-CHO中羰基(C=O)的伸缩振动吸收峰,2880cm-1为CH特征吸收峰。ELA-11的曲线中在1630cm-1检测到酰胺键的特征吸收峰。在MPEG@ELA-11中同时检测到mPEG-CHO与ELA-11的特征吸收峰,表明MPEG@ELA-11的成功制备。
2.水合粒径测试
如图3所示,mPEG@ELA-11组装体在PBS缓冲液中水合动力学直径约为35nm,具有优异的溶解性能,可以应用于后续的细胞实验和动物实验。由于动态光散射测量的是胶体纳米粒子在溶液中的水合直径,而透射电子显微镜所拍摄的为脱水后的纳米粒子,故水合直径(~35nm)相较下文透射电镜测得的纳米粒子直径(~25nm)偏大。
3.透射电子显微镜分析
如图4所示,透射电子显微镜表明mPEG@ELA-11成功组装,组装体呈现片层结构,具有良好的单分散性,尺寸约为25nm。
4.核磁分析
如图5所示在核磁数据中a处可以观察到mPEG-CHO醛基的强特征值,而当与ELA-11反应后制备得到的mPEG@ELA-11在该处的特征值消失,表明mPEG-CHO和ELA-11的完全反应,且同时存在mPEG-CHO和ELA-11的特征值,说明mPEG@ELA-11的成功制备。
5.胶体稳定性测试
如图6所示,mPEG@ELA-11水合动力学直径能够长时间稳定,第一天在PBS中血清以及1640培养基中的尺寸分别约为36±2.12nm、43±3.01nm和44±4.53nm,第五天分别为42±3.36nm、49±3.49nm和50±2.98nm,证明了mPEG@ELA-11具有良好的胶体稳定性,可以应用于后续的细胞实验和动物实验。
6.pH响应性药物多肽释放
如图7所示,mPEG@ELA-11在pH=7.4的缓冲液中降解缓慢,48h组装体内包裹的荧光物质释放率为38.7%,在pH=5.5和6.5条件下释放率分别为91.2%和74.1%,表明组装体具有明显的酸响应降解的性能。这是由于在酸性条件下,mPEG@ELA-11组装体的席夫碱结构被破坏从而解组装。这种性能既可延长ELA-11的体内半衰期,又能实现在不稳定斑块的低pH微环境下mPEG@ELA-11降解为ELA-11原药。
实施例2
一种pH值响应性生物活性短肽的生物活性验证。
一:实验内容
(1)mPEG@ELA-11组装体体内代谢检测
称取5mg用Cy5荧光标记的mPEG@ELA-11用PBS溶解并均匀分散,用1ml胰岛素注射器小心沿小鼠尾静脉注射。每只小鼠事先用异氟烷麻醉5秒钟。注射后沿小鼠眼眶通过毛细血管微针小心扎破眼睛来取血。时间节点依次设置为0小时,2小时,6小时,12小时,24h。每只小鼠体内注射剂量为100μl。实验小鼠每次取血10μl,加入提前用锡箔纸包好的96孔板中,每个孔板提前加入5μl的肝素钠防止血液凝固。每个组别设置3只小鼠,重复3次实验。
(2)mPEG@ELA-11组装体体内荧光成像
称取10mg用ICG荧光标记的mPEG@ELA-11用PBS溶解并均匀分散,用1ml胰岛素注射针小心沿提前用高脂饲料(成分同前)喂养2个月的AS模型的小鼠尾静脉,分别注射ICG-mPEG@ELA-11、ICG-ELA-11、并给予相同剂量的Free ICG(1mg kg-1),每只小鼠体内注射剂量为100μl。24h后,异氟烷麻醉后安乐处死,然后用PBS灌流以去除未结合的染料,剖取心肝脾肺肾和主动脉,通过荧光成像仪器进行组织成像(激发/发射波长为788/808nm)。
(3)体内治疗作用的组织病理学评估
8周龄雄性ApoE-/-小鼠随机、盲法分为3组(每组n=8),包括高脂饮食+生理盐水组、高脂饮食组+ELA-11组、高脂饮食组+mPEG@ELA-11组。8周龄C57BL/6雄性小鼠8只作为阴性对照。ApoE-/-小鼠连续3个月喂食高脂饲料(成分同前)。高脂饮食第9周开始,分别给予生理盐水、ELA-11和mPEG@ELA-11,剂量为1mg·kg-1,每3天1次,连续8周后安乐处死,取AS斑块进行油红O染色,对AS斑块进行成像。取不同处理组小鼠的主动脉根部进行HE染色和Masson染色(方法同前),分别用CD31、α-SMA抗体孵育主动脉根部切片,进行免疫组织化学分析。并用Image J软件对AS斑块进行定量分析,评估这些不同制剂的治疗效果。统计分析采用单因素方差分析和双因素方差分析。用*P≤0.0 5、**P≤0.0 1、*P≤0.001进行统计学处理。所有数据均以均值±标准差表示。
二:实验结果分析:
1.mPEG@ELA-11的代谢时间曲线
如图8所示,Cy5-mPEG@ELA-11较Cy5-ELA-11在小鼠体内代谢明显减慢,在注射药物后12小时,仅有45%的Cy5-mPEG@ELA-11降解,而70%的Cy5-ELA-11已降解,至第48小时二者降解率趋同。说明mPEG@ELA-11有效增加了ELA-11的体内循环半衰期。
2.mPEG@ELA-11的体内生物相容性
