CN113995855A - 一种抗纤维化纳米载体和纳米制剂及其制备方法 - Google Patents
一种抗纤维化纳米载体和纳米制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种抗纤维化纳米载体和纳米制剂及其制备方法,所述纳米载体包括磷脂、胆固醇、B‑PEG‑MAL、B‑PEG、接枝在纳米制剂外层的胶原酶C和/或肽段,所述磷脂为大豆磷脂、HSPC、蛋黄卵磷脂、合成磷脂的一种或几种;所述B为DSPE、PLGA、PLA、PGA、PCL或PS;所述肽段为胶原靶向肽段。本发明纳米制剂到达纤维灶的效率高,对其他正常器官的毒副作用低,改善纤维化微环境,载体外接枝了具有胶原靶向能力的肽段可将纳米载体有效递送至纤维化部位,降低其他器官的毒副作用,纳米载体外还修饰了胶原酶可将过量的胶原降解,胶原酶和两种药物同时起治疗纤维化作用。
Description
技术领域
本发明属于领域生物医药领域,尤其涉及一种抗纤维化纳米载体和纳米制剂及其制备方法。
背景技术
纤维化是一种组织损伤后修复失调的结果,并且被认为是慢性、进行性和不可逆的过程。纤维化可发生在多种器官的组织中,包括心脏、肺、肝脏、肾脏和胰腺等。当组织受到损伤时,局部组织中的成纤维细胞被激活,导致其收缩能力增强,并且分泌炎症介质和细胞外基质成分(如胶原、纤维连接蛋白等)进行损伤的修复。当损伤比较轻微时,修复是有效的,仅存在细胞外基质成分的短暂沉积,从而促进功能性组织结构的恢复;而当损伤较严重或受到重复的损伤时,修复出现失调,细胞外基质成分会持续积累,这可能导致组织结构的破坏,进而造成器官功能障碍,最终导致器官衰竭。虽然目前美国食品药品监督管理局(FDA)已批准新型的抗纤维化药物吡非尼酮(PFD)上市,但由于药物的非选择性,大量给药也会对其他正常器官产生毒副作用。
在各种类型的纤维化的发病过程中,细胞外基质中过度累积的胶原都起着关键作用。由于肌成纤维细胞的不断激活以及凋亡异常,导致其持续在ECM中产生大量胶原,从而使正常组织结构被破坏,造成器官功能障碍,最终导致器官衰竭。此外,过量胶原的不断交联还会导致组织的刚性增加,进一步阻碍了器官功能的正常发挥。现有技术未有针对上述情况,有效的解决方法,常用的抗纤维化纳米载体达到纤维灶的效率低,对其他正常器官的毒副作用高,不能改善纤维化微环境。
发明内容
发明目的:本发明的目的提供一种提高纳米制剂到达纤维灶的效率、降低对其他正常器官的毒副作用、改善纤维化微环境的抗纤维化纳米载体;本发明的另一目的是提供一种抗纤维化纳米载体的制备方法;本发明的另一目的是提供一种抗纤维化纳米制剂;本发明的另一目的是提供一种抗纤维化纳米制剂的制备方法。
技术方案:本发明的抗纤维化纳米制剂,所述纳米载体包括磷脂、胆固醇、B-PEG-MAL、B-PEG、接枝在纳米制剂外层的胶原酶C和/或肽段,所述磷脂为大豆磷脂、HSPC、蛋黄卵磷脂、合成磷脂的一种或几种;所述B为DSPE、PLGA、PLA、PGA、PCL或PS,不同种类的B-PEG-MAL和B-PEG都能够通过薄膜分散法、乙醇注入法或逆向蒸发法制备纳米载体,且不会影响纳米载体通过PEG-MAL实现胶原靶向肽段和/或胶原酶C的接枝,以及通过PEG增加纳米制剂在体内的长循环,从而减少其他正常脏器毒副作用;所述肽段为胶原靶向肽段。
进一步地,磷脂和胆固醇的质量比为10:0~4:6,B-PEG和B-PEG-MAL的质量比为1:1~1:5,更优选为7:3,;B-PEG-MAL和胶原酶C的质量比为1:15~2:5,更优选为1:3;B-PEG-MAL和胶原靶向肽段的质量比为10:1~1:1,更优选为6:1。
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,不同类型的胶原酶针对不同类型的胶原,而在不同的纤维化环境中有出现不同类型的胶原沉积的可能,因此针对不同的纤维化应选择不同的胶原酶。
进一步地,所述的肽段的序列为LRELHLNNNC。
一种上述不负载药物的抗纤维化纳米载体的制备方法,包括以下步骤:
