CN115429898B - 一种用于治疗肺纤维化的干细胞制剂及其制备方法 - Google Patents
一种用于治疗肺纤维化的干细胞制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于治疗肺纤维化的干细胞制剂。所述干细胞制剂包括间充质干细胞和纳米制剂,纳米制剂连接在间充质干细胞表面;所述纳米制剂为包载有抗肺纤维化药物的纳米载体。本发明以间充质干细胞作为递送载体高效递送抗肺纤维化药物达到治疗肺纤维化的目的,间充质干细胞的炎症趋向性使其高效靶向至受损肺部,在肺部病理微环境条件下,间充质干细胞和纳米制剂响应性分离,释放的纳米制剂通过胶原酶C降解纤维化病灶部位过量蓄积的胶原,靶向肺部大量增殖的成纤维细胞并释放抗肺纤维化药物,抑制其激活;间充质干细胞可分化为肺泡上皮细胞,重建肺部结构,最终修复肺功能。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及间充质干细胞负载纳米制剂靶向受损肺部治疗肺纤维化的干细胞制剂及其制备方法。
背景技术
肺纤维化是一类起病隐匿、易发于中老年男性的肺部进行性疾病。其发病机制为环境、年龄或基因突变触发肺泡上皮细胞持续性损伤,进而引起成纤维细胞异常增殖,导致细胞外基质过度沉积,纤维化瘢痕取代正常组织,最终导致器官功能异常。临床药物尼达尼布和吡非尼酮通过抑制炎症反应和成纤维细胞激活延缓疾病的进展,但由于缺乏高效的递送策略,仅通过口服给药难以使药物有效突破胶原基质并在病灶部位高效蓄积,最终导致临床疗效不佳。
因此,亟待设计一种能够突破胶原基质高效递送药物并有效修复受损的肺泡上皮细胞的药物递送系统。
发明内容
本发明的目的之一是提供一种用于治疗肺纤维化的干细胞制剂。
本发明的干细胞制剂包括间充质干细胞和纳米制剂,纳米制剂连接在间充质干细胞表面。
进一步地,所述间充质干细胞选自脂肪间充质干细胞、骨髓间充质干细胞、脐带间充质干细胞或皮肤间充质干细胞。间充质干细胞具有炎症趋向性,可靶向受损肺部,实现药物的高效递送。在本发明的一个实施例中,采用脂肪间充质干细胞。
间充质干细胞与纳米制剂的连接方式包括:受体-配体作用,静电吸附作用,物理穿插,共价结合作用。在本发明中,采用A6肽与间充质干细胞上的CD44受体发生生物偶联反应相互连接。
进一步地,所述纳米制剂为包载有抗肺纤维化药物的纳米载体,纳米载体由磷脂、胆固醇、DSPE-PEG2000-MAL、胶原酶、A6肽(KPSSPPEECGPLGIAGQC)和成纤维细胞激活蛋白靶向肽(FAP靶向肽,DRGETGPAC)制成。A6肽可以特异性结合间充质干细胞表面CD44受体,FAP靶向肽可以靶向成纤维细胞。
进一步地,所述抗肺纤维化药物为抑制成纤维细胞的激活及抑制胶原生成的药物中的一种或几种。选自尼达尼布、吡非尼酮、硼替佐米、西罗莫司、阿那白滞素、氯沙坦、秋水仙碱、干扰素-γ、脯氨酸-4-羟化酶抑制剂中的一种或多种。
进一步地,所述磷脂为大豆磷脂、氢化大豆卵磷脂、蛋黄卵磷脂或合成磷脂(如DPPC、DSPC、DPPG等)中的一种或几种。
进一步地,所述胶原酶为I型胶原酶、II型胶原酶、III型胶原酶、IV型胶原酶、V型胶原酶、明胶酶、基质溶素或溶血素。
进一步地,磷脂和胆固醇的质量比为4:1~8:1,磷脂和DSPE-PEG2000-MAL的质量比为10:1~3:1,磷脂和胶原酶的质量比为15:1~5:2,胶原酶和A6肽的质量比为30:1~10:1,A6肽和FAP靶向肽的质量比为2:1~1:2。