采用血液生化分析方法评价ELA-11和mPEG@ELA-11的体内生物相容性。结果(图9)显示,肝功能生物标志物(AST和ALT)和肾功能生物标志物(BUN和Cre)与生理盐水组无明显差异;高脂饮食组总胆固醇和甘油三酯高于ELA-11和mPEG@ELA-11组(p<0.05);LDL和HDL在各组无显著差异。血清中炎症因子水平,高脂饮食组TNF-α和IL-6明显高于ELA-11和mPEG@ELA-11组(p<0.05),而IL-1β各组无显著差异。ELA-11和mPEG@ELA-11处理组小鼠在20周的随访中体重变化与对照组相当。上述结果显示ELA-11和mPEG@ELA-11具有良好生物相容性。
3.mPEG@ELA-11对小鼠AS斑块的靶向作用
为了研究mPEG@ELA-11对动脉粥样硬化斑块的靶向性,采用近红外发射(激发/发射波长为788/808nm)的合成染料吲哚菁绿(ICG)制备了负载ICG的ICG-ELA-11和ICG-mPEG@ELA-11。8周龄的雄性ApoE-/-小鼠在接受高脂饮食2个月后被用于靶向递送研究。将不同的制剂(游离ICG、ICG-ELA-11和ICG-mPEG@ELA-11)以相同剂量(1mg/kg)尾静脉注射小鼠体内24h后,对比检测小鼠主要脏器和主动脉荧光强度,所有处理组小鼠的主要脏器和主动脉显示出不同水平的荧光强度(图10、图11)。结果显示,ICG-mPEG@ELA-11处理组分离的小鼠主动脉组织中观察到强烈的荧光,荧光强度明显强于游离ICG和ICG-ELA-11处理组。主要脏器对比结果显示,ICG-mPEG@ELA-11处理组肝脏蓄积的荧光强度较ICG和ICG-ELA-11处理组明显增强。
4.mPEG@ELA-11对ApoE-/-小鼠动脉粥样硬化的治疗作用
如图12A、12B所示,通过油红O对主动脉内膜冠状面病变分析(en face analysis)以及HE染色对冰冻切片AS斑块面积分析,AS模型组小鼠主动脉粥样斑块面积较正常对照组明显增大,与HFD组比较,ELA-11和mPEG@ELA-11干预后斑块面积占比明显减小,且mPEG@ELA-11治疗效果优于单纯ELA-11组(n=8,p<0.05)。
α-SMA免疫荧光显示(图12C):与HFD组相比,mPEG@ELA-11显著抑制血管平滑肌细胞(SMC)增生(图14F,p<0.01),SMC占斑块比例减少,提示mPEG@ELA-11可能通过抑制斑块内SMC趋化转变为巨噬细胞,从而稳定斑块。但mPEG@ELA-11与ELA-11组对SMC增生或表型转化的抑制无显著差异。
Masson染色显示(图13D):ELA-11和mPEG@ELA-11干预后,胶原纤维/斑块面积比例增大(图14G,p<0.05),提示用药后斑块更加稳定。
CD31存在于血管内皮细胞间紧密连接处,参与白细胞的迁移、血管生成和整合素的激活。CD31免疫组织化结果显示(图13E):对比ELA-11组和HFD组(箭头处可见CD31表达存在断续),mPEG@ELA-11组血管内膜较为完整,提示mPEG@ELA-11可以较好维持AS病变部位血管内皮的完整性。
综上所述,一系列证据表明mPEG@ELA-11可显著减少斑块面积、增加胶原纤维含量、抑制平滑肌增生和表型转化,维持血管内膜稳定性,对小鼠动脉粥样硬化具有良好的治疗效果,并显示出比ELA-11更优的治疗效果。
以上显示和描述了本发明的基本原理、主要特征和优点。本行业的技术人员应该了解,上述实施例不以任何形式限制本发明,凡采用等同替换或等效变换的方式所获得的技术方案,均落在本发明的保护范围内。
Claims (9)
1.一种pH值响应性生物活性短肽,其特征在于,由以下步骤制备:
1)将氨基酸序列如SEQ ID NO.1所示的短肽ELA-11与单端醛基的mPEG在室温下溶于二甲基亚砜中反应;
2)步骤1)反应完成后,将上述溶液用超纯水稀释,进行自组装;
3)自组装完成后进行透析纯化,得到纯的mPEG@ELA-11组装体,即为所述的pH值响应性生物活性短肽。
2.根据权利要求1所述的一种pH值响应性生物活性短肽,其特征在于,所述步骤1)中,短肽ELA-11与mPEG的摩尔比为0.5:1-1:2,反应时间12-36h。
3.根据权利要求1所述的一种pH值响应性生物活性短肽,其特征在于,所述步骤2)中,超纯水稀释倍数为5-20倍,自组装时间1-5h。
4.根据权利要求1所述的一种pH值响应性生物活性短肽,其特征在于,所述步骤3)中透析纯化的时间为24-120h,透析袋截留分子量小于等于2kDa,透析缓冲液为PBS缓冲液。
5.根据权利要求1所述的一种pH值响应性生物活性短肽,其特征在于,所述pH值响应性生物活性短肽在弱酸性环境下的释放速度快于在中性或者碱性环境中。
6.如权利要求1-5任一项所述的短肽在制备靶向治疗动脉粥样硬化的药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述药物为静脉注射剂,单次剂量0.1-2mg.kg-1。
8.根据权利要求6所述的应用,其特征在于,所述动脉粥样硬化由高脂饮食造成。
9.一种靶向治疗动脉粥样硬化的药物组合物,其特征在于,含有如权利要求1-5任一项所述的pH值响应性生物活性短肽。
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