CN112957477A - 一种调控肝窦内皮细胞的纳米载体及其制备方法和应用 - Google Patents
一种调控肝窦内皮细胞的纳米载体及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种调控肝窦内皮细胞的纳米载体及其制备方法和在治疗肝脏相关疾病领域中的应用。负载肝窦内皮细胞调节药物的纳米制剂,通过调控患病肝脏的微血管、微环境,在肝脏相关疾病(如肝纤维化)治疗中促进维持或修复肝窦内皮细胞的窗孔和功能,提高肝窦内皮细胞通透性,从而达到增加药物渗透和蓄积,提高疗效的目的。本发明首次利用通过预防或修复肝窦毛细血管化,来克服慢性肝脏疾病病程中肝窦毛细血管化造成的物质交换屏障,促进治疗药物的渗透和蓄积,为治疗药物的高效递送提供了一种新的途径和策略。该调控肝窦内皮细胞的纳米载体也可用于其他伴有肝窦毛细血管化症状的肝脏疾病,如各类慢性肝炎、肝硬化、肝癌等。
Description
技术领域
本发明涉及一种调控肝窦内皮细胞的纳米载体及其制备方法和应用,达到在肝脏相关疾病治疗中促进维持或修复肝窦内皮细胞的窗孔和功能,提高肝窦内皮细胞通透性,从而达到增加药物渗透和蓄积,提高疗效的目的。属于医药技术领域。
背景技术
肝窦内皮细胞(Liver sinusoidal endothelial cells,LSECs)作为肝脏重要的非实质细胞之一,是构成肝窦壁的主要成分,不同于一般的血管内皮细胞,LSECs因为拥有独特的窗孔结构和缺乏基底膜,具有良好的通透性有利于调控肝窦血液和肝细胞之间的物质交换,在维持肝脏整体内稳态方面发挥着重要作用。正常生理条件下,LSECs负责调节肝窦血液中的大分子、溶质和液体与周围组织之间的交换,可被视为是将物质从血液传递到实质细胞和储脂细胞的“选择性滤筛”。除了内吞作用和转胞吞作用外,LSECs中还可以通过没有基底膜的窗孔发生内皮转运,此过程绕过了内体和溶酶体环节。总之,LSECs是一个屏障,将血液与肝脏的其他部分分隔开来,从而能够选择性地限制或促进循环中的物质进入肝脏组织,在血浆超滤和肝脏微循环方面发挥重要作用。
近年来,LSECs在肝脏疾病中的作用受到广泛重视。LSECs作为血液与肝细胞之间的过滤器,是肝脏面对外来物质损伤的第一道防线。当肝脏因各种急、慢性刺激而发生损伤时,会发生肝窦毛细血管化,表现为窗孔减少甚至消失以及形成内皮下基底膜,会导致肝脏微循环改变。这一过程是许多肝脏疾病包括肝炎、肝纤维化、肝硬化、肝癌等的始动环节,对肝脏疾病的发生发展尤为关键。LSECs功能障碍不仅促进各类肝脏疾病及其并发症的进程,而且肝窦毛细血管化还会导致LSECs通透性降低和基底膜形成,微循环障碍造成肝窦血液中的物质(如药物分子)难以顺利达到靶细胞(如肝星状细胞、肝细胞),降低有效治疗浓度,从而影响药物疗效。
因此,为了提高药物在肝脏疾病部位的有效渗透和蓄积,以及预防肝病和相关并发症的发展,本发明利用一种调控肝窦内皮细胞的纳米载体用于改善LSECs的窗孔和功能,可能为更有效的慢性肝病治疗找到新契机,具有重要的意义。
发明内容
本发明的目的在于提供一种调控肝窦内皮细胞的纳米载体及其制备方法和应用,该纳米载体可用于肝纤维化以及其他肝脏相关疾病的治疗,促进维持或修复肝窦内皮细胞的窗孔和功能,提高肝窦内皮细胞通透性,从而达到增加药物渗透和蓄积,提高疗效的目的。
技术方案:为解决上述技术问题,本发明采用的技术方案为:
