CN113679851A - 一种包载加尼舍替与他达拉非的酶响应杂化纳米粒及其制备方法和应用 - Google Patents
一种包载加尼舍替与他达拉非的酶响应杂化纳米粒及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及包载加尼舍替与他达拉非的酶响应杂化纳米粒及其制备方法和应用,可有效对加尼舍替进行包裹从而降低其毒性,增加了药物的递送量,继而使加尼舍替的临床转化成为可能的问题,其解决的技术方案是,该纳米粒包括两亲性聚合物纳米粒子和包裹于两亲性聚合物纳米粒子外层的一种酶响应两亲性多肽的脂质体,还有包埋于所述的两亲性聚合物纳米粒子膜上的疏水性药物他达拉非以及包埋于外层的一种酶响应两亲性多肽的脂质体膜上的疏水性药物加尼舍替,本发明实现了对肿瘤微环境的调控和对肿瘤细胞的杀伤作用,从而实现了药物载体对药物逐级递送的效果,是纳米药物上的创新。
Description
技术领域
本发明涉及纳米药物制剂领域,特别是一种包载加尼舍替与他达拉非的酶响应杂化纳米粒及其制备方法和应用。
背景技术
转化生长因子-β(TGF-β)是慢性肝病的调节因子,参与了从最初肝损伤、炎症和纤维化到肝硬化和肝细胞癌的所有疾病进展阶段。在肝癌中,TGF-β具有较强的侵袭性和侵袭性表型,触发癌细胞的上皮-间充质转化,肝纤维化沉积,基质金属蛋白酶-2、α-平滑肌肌动蛋白、胶原增多。此外,TGF-β信号通路在促进肿瘤生长中发挥重要作用,包括细胞生长,细胞分化,细胞凋亡,细胞动态平衡等其它细胞功能。其过程为TGF-βII是TGF-β的受体,TGF-β配体与II型受体结合,II型受体招募并磷酸化I型受体,I型受体再磷酸化受体调控的SMAD蛋白(R-SMAD),这些蛋白再与coSMAD结合。R-SMAD/coSMAD复合体作为转录因子在细胞核内聚集,参与目标基因表达的调控。因此,阻断该通路可抑制肿瘤的生长。疏水性药物加尼舍替是一种新型的口服TGF-βRII小分子抑制剂,可特异性下调SMAD2和SMAD3的磷酸化,阻止SMAD2和SMAD3与SMAD4形成三聚体复合物,下调复合体在细胞核中的聚集,降低纤维化相关基因的表达。据报道加尼舍替在乳腺癌、结肠