本发明的另一目的是提供上述干细胞制剂的制备方法。具体包括以下步骤:
步骤1,制备包载抗肺纤维化药物的纳米粒;
步骤2,将纳米粒依次与胶原酶、A6肽和FAP靶向肽进行孵育,得到纳米制剂;
步骤3,将纳米制剂与间充质干细胞共培养,得到所述干细胞制剂。
本发明的目的之三是提供上述干细胞制剂在制备肺纤维化治疗药物中的应用。
进一步地,所述肺纤维化治疗药物同时适用于青年患者和老年患者。
本发明以间充质干细胞作为递送载体高效递送抗肺纤维化药物达到治疗肺纤维化的目的。间充质干细胞负载的纳米制剂借助炎症趋向能力归巢至纤维化肺部,病理微环境条件下纳米制剂和干细胞响应性分离,纳米制剂的胶原酶能够有效降解纤维化病灶致密的胶原层,高效递送抗肺纤维化药物并抑制成纤维细胞的激活,恢复胶原基质稳态,同时间充质干细胞能调控免疫微环境,分化为肺泡上皮细胞,修复肺功能。
与现有技术相比,本发明具有如下显著优点:
(1)本发明创新利用间充质干细胞作为递送载体,实现抗肺纤维化药物的高效靶向递送,以肺纤维化中大量增殖的成纤维细胞作为治疗靶点,为肺纤维化药物制剂高效递送及逆转治疗提供了一种新的途径。
(2)本发明所采用的间充质干细胞具有强大的免疫调控能力,使肺部病理微环境趋向正常化,同时,间充质干细胞能分化为肺泡上皮细胞,重建肺功能。
附图说明
图1为本发明干细胞制剂制备的流程示意图。
图2为实施例1中间充质干细胞的流式鉴定图。
图3为实施例1中纳米制剂的粒径图。
图4为实施例1中纳米制剂的电位图。
图5为实施例1中干细胞制剂的扫描电镜图。
图6为试验例1中干细胞制剂体内程序化治疗过程。
图7为试验例2中干细胞制剂对青年鼠肺纤维化治疗的效果分析。
图8为试验例3中干细胞制剂对老年鼠肺纤维化治疗的效果分析。
具体实施方式
下面结合附图和具体实施例对本发明作进一步详细说明,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
实施例1
一、间充质干细胞的提取和鉴定
(一)间充质干细胞的提取
1、组织处理:雄性SD大鼠脱颈处死,75%乙醇浸泡5-10 min消毒。无菌手术剪剪取大鼠附睾脂肪或肾周脂肪,并将其快速剪碎;将组织碎块转移至EP管中,加入等体积PBS(0.1 M,pH7.4),晃匀后加入I型胶原酶,封口,37℃消化15 min;加入FBS终止消化,1600rpm离心5 min;弃去上清,加2 mL PBS重悬,过200目筛网滤除不溶物,收集滤液,1600 rpm离心5 min;弃去上清,加2 mL红细胞裂解液室温裂解2 min,加入3 mL PBS混匀,1600 rpm离心5 min;弃去上清,加3 mL PBS重悬,1600 rpm离心5 min,此步操作重复2~3次;弃去上清,加5 mL 含10%胎牛血清的DMEM重悬,转移至T25培养瓶中培养。
2、细胞培养:原代细胞接种后,需置于37℃、含5%二氧化碳的培养箱中进行培养,3天左右间充质干细胞贴壁,镜下呈梭状,此时需更换培养基去除杂细胞;待原代间充质干细胞长至80~90%时,进行传代培养。
(二)间充质干细胞的鉴定
间充质干细胞接种于6孔板中,密度为1×105个/孔,培养24 h后,细胞密度达到90%,加入荧光标记的CD29、CD44、CD45和CD90抗体,孵育1 h后,收集细胞,使用流式细胞仪进行检测。
如图2所示,流式结果显示所提细胞表面高表达CD29、CD44和CD90,低表达CD45,鉴定为间充质干细胞。
二、纳米制剂的制备