(1)将磷脂、胆固醇和B-PEG-MAL、B-PEG混合,通过薄膜分散法、乙醇注入法或逆向蒸发法制备纳米载体;
(2)将活化后的胶原酶C和/或胶原靶向肽段、纳米载体混合,将纳米载体与胶原酶C上的巯基通过纳米载体外层暴露的MAL反应接枝在纳米制剂外层,即得抗纤维化纳米载体。
进一步地,所述步骤(1)中,磷脂A和胆固醇的质量比为10:0~4:6,更优选为7:3,B-PEG和B-PEG-MAL的质量比为1:1~1:5,更优选为1:3;
步骤(2)中,B-PEG-MAL和胶原酶C的质量比为1:15~2:5,更优选为3:7,B-PEG-MAL和胶原靶向肽段的质量比为10:1~1:1,更优选为6:1。
一种包含上述抗纤维化纳米载体的纳米制剂,所述纳米制剂包括纳米载体和负载药物,所述负载药物为抗炎症因子分泌药物和抗纤维化的药物。
所述抗纤维化的药物为抑制肌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。抗炎症因子为降低细胞分泌炎症因子的药物或生物活性分子,抑制肌成纤维细胞的激活及抑制胶原生成的药物为抑制成纤维细胞向肌成纤维细胞细胞转化、促进成纤维细胞的凋亡、促进肌成纤维细胞的凋亡及减少胶原的基因转录和表达、降低胶原合成、促进胶原分解、抑制胶原蛋白分泌等的药物或生物活性分子。
优选的,所述抗纤维化纳米制剂中的载药量为1-15%之间,纳米制剂的粒径为20-1000nm。
进一步地,抗炎症因子分泌药物为地塞米松、氟美松、倍氯米松、甲泼尼松、泼尼松龙、可的松、氢化可的松、强的松和布地奈德中的一种或多种。
进一步地,抗纤维化的药物为吡非尼酮、尼达尼布、硼替佐米、西罗莫司、阿那白滞素、氯沙坦、秋水仙碱、干扰素-γ、脯氨酰-4-羟化酶抑制剂、拉坦前列腺素、曲伏前列腺素、比马前列腺素、己酮可可碱、马洛替脂、汉防己甲素、维生素A和青霉胺中的一种或多种。
上述负载药物的抗纤维化纳米制剂的制备方法,包括以下步骤:
(1)将负载药物、磷脂、胆固醇和B-PEG-MAL、B-PEG混合,通过薄膜分散法、乙醇注入法或逆向蒸发法制备纳米粒;
(2)将活化后的胶原酶C和/或胶原靶向肽段、纳米粒混合,将纳米粒与胶原酶C上的巯基通过纳米载体外层暴露的MAL反应接枝在纳米制剂外层,即得抗纤维化纳米制剂。
进一步地,所述步骤(1)中,磷脂A和胆固醇的质量比为10:0~4:6,更优选为7:3,B-PEG和B-PEG-MAL的质量比为1:1~1:5,更优选为1:3;
步骤(2)中,B-PEG-MAL和胶原酶C的质量比为1:15~2:5,更优选为3:7,B-PEG-MAL和胶原靶向肽段的质量比为10:1~1:1,更优选为6:1。
进一步地,步骤(1)中负载药物为地塞米松和吡非尼酮;优选地,吡非尼酮包封率为10-40%,载药量为1-10%。
本发明通过高分子材料磷脂、胆固醇、B-PEG-MAL和B-PEG,实现抗纤维化药物负载,通过PEG-MAL实现胶原靶向肽段和/或胶原酶C的接枝。除通过PEG增加纳米制剂在体内的长循环减少其他正常脏器毒副作用外,还可实现纳米制剂的胶原靶向、在纤维化部位高效释放和胶原消融的目的。采用联合过程作为纤维化的治疗体系。通过胶原靶向达到高效递送纳米载体;双药协同调控纤维化微环境;胶原消融缓解细胞外基质过度积累的胶原等策略,实现逆转纤维化的目的。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)纳米制剂到达纤维灶的效率高,对其他正常器官的毒副作用低,改善纤维化微环境,载体外接枝了具有胶原靶向能力的肽段可将纳米载体有效递送至纤维化部位,降低其他器官的毒副作用,纳米载体外还修饰了胶原酶可将过量的胶原降解,胶原酶和两种药物同时起治疗纤维化作用。
(2)载体对脂溶性的药物的包载效果好,载体中的PEG片段可延长载体在血液中的循环时间;胶原靶向肽段可增加纳米粒在靶部位的蓄积;胶原酶C可通过降解细胞外基质中过量沉积的胶原,有助于功能性组织结构的正常化,促进器官功能的恢复;抗炎症因子分泌药物和抗纤维化药物可通过减少某些促纤维化的细胞因子和抑制胶原合成或分泌来治疗纤维化,以上各种效果联合治疗达到逆转纤维化的目的。