本发明提供一种用于负载调控肝窦内皮细胞药物的纳米制剂载体,所述纳米制剂载体包括X-PEG、磷脂Y、辅助脂质Z;
其中,X为疏水段,X选自DSPE,DPPE,DMPE,DOPE;
Y为磷脂,选自蛋黄卵磷脂、氢化大豆卵磷脂及大豆磷脂及各类合成磷脂(DPPD,DOPS,DEPE,DMPE,DSPE,DPPE,DOPE,DOPG,EPG,POPG,DPPG,DSPG,DMPG,DPPA,DEPC,DOPC,DMPC,POPC,DSPC,DPPC);
辅助脂质Z,含有疏水端Z2和亲水端,所述亲水端富含氨基段Z1,Z1包括含有三氨内核的多代数PAMAM树枝状高分子结构,代数n=1,2,3,4,5,Z2为碳数15以上的直链或含支链的饱和/不饱和烷烃,其化学结构如下:
进一步的,本发明中所述药物包括亲水性和/或疏水性的肝窦内皮细胞调节药物;
肝窦内皮细胞调节药物为调控肝窦内皮细胞窗孔变化及功能的药物或生物活性分子。
本发明中,肝窦内皮细胞调节药物包括但不限于他汀类药物、非选择性β受体阻滞剂、NO供体药物、sGC激动剂、Hedgehog抑制剂,选自辛伐他汀、阿托伐他汀、氟伐他汀、卡维地洛、S-亚硝基硫醇、NONOates、BAY 60-2770、维莫德吉中的一种或几种。
具体的,本发明所述纳米制剂的制备方法:
步骤(1)将疏水性药物与X-PEG、磷脂Y、辅助脂质Z混合,溶于有机溶剂,形成有机相;和/或,将亲水性肝窦内皮细胞调节药物溶于水相;
步骤(2)通过注入法、薄膜分散法、直接滴定法或反向溶剂法制备负载肝窦内皮细胞调节药物的纳米粒。
优选地,所述的负载肝窦内皮细胞调节药物的纳米制剂,其特征在于:X-PEG中,其中X的分子量范围为1000-30000,PEG的分子量范围为200-10000。更优选地使用分子量为2000的PEG。
优选地,所述的负载肝窦内皮细胞调节药物的纳米制剂,其特征在于:所述纳米制剂的载药量为2%-20%,粒径大小为50nm-300nm。
本发明要求所述的纳米制剂载体、负载肝窦内皮细胞调节药物的纳米制剂在制备适应症为肝炎、肝纤维化、肝硬化、肝癌疾病的治疗药物中的应用。
本发明要求所述的纳米制剂载体、负载肝窦内皮细胞调节药物的纳米制剂在制备对抗伴有肝纤维化、肝炎、肝硬化、肝癌症状的治疗药物中的应用。
本发明要求所述的纳米制剂载体、负载肝窦内皮细胞调节药物的纳米制剂在制备促进维持或修复肝窦内皮细胞窗孔和功能的治疗药物中的应用。
本发明要求所述的纳米制剂载体、负载肝窦内皮细胞调节药物的纳米制剂在制备对抗伴有肝窦毛细血管化症状的治疗药物中的应用。
本发明公开了一种调控肝窦内皮细胞的纳米载体及其制备方法和应用,在肝脏相关疾病治疗中促进维持或修复肝窦内皮细胞的窗孔和功能,提高肝窦内皮细胞通透性,从而达到增加药物渗透和蓄积,提高疗效的目的。
有益效果:对于健康肝脏而言,LSECs处于分化表型,特殊的窗孔结构和缺乏基底膜赋予其良好的通透性;然而,对伴有肝窦毛细血管化症状的患病肝脏而言,LSECs处于去分化表型,窗孔的减少甚至消失和基底膜形成会导致LSECs通透性降低,故而,针对各类肝脏疾病的治疗药物难以顺利达到靶细胞,降低了有效治疗浓度,影响药物疗效。本发明公开了一种调控肝窦内皮细胞的纳米载体及其制备方法和在治疗肝脏相关疾病领域的应用;创新性地利用通过预防或修复肝窦毛细血管化,来克服慢性肝脏疾病病程中肝窦毛细血管化造成的物质交换屏障,促进治疗药物的渗透和蓄积,为治疗药物的高效递送提供了一种新的途径和策略。因此,对于伴有肝窦毛细血管化症状的肝病患者而言具有重要的实际价值和应用价值。