以下纳米制剂名称缩写中:Lip为纳米载体,包括磷脂、胆固醇、DSPE-PEG2000-MAL,N为尼达尼布,C为I型胶原酶,A为A6肽,F为FAP靶向肽。
1、Lip@NCAF的制备方法如下:
(1)称取30 mg大豆磷脂、5 mg胆固醇、5 mg DSPE-PEG2000-MAL和1 mg尼达尼布溶于5 mL二氯甲烷,加入至250 mL圆底烧瓶中,通过旋转蒸发仪将有机溶剂旋干至圆底烧瓶内形成均匀透明的薄膜,加入5 mL PBS水化10 min,冰浴条件下,利用超声波细胞破碎仪超声3 min,待用;
(2)称取2 mg I型胶原酶、2 mg A6肽和2 mg FAP靶向肽于西林瓶,加入步骤(1)中未修饰的脂质体1 mL,4℃搅拌6~8 h,即得纳米制剂Lip@NCAF。
2、Lip@NC的制备方法如下:
(1)称取30 mg大豆磷脂、5 mg胆固醇、5 mg DSPE-PEG2000-MAL和1 mg尼达尼布溶于5 mL二氯甲烷,加入至250 mL圆底烧瓶中,通过旋转蒸发仪将有机溶剂旋干至圆底烧瓶内形成均匀透明的薄膜,加入5 mL PBS水化10 min,冰浴条件下,利用超声波细胞破碎仪超声3 min,待用;
(2)称取2 mg I型胶原酶于西林瓶,加入步骤(1)中未修饰的脂质体1 mL,4℃搅拌6~8 h,即得纳米制剂Lip@NC。
3、Lip@NF的制备方法如下:
(1)称取30 mg大豆磷脂,5 mg胆固醇,5 mg DSPE-PEG2000-MAL和1 mg尼达尼布溶于5 mL二氯甲烷,加入至250 mL圆底烧瓶中,通过旋转蒸发仪将有机溶剂旋干至圆底烧瓶内形成均匀透明的薄膜,加入5 mL PBS水化10 min,冰浴条件下,利用超声波细胞破碎仪超声3 min,待用;
(2)称取2 mg FAP靶向肽于西林瓶,加入步骤(1)中未修饰的脂质体1 mL,4℃搅拌6~8 h,即得纳米制剂Lip@NF。
4、Lip@N的制备方法如下:
称取30 mg大豆磷脂,5 mg胆固醇,5 mg DSPE-PEG2000-MAL和1 mg尼达尼布溶于5mL二氯甲烷,加入至250 mL圆底烧瓶中,通过旋转蒸发仪将有机溶剂旋干至圆底烧瓶内形成均匀透明的薄膜,加入5 mL PBS水化10 min,冰浴条件下,利用超声波细胞破碎仪超声3min,即得纳米制剂Lip@N。
如图3和图4所示,利用上述方法制备的纳米制剂Lip@NCAF、Lip@NC、Lip@NF、Lip@N的粒径分布在50 nm~150 nm之间,电位在-10 mV~0 mV之间。
三、干细胞制剂的制备
在T25培养瓶中培养间充质干细胞(MSCs),密度为5×105个,培养24 h后,与制备得到的纳米制剂Lip@NCAF共培养2 h,使间充质干细胞上的CD44受体与纳米制剂上的A6肽发生生物偶联反应,即得干细胞制剂MSCs-Lip@NCAF。如图5扫描电镜所示,纳米制剂均匀分布在间充质干细胞膜表面,表明二者成功连接。
试验例1
干细胞制剂在小鼠体内的程序化治疗机制
1、纳米制剂的制备
(1)Lip@CAF/DiI的制备方法如下:
① 称取30 mg大豆磷脂、5 mg胆固醇、5 mg DSPE-PEG2000-MAL和1 mg DiI溶于5mL二氯甲烷,加入至250 mL圆底烧瓶中,通过旋转蒸发仪将有机溶剂旋干至圆底烧瓶内形成均匀透明的薄膜,加入5 mL PBS水化10 min,冰浴条件下,利用超声波细胞破碎仪超声3min,待用。
② 称取2 mg I型胶原酶、2 mg A6肽和2 mg FAP靶向肽于西林瓶,加入步骤①中未修饰的脂质体1 mL,4℃搅拌6~8 h,即得纳米制剂Lip@CAF/DiI。