附图说明
图1是本发明纳米制剂制备的流程示意图;
图2是实施例1中所制备的各纳米制剂的粒径图、载药量和包封率测试;
图3是实施例2中所制备的各纳米制剂的粒径图;
图4是实施例2中所制备的各纳米制剂的电位图;
图5是实施例3中的载体包载药物的紫外-可见光谱;
图6是实施例4中的纳米制剂外接枝的胶原酶可特异降解胶原的活力测试;
图7是实施例5中的纳米载体在体外水平考察对细胞的毒性;
图8是实施例6中的在体外水平考察不同纳米制剂在逆转纤维化的效果分析。
具体实施方式
下面结合附图对本发明的技术方案作进一步说明。
实施例1
如图1所示,纳米载体和制剂的处方筛选/制备过程包括:
(1)分别称取质量比例为10:0、9:1、8:2、7:3、6:4、5:5、4:6的大豆磷脂和胆固醇,其中大豆磷脂和胆固醇工120mg,再称取1mg DSPE-PEG和3mg DSPE-PEG-MAL,50μg抗炎症因子分泌药物D和15mg抗纤维化药物P溶于20mL二氯甲烷中,超声溶解,混合均匀。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5mL PBS水化10min,超声震荡洗膜5min,冰浴条件下,利用超声波细胞破碎仪超声5min。先在3000rpm条件下离心5min,去除游离脂溶性药物,收集上清液,再将上清液加入截流量为100K超滤管中,在2500rpm条件下超滤离心,将纳米制剂浓缩至1ml。得到纳米制剂LIDP。
如图2所示,利用上述方法制备的纳米制剂LIDP,载药量在1%-10%之间,粒径大小在50-500nm之间,根据粒径分布与载药量综合分析,更优选的比例为磷脂与胆固醇的比例为7:3。按照同样过程,选取B-PEG和B-PEG-MAL的质量比为1:1、1:5、1:3替换上述方法中的B-PEG和B-PEG-MAL比例,重复步骤(1),均能制备效果相似的纳米制剂,但B-PEG和B-PEG-MAL的优选的比例为1:3。
(2)将活化后的胶原酶C、纳米制剂LIDP混合,将纳米制剂LIDP与胶原酶C上的巯基通过纳米载体外层暴露的MAL反应接枝在纳米制剂外层,即得抗纤维化纳米制剂。胶原酶C和纳米制剂LIDP的比例分别为1:15、2:5、3:7,重复步骤(2),均能制备效果相似的纳米制剂,但B-PEG-MAL和胶原酶C的更优选的比例为3:7;
(3)将胶原靶向肽段(CBP)、纳米制剂LIDP混合,将纳米制剂LIDP与胶原靶向肽段上的巯基通过纳米载体外层暴露的MAL反应接枝在纳米制剂外层,即得抗纤维化纳米制剂。CBP的序列为LRELHLNNNC。胶原酶C和纳米制剂LIDP的比例分别为10:1、1:1、6:1,重复步骤(3),均能制备效果相似的纳米制剂,但B-PEG-MAL和胶原靶向肽段的更优选的比例为6:1。
可选的,步骤(1)中大豆磷脂为替换为HSPC、蛋黄卵磷脂、合成磷脂;DSPE可替换为DSPE、PLGA、PLA、PGA、PCL或PS;
可选的,步骤(1)中,抗炎症因子分泌药物D为地塞米松、氟美松、倍氯米松、甲泼尼松、泼尼松龙、可的松、氢化可的松、强的松和布地奈德中的一种或多种。
可选的,步骤(1)中,抗纤维化药物P为吡非尼酮、尼达尼布、硼替佐米、西罗莫司、阿那白滞素、氯沙坦、秋水仙碱、干扰素-γ、脯氨酰-4-羟化酶抑制剂、拉坦前列腺素、曲伏前列腺素、比马前列腺素、己酮可可碱、马洛替脂、汉防己甲素、维生素A和青霉胺中的一种或多种。
可选的,步骤(2)中胶原酶C可为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。
实施例2
纳米载体和制剂的制备
一、LIDP-CC纳米制剂的制备
(1)称取30mg胶原酶C和0.825mg 2-亚氨基硫烷盐酸盐,溶于6ml的PBS缓冲液中。在室温条件下,于磁力搅拌器上搅拌反应1h。随后用葡聚糖凝胶G-25柱脱盐纯化,除去2-亚氨基硫烷盐酸盐,收集活化后的胶原酶C备用;