附图说明
图1为本发明的纳米制剂的原理图。
图2为本发明按照实施例制备的纳米制剂粒径分布图及其稳定性情况。
图3为本发明按照实施例制备的纳米制剂的透射电镜图。
图4为本发明按照实施例制备的纳米制剂给予不同细胞处理后的细胞生存率的变化。
图5为肝纤维化造模和治疗期间,各实验组的小鼠体重的变化。
图6为血清ALT及AST检测显示各实验组的肝纤维化小鼠肝脏功能的变化。
图7为扫描电镜图像显示各实验组的肝纤维化小鼠肝脏LSECs表面窗孔结构的变化。
图8为免疫荧光染色图像显示所制备包覆荧光染料(DiI)的纳米制剂在各实验组的肝纤维化小鼠肝脏的渗透和蓄积的变化。
具体实施方式
下面结合附图和具体实施例对本发明作更进一步的说明。
实施例1纳米制剂成份的合成及制备
采用薄膜分散法、注入法及反向溶剂法均可制备负载肝窦内皮细胞调节药物或荧光染料(作为代替药物的模型,用于制剂追踪)的纳米制剂,原理如图1所示。本发明优选地采用注入法制备负载肝窦内皮细胞调节药物的纳米制剂。具体制备方法如下:
称取100mg磷脂,20mg DSPE-PEG,5mg C15-PA,5mg辛伐他汀溶于500μL无水乙醇中,在搅拌条件下,将乙醇溶液滴加至5mL葡萄糖溶液中,40℃下继续搅拌1h后,200W冰浴超声10min。2500rpm/min离心20min除去未包被的游离药物。
肝窦内皮细胞调节药物包括但不限于他汀类药物、非选择性β受体阻滞剂、NO供体药物、sGC激动剂、Hedgehog抑制剂,选自辛伐他汀、阿托伐他汀、氟伐他汀、卡维地洛、S-亚硝基硫醇、NONOates、BAY 60-2770、维莫德吉中的一种或几种。
利用本法所制备的纳米制剂载药量在2%-20%之间,粒径大小在50nm-300nm之间。本发明按照实施例制备的纳米制剂的各成份最佳投料比、粒径、电位如表1所示;最优纳米制剂的粒径分布图及稳定性考察、透射电镜图如图2、图3所示。该纳米制剂粒径分布均匀,形态均一。
表1
实施例2细胞生存率实验
按照实施例1所述制备载药纳米制剂。
将L02、HSC-T6细胞分别以1×104/孔接种于96孔板中,于37℃,5%CO2细胞培养箱中贴壁生长24h后,吸去培养基,分别加入无血清培养基稀释的梯度浓度的纳米载体和载药纳米制剂,每组别设置5个复孔。此外,在每块板中均设置加入相同体积培养基的阴性对照组和不加细胞的空白对照组。继续培养24h和48h后,对细胞最终存活率进行检测。本实施例采用MTT法,测定570nm处的吸光度并计算细胞生存率。
本实施例所测得的细胞生存率实验结果如图4所示。载体材料在正常肝细胞L02和肝星状细胞HSC-T6上均具有非常好的细胞相容性;并且从载药纳米制剂和游离药物结果比较可以看出,纳米载体可以提高药物在细胞上的安全性,特别是对正常肝细胞。
实施例3肝纤维化造模和治疗期间,各实验组的小鼠体重的变化
按实施例1所述制备载药纳米制剂。
首先采用6-8周龄的雄性C57BL/6小鼠进行肝纤维化模型试验。将小鼠随机分配为5组,分别为1)正常组(i.p.Oil 5周+i.v.PBS 5周)、2)肝纤维化组(i.p.CCl4 5周)、3)肝纤维化+游离辛伐他汀预防给药组(i.p.CCl4 5周+i.v.辛伐他汀5周)、4)肝纤维化+纳米制剂预防给药组(i.p.CCl4 5周+i.v.辛伐他汀-NPs 5周)、5)肝纤维化+纳米制剂治疗给药组(i.p.CCl4 5周+i.v.辛伐他汀-NPs 3周)。配置含25%CCl4的橄榄油溶液,将溶液以2.5μL/g的剂量,通过腹腔注射(i.p.)的方式,每周注射两次,持续注射5周。各给药组按辛伐他汀5mg/kg的剂量,通过尾静脉注射(i.v.)的方式,每周注射两次,持续注射5周或3周。