(2)Lip@CA/DiI的制备方法如下:
① 称取30 mg大豆磷脂、5 mg胆固醇、5 mg DSPE-PEG2000-MAL和1 mg DiI溶于5mL二氯甲烷,加入至250 mL圆底烧瓶中,通过旋转蒸发仪将有机溶剂旋干至圆底烧瓶内形成均匀透明的薄膜,加入5 mL PBS水化10 min,冰浴条件下,利用超声波细胞破碎仪超声3min,待用;
② 称取2 mg I型胶原酶、2 mg A6肽于西林瓶,加入步骤①中未修饰的脂质体1mL,4℃搅拌6~8 h,即得纳米制剂Lip@CA/DiI。
(3)Lip@AF/DiI的制备方法如下:
① 称取30 mg大豆磷脂、5 mg胆固醇、5 mg DSPE-PEG2000-MAL和1 mg DiI溶于5mL二氯甲烷,加入至250 mL圆底烧瓶中,通过旋转蒸发仪将有机溶剂旋干至圆底烧瓶内形成均匀透明的薄膜,加入5 mL PBS水化10 min,冰浴条件下,利用超声波细胞破碎仪超声3min,待用;
② 称取2 mg A6肽、2 mgFAP靶向肽于西林瓶,加入步骤①中未修饰的脂质体1mL,4℃搅拌6~8 h,即得纳米制剂Lip@AF/DiI。
2、干细胞制剂的制备
在T25培养瓶中培养MSCs,密度为5×105个,培养24 h后,加入细胞膜绿色荧光染料DiO共培养,再分别与纳米制剂Lip@CAF/DiI、Lip@CA/DiI、Lip@AF/DiI共培养2 h,即得干细胞制剂MSCs-Lip@CAF/DiI、MSCs-Lip@CA/DiI、MSCs-Lip@AF/DiI。
3、干细胞制剂体内的程序化治疗
首先采用6~8周龄的雄性C57BL/6小鼠进行肺纤维化造模,造模时应用气管插管法对小鼠肺部直接造模。造模时应用盐酸博来霉素作为小鼠肺纤维化诱导剂,浓度为2USP/Kg,一周以后待小鼠肺纤维化成型则继续进行干细胞制剂程序化治疗机制实验。将造模一周的小鼠随机分配为3组,通过尾静脉注射干细胞制剂MSCs-Lip@CAF/DiI,分别于给药后1 h、2 h解剖小鼠取肺,冰冻切片后进行荧光切片实验,用于考察干细胞制剂的肺部靶向能力和响应性断裂。同时,通过尾静脉注射未使用DiO标记间充质干细胞的制剂MSCs-Lip@CA/DiI、MSCs-Lip@AF/DiI和MSCs-Lip@CAF/DiI,于给药后4 h解剖小鼠取肺,冰冻切片后进行荧光切片实验,用于考察纳米制剂的再靶向能力。
如图6所示,给药1 h后,干细胞制剂的红光荧光与间充质干细胞的绿色荧光重叠为黄色,表明MSCs-Lip@CAF/DiI靶向至肺部,给药2 h后,纳米粒的红光荧光与间充质干细胞的绿色荧光分开,MSCs-Lip@CAF/DiI在肺部病理微环境下可响应性断裂释放MSCs和Lip@CAF/DiI,给药4 h后,干细胞制剂的红光荧光与成纤维细胞的绿色荧光重叠,其中MSCs-Lip@CAF/DiI组重叠程度最高,表明胶原酶和FAP靶向肽可提高纳米制剂靶向成纤维细胞的能力。
试验例2
干细胞制剂对青年鼠肺纤维化治疗的效果分析
按照实施例1的方法提取间充质干细胞,制备纳米制剂(Lip@NCAF、Lip@NCA、Lip@NAF)以及干细胞制剂(MSCs-Lip@NCAF、MSCs-Lip@NCA、MSCs-Lip@NAF)。