称取70mg大豆磷脂、30mg的胆固醇、1mg DSPE-PEG和3mg DSPE-PEG-MAL,50μg抗炎症因子分泌药物D和15mg抗纤维化药物P溶于20mL二氯甲烷中,超声溶解,混合均匀。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5mL PBS水化10min,超声震荡洗膜5min,冰浴条件下,利用超声波细胞破碎仪超声5min,待用;
(2)称取0.5mg的CBP,用适量PBS溶解,待用。将上述制备好的胶原酶C和CBP与步骤(1)中未修饰脂质体于室温孵育,置于磁力搅拌器上反应12h,得到接枝后的纳米制剂LIDP-CC。先在3000rpm条件下离心5min,去除游离脂溶性药物,收集上清液,再将上清液加入截流量为100K超滤管中,在2500rpm条件下超滤离心,将纳米制剂浓缩至1ml。
二、LIDP-COL纳米制剂的制备
(1)称取30mg胶原酶C和0.825mg 2-亚氨基硫烷盐酸盐,溶于6ml的PBS缓冲液中。在室温条件下,于磁力搅拌器上搅拌反应1h。随后用葡聚糖凝胶G-25柱脱盐纯化,除去2-亚氨基硫烷盐酸盐,收集活化后的胶原酶C备用;
称取70mg大豆磷脂、30mg的胆固醇、1mg DSPE-PEG和3mg DSPE-PEG-MAL,50μg抗炎症因子分泌药物D和15mg抗纤维化药物P溶于20mL二氯甲烷中,超声溶解,混合均匀。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5mL PBS水化10min,超声震荡洗膜5min,冰浴条件下,利用超声波细胞破碎仪超声5min,待用。
(2)将上述制备好的胶原酶C与步骤(1)中未修饰脂质体于室温孵育,置于磁力搅拌器上反应12h,得到接枝后的纳米制剂LIDP-COL。先在3000rpm条件下离心5min,去除游离脂溶性药物,收集上清液,再将上清液加入截流量为100K超滤管中,在2500rpm条件下超滤离心,将纳米制剂浓缩至1ml。
三、LIDP-CBP纳米制剂的制备
(1)称取70mg大豆磷脂、30mg的胆固醇、1mg DSPE-PEG和3mg DSPE-PEG-MAL,50μg抗炎症因子分泌药物D和15mg抗纤维化药物P溶于20mL二氯甲烷中,超声溶解,混合均匀。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5mL PBS水化10min,超声震荡洗膜5min,冰浴条件下,利用超声波细胞破碎仪超声5min,待用。
(2)称取0.5mg的CBP,用适量PBS溶解,待用。将上述制备好CBP与步骤(1)中未修饰脂质体于室温孵育,置于磁力搅拌器上反应12h,得到接枝后的纳米制剂LIDP-CBP。先在3000rpm条件下离心5min,去除游离脂溶性药物,收集上清液,再将上清液加入截流量为100K超滤管中,在2500rpm条件下超滤离心,将纳米制剂浓缩至1ml。
四、LIDP纳米制剂的制备
称取70mg大豆磷脂、30mg的胆固醇、1mg DSPE-PEG和3mg DSPE-PEG-MAL,50μg抗炎症因子分泌药物D和15mg抗纤维化药物P溶于20mL二氯甲烷中,超声溶解,混合均匀。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5mL PBS水化10min,超声震荡洗膜5min,冰浴条件下,利用超声波细胞破碎仪超声5min。先在3000rpm条件下离心5min,去除游离脂溶性药物,收集上清液,再将上清液加入截流量为100K超滤管中,在2500rpm条件下超滤离心,将纳米制剂浓缩至1ml。得到纳米制剂LIDP。
五、LI-CC纳米载体的制备
(1)称取30mg胶原酶C和0.825mg 2-亚氨基硫烷盐酸盐,溶于6ml的PBS缓冲液中。在室温条件下,于磁力搅拌器上搅拌反应1h。随后用葡聚糖凝胶G-25柱脱盐纯化,除去2-亚氨基硫烷盐酸盐,收集活化后的胶原酶C备用;