每周两次称量并记录各实验组小鼠的体重,观察造模及给药治疗对小鼠体重变化的影响。
本实施例中,各实验组的小鼠在肝纤维化造模和治疗期间的体重变化如图5所示,均没有发生显著的降低,纳米制剂具有较好的体内生物安全性。
实施例4不同治疗组的肝纤维化小鼠肝脏功能的分析
按实施例1所述制备载药纳米制剂。
不同实验组的小鼠治疗结束后,眼球取血,置于室温2h后,3000rpm离心15min取上层血清用于肝脏功能的生化检测。
本实施例中,对于不同治疗组的肝纤维化小鼠肝脏功能的分析通过血清ALT和AST浓度进行监测。结果如图6显示,与正常组(1)小鼠相比,肝纤维化组(2)的小鼠血清ALT、AST水平显著升高,而游离辛伐他汀预防给药组(3)、纳米制剂预防给药组(4)和治疗给药组(5)可以显著降低小鼠的血清ALT和AST水平,对恢复肝功能具有有益效果。
实施例5纳米制剂在肝纤维化小鼠中对LSECs窗孔的调节作用
按实施例1所述制备载药纳米制剂。
扫描电镜的肝脏组织准备具体方法如下:
(1)取材:小鼠麻醉后,经肝门静脉插管,用电镜固定液灌注,待肝脏发白后,将组织取下固定在滤纸或卡片纸上,以充分暴露待观察的组织表面,用手术刀切成面积达2mm×2mm,厚度约2mm的小块;
(2)清洗:用等渗的PBS缓冲液清洗;
(3)固定:3%戊二醛固定。4℃过夜;
(4)次日用PBS清洗细胞,依次用50%,70%,80%,90%和100%乙醇脱水,其中100%乙醇脱水3次,每次10min;
(5)使用乙醇:叔丁醇=1:1的混合溶液脱水;
(6)使用纯叔丁醇脱水2次,每次10min;
(7)加入新鲜的叔丁醇以没过组织样品为宜;
(8)冷冻干燥;
(9)样品喷金;
(10)扫描电镜观测。
本实施例所检测的各组别小鼠中的LSECs窗孔结果如图7所示。相较于正常组(1)小鼠,肝纤维化组(2)小鼠出现窗孔减少或消失的现象,而游离辛伐他汀预防给药组(3)、纳米制剂预防给药组(4)和治疗给药组(5)能够促进维持或修复肝窦内皮细胞窗孔和功能。
实施例6包覆荧光染料(DiI)的纳米制剂在不同治疗组的肝纤维化小鼠肝脏的蓄积和渗透的分析
按实施例1所述制备包覆荧光染料(DiI)的纳米制剂。
不同实验组的小鼠最后一次尾静脉给药治疗24h后,分别以CDiI=1μg/g的剂量,尾静脉注射包覆荧光染料(DiI)的纳米制剂,每天一次,连续三天,在最后一次注射24h后,脱颈处死,小心取出肝脏,用生理盐水清洗干净血渍,迅速于液氮中冷冻,冰冻切片,对细胞核及LSECs进行免疫荧光染色,利用数字切片扫描仪进行图像采集。
本实施例中所制备的包覆荧光染料(DiI)的纳米制剂在肝纤维化小鼠中的渗透和蓄积情况如图8所示。其中蓝色荧光为DAPI标记细胞核,绿色荧光为CD31标记LSECs,红色荧光为DiI标记的纳米制剂。结果显示,相较于其他组,游离辛伐他汀预防给药组(3)和纳米制剂预防给药组(4)的肝脏红色荧光强度显著,并且在肝组织的肝窦周围呈现广泛的弥散性渗透。证明通过促进维持或修复肝窦内皮细胞的窗孔和功能,能够克服慢性肝脏疾病病程中肝窦毛细血管化造成的物质交换屏障,从而可以提高肝窦内皮细胞通透性,实现促进治疗药物在肝脏的渗透和蓄积的目的。