首先采用6-8周龄的雄性C57BL/6小鼠进行肺纤维化模型的造模试验,造模时应用气管插管法对小鼠肺部直接造模。造模时应用盐酸博来霉素作为小鼠肺纤维化诱导剂,浓度为2 USP/Kg,将造模一周的小鼠随机分配为7组,每组10只,分别通过尾静脉注射Lip@NCAF、MSCs、MSCs-Lip@NCA、MSCs-Lip@NAF和MSCs-Lip@NCAF,同时设置正常小鼠作为阴性对照(control),博来霉素造模小鼠作为阳性对照(BLM)和口服尼达尼布组(NIN)。在治疗3周后,对于不同制剂治疗肺纤维化效果通过H&E染色和Masson染色及免疫组化进行分析。结果如图7所示, MSCs-Lip@NCA组、MSCs-Lip@NAF组和MSCs-Lip@NCAF组与BLM组相比较,肺纤维化程度明显减弱,其中,最终制剂MSCs-Lip@NCAF组效果最佳,可以看出清晰的肺泡结构,较少的胶原蓄积及α-SMA表达,表明通过间充质干细胞负载纳米制剂的递送体系可有效的治疗青年鼠肺纤维化。
试验例3
干细胞制剂对老年鼠肺纤维化治疗的效果分析
按照实施例1的方法提取间充质干细胞、制备纳米制剂Lip@NCAF以及干细胞制剂MSCs-Lip@NCAF。
首先采用16-18月龄的雄性C57BL/6小鼠进行肺纤维化模型的造模试验,造模时应用气管插管法对小鼠肺部直接造模。造模时应用盐酸博来霉素作为小鼠肺纤维化诱导剂,浓度为2 USP/Kg,将造模一周的小鼠随机分配为5组,每组10只,分别通过尾静脉注射Lip@NCAF、MSCs和MSCs-Lip@NCAF,同时设置正常小鼠作为阴性对照(control),博来霉素造模小鼠作为阳性对照(BLM)和口服尼达尼布组(NIN)。在治疗3周后,通过H&E染色、Masson染色及免疫组化分析不同制剂抗肺纤维化效果。结果如图8所示,可以发现,与BLM组相比较,MSCs-Lip@NCAF组呈现出最佳的抗肺纤维化疗效。
结果表明间充质干细胞负载纳米制剂的递送体系对青年患者和老年患者的肺纤维化均有良好的治疗效果。
以上所述仅是本发明的优选实施方式,应当指出:对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种干细胞制剂,其特征在于:包括间充质干细胞和纳米制剂,纳米制剂连接在间充质干细胞表面;
所述纳米制剂为包载有抗肺纤维化药物的纳米载体,纳米载体由磷脂、胆固醇、DSPE-PEG2000-MAL、胶原酶、A6肽和FAP靶向肽制成;
所述抗肺纤维化药物为尼达尼布;所述胶原酶为I型胶原酶;所述A6肽的序列为KPSSPPEECGPLGIAGQC;所述FAP靶向肽的序列为DRGETGPAC;
所述磷脂和胆固醇的质量比为4:1~8:1,磷脂和DSPE-PEG2000-MAL的质量比为10:1~3:1,磷脂和胶原酶的质量比为15:1~5:2,胶原酶和A6肽的质量比为30:1~10:1,A6肽和FAP靶向肽的质量比为2:1~1:2;
所述干细胞制剂的制备方法包括以下步骤:
步骤1,制备包载抗肺纤维化药物的纳米载体;
步骤2,将纳米载体依次与胶原酶、A6肽和FAP靶向肽进行孵育,得到纳米制剂;
步骤3,将纳米制剂与间充质干细胞共培养,得到所述干细胞制剂。
2.根据权利要求1所述的干细胞制剂,其特征在于:所述间充质干细胞选自脂肪间充质干细胞、骨髓间充质干细胞、脐带间充质干细胞或皮肤间充质干细胞。
3.根据权利要求1所述的干细胞制剂,其特征在于:所述磷脂为大豆磷脂、氢化大豆卵磷脂、蛋黄卵磷脂或合成磷脂中的一种或几种。
4.权利要求1所述的干细胞制剂在制备肺纤维化治疗药物中的应用。
5.根据权利要求4所述的应用,其特征在于:所述肺纤维化治疗药物同时适用于青年患者和老年患者。
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