称取70mg大豆磷脂、30mg的胆固醇、1mg DSPE-PEG和3mg DSPE-PEG-MAL,以上材料溶于20mL二氯甲烷中,超声混合均匀。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5mL PBS水化10min,超声震荡洗膜5min,冰浴条件下,利用超声波细胞破碎仪超声5min,待用。
(2)称取0.5mg的CBP,用适量PBS溶解,待用。将上述制备好的胶原酶C和CBP与步骤(1)中未修饰脂质体于室温孵育,置于磁力搅拌器上反应12h,得到接枝后的纳米载体LI-CC。将LI-CC加入截流量为100K超滤管中,在2500rpm条件下超滤离心,将纳米制剂浓缩至1ml。
六、LI-COL纳米载体的制备
(1)称取30mg胶原酶C和0.825mg 2-亚氨基硫烷盐酸盐,溶于6ml的PBS缓冲液中。在室温条件下,于磁力搅拌器上搅拌反应1h。随后用葡聚糖凝胶G-25柱脱盐纯化,除去2-亚氨基硫烷盐酸盐,收集活化后的胶原酶C备用;
称取70mg大豆磷脂、30mg的胆固醇、1mg DSPE-PEG和3mg DSPE-PEG-MAL,以上材料溶于20mL二氯甲烷中,超声混合均匀。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5mL PBS水化10min,超声震荡洗膜5min,冰浴条件下,利用超声波细胞破碎仪超声5min,待用。
(2)将上述制备好的胶原酶C与步骤(1)中未修饰脂质体于室温孵育,置于磁力搅拌器上反应12h,得到接枝后的纳米载体LI-COL。将LI-COL加入截流量为100K超滤管中,在2500rpm条件下超滤离心,将纳米制剂浓缩至1ml。
如图3-5所示,利用上述方法制备的纳米制剂LIDP-CC、LIDP-COL、LIDP-CBP、LIDP载药量在1%-10%之间,粒径大小在50-500nm之间,粒径分布均匀。电位在-10mv-0mv之间。
实施例3
纳米载体包载药物紫外-可见光谱测定
取适量纳米制剂实施例2制备的LIDP-CC作为研究对象,称取适量的药物D和药物P并配置成适宜浓度,以溶剂作为空白对照,使用紫外分光光度计在200-1000nm波长范围内分别进行全波长扫描。如图5所示,结果表明,制备的纳米制剂可成功包载两种药物。
实施例4
纳米制剂降解胶原活力测定
将实施例2制备的LIDP-CC、LIDP-COL、LIDP-CBP、LIDP作为研究对象。向96微孔板每孔加入20μL胶原–FITC,将上述纳米制剂溶液各取180μL与之吹打混匀,每个制剂取3份,做3个复孔。随后置于37℃恒温摇床中避光反应,孵育2h。2h后取出孔板中反应后的液体,在5000rpm的条件下离心15min,小心吸取50μL上清液加到微孔板中,并且每孔加入50μL PBS稀释,混匀。利用Molecular Devices ID5多功能酶标仪进行测定。固定激发波长为485nm,发射波长为530nm处测定上清液的荧光值,PBS作为空白对照。如图6所示,结果表明,各接枝了胶原酶C的纳米制剂具有降解胶原的能力。
实施例5
纳米载体在体外安全性考察
将实施例2制备的LI-COL和LI-CC作为研究对象。将对数生长期的A549细胞按照8000个细胞/孔的密度接种于96孔板内,培养过夜。然后使用不含FBS的1640培养基将LI-COL和LI-CC稀释成一系列浓度梯度,并以不给予纳米载体的细胞作为对照组,只在空白孔中加培养基的作为空白组。A549给予的不同浓度的纳米载体,每个浓度重复3个孔。吸去培养基,然后每孔加入100μL不同浓度梯度的纳米载体。加入后继续培养24h,避光条件下加入20μL的5mg/mL MTT溶液,细胞培养箱中继续培养4h。取出96板,用1mL注射器吸走上清液,加入150μL DMSO,在37℃摇床中振摇10-15min,酶标仪490nm处检测各孔的OD值,不处理组细胞活力为100%。
如图7所示,结果显示,制备的纳米载体的体外安全性较好。
实施例6纳米制剂在体外逆转纤维化效果分析