功能化磷脂包括DSPE、DPPE;天然磷脂包括蛋黄卵磷脂、氢化大豆卵磷脂、大豆磷脂及各类合成磷脂是常见的具有良好生物相容性的疏水嵌段,常在双亲性嵌段共聚物中作为疏水性内核,对大多数的具有一定疏水性的药物具有较好的亲和力。在上述实施例中,利用DPPE-PEG嵌段共聚物代替DSPE-PEG嵌段共聚物,用蛋黄卵磷脂和大豆磷脂代替大豆卵磷脂同样可以负载具有一定疏水性的药物,形成聚合物胶束的目的,对于本领域技术人员来说,是清楚的。
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 (10)
1.一种用于负载肝窦内皮细胞调节药物的纳米制剂载体,其特征在于:所述纳米制剂载体包括X-PEG、磷脂Y、辅助脂质Z;
其中,X为疏水段,X选自DSPE、DPPE、DMPE、DOPE;
磷脂Y,选自蛋黄卵磷脂、氢化大豆卵磷脂、大豆磷脂及各类合成磷脂、DPPD,DOPS,DEPE,DMPE,DSPE,DPPE,DOPE,DOPG,EPG,POPG,DPPG,DSPG,DMPG,DPPA,DEPC,DOPC,DMPC,POPC,DSPC,DPPC;
辅助脂质Z,含有疏水端Z2和亲水端,所述亲水端富含氨基段Z1,Z1包括含有三氨内核的多代数PAMAM树枝状高分子结构,代数n=1,2,3,4,5,Z2为碳数15以上的直链或含支链的饱和/不饱和烷烃,其化学结构如下:
2.根据权利要求1所述的纳米制剂载体,其特征在于:所述药物包括亲水性肝窦内皮细胞调节药物和/或疏水性肝窦内皮细胞调节药物;
肝窦内皮细胞调节药物包括但不限于他汀类药物、非选择性β受体阻滞剂、NO供体药物、sGC激动剂、Hedgehog抑制剂,选自辛伐他汀、阿托伐他汀、氟伐他汀、卡维地洛、S-亚硝基硫醇、NONOates、BAY 60-2770、维莫德吉中的一种或几种。
3.一种负载肝窦内皮细胞调节药物的纳米制剂,其特征在于:为权利要求1-2任一项所述的纳米制剂载体负载有肝窦内皮细胞调节药物。
4.根据权利要求3所述的负载肝窦内皮细胞调节药物的纳米制剂,其制备方法包括:
将疏水性肝窦内皮细胞调节药物与X-PEG、磷脂Y、辅助脂质Z混合,溶于有机溶剂,形成有机相;和/或,将亲水性肝窦内皮细胞调节药物溶于水相;
通过注入法、薄膜分散法、直接滴定法或反向溶剂法制备负载肝窦内皮细胞调节药物的纳米制剂。
5.根据权利要求4所述的负载肝窦内皮细胞调节药物的纳米制剂,其特征在于:X-PEG中,其中X的分子量范围为1000-30000,PEG的分子量范围为200-10000。
6.根据权利要求3-5任一项所述的负载肝窦内皮细胞调节药物的纳米制剂,其特征在于:所述纳米制剂的载药量为2%-20%,粒径大小为50nm-300nm。
7.权利要求1-2任一项所述的纳米制剂载体、权利要求3-6所述的负载肝窦内皮细胞调节药物的纳米制剂在制备适应症为肝炎、肝纤维化、肝硬化、肝癌的药物中的应用。
8.权利要求1-2任一项所述的纳米制剂载体、权利要求3-6所述的纳米制剂在制备对抗伴有肝炎、肝纤维化、肝硬化、肝癌症状的治疗药物中的应用。
9.权利要求1-2任一项所述的纳米制剂载体、权利要求3-6所述的纳米制剂在制备促进维持或修复肝窦内皮细胞窗孔和功能的治疗药物中的应用。
10.权利要求1-2任一项所述的纳米制剂载体、权利要求3-6所述的纳米制剂在制备对抗伴有肝窦毛细血管化症状疾病的治疗药物中的应用。
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