按照实施例2制备LIDP-CC。将成纤维细胞按照8×104/皿接种于激光共聚焦皿中,于37℃细胞培养箱培养12h。待细胞汇合度达到约80%,弃去培养基,加入用不含FBS的1640培养基稀释的LIDP-CC与TGF-β共孵育8h,8h后弃去药液,进行免疫荧光染色。步骤如下:加入2mL PBS洗3次,每次3min;加入1.5mL 4%多聚甲醛,室温固定20-30min;加入2mL PBS洗3次,每次3min;加入1.5mL 0.2%Triton X-100透化2-5min;加入400μL 1%BSA室温封闭30min,吸走,不用清洗;加入400μL利用1%BSA稀释的一抗(Rabbit polyclonal toCollagen I),放入湿盒里,4℃孵育过夜;加入2mL PBS洗3次,每次5min;加入400μL 1%BSA稀释的二抗(Cy3 Goat Anti-Rabbit IgG(H+L)),4℃避光孵育30min;加入2mL PBS洗3次,每次5min;加入1mL Hoechst 33342,置于37℃培养箱中,孵育20min;加入2mL PBS洗2次,每次2min;加入2mL 50%甘油,4℃避光保存。最后利用激光共聚焦进行图像采集。如图8所示,结果显示所制备的纳米制剂能有效消融胶原,即具有较好的抗纤维化能力。
Claims (10)
1.一种抗纤维化纳米载体,其特征在于,所述纳米载体包括磷脂、胆固醇、B-PEG-MAL、B-PEG、接枝在纳米制剂外层的胶原酶C和/或肽段,所述磷脂为大豆磷脂、HSPC、蛋黄卵磷脂、合成磷脂的一种或几种;所述B为DSPE、PLGA、PLA、PGA、PCL或PS;所述肽段为胶原靶向肽段。
2.根据权利要求1所述的抗纤维化纳米载体,其特征在于,磷脂和胆固醇的质量比为10:0~4:6,B-PEG和B-PEG-MAL的质量比为1:1~1:5;B-PEG-MAL和胶原酶C的质量比为1:15~2:5;B-PEG-MAL和胶原靶向肽段的质量比为10:1~1:1。
3.根据权利要求1所述的抗纤维化纳米载体,其特征在于,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。
4.根据权利要求1所述的抗纤维化纳米载体,其特征在于,所述的肽段的序列为LRELHLNNNC。
5.一种根据权利要求1-4任一所述的抗纤维化纳米载体的制备方法,其特征在于,包括以下步骤:
(1)将磷脂、胆固醇和B-PEG-MAL、B-PEG混合,通过薄膜分散法、乙醇注入法或逆向蒸发法制备纳米载体;
(2)将活化后的胶原酶C和/或胶原靶向肽段、纳米载体混合,将纳米载体与胶原酶C上的巯基通过纳米载体外层暴露的MAL反应接枝在纳米制剂外层,即得抗纤维化纳米载体。
6.一种包含根据权利要求1-4所述的抗纤维化纳米载体的纳米制剂,其特征在于,所述纳米制剂包括纳米载体和负载药物,所述负载药物为抗炎症因子分泌药物和抗纤维化的药物。
7.根据权利要求6所述的纳米制剂,其特征在于,所述纳米制剂中负载药物的载药量为1-10%。
8.根据权利要求6所述的纳米制剂,其特征在于,抗炎症因子分泌药物为地塞米松、氟美松、倍氯米松、甲泼尼松、泼尼松龙、可的松、氢化可的松、强的松和布地奈德中的一种或多种。
9.根据权利要求6所述的纳米制剂,其特征在于,抗纤维化的药物为吡非尼酮、尼达尼布、硼替佐米、西罗莫司、阿那白滞素、氯沙坦、秋水仙碱、干扰素-γ、脯氨酰-4-羟化酶抑制剂、拉坦前列腺素、曲伏前列腺素、比马前列腺素、己酮可可碱、马洛替脂、汉防己甲素、维生素A和青霉胺中的一种或多种。
10.一种根据权利要求6-9任一所述的纳米制剂的制备方法,其特征在于,包括以下步骤:
(1)将负载药物、磷脂、胆固醇和B-PEG-MAL、B-PEG混合,通过薄膜分散法、乙醇注入法或逆向蒸发法制备纳米粒;
(2)将活化后的胶原酶C和/或胶原靶向肽段、纳米粒混合,将纳米粒与胶原酶C上的巯基通过纳米载体外层暴露的MAL反应接枝在纳米制剂外层,即得抗纤维化纳米制剂。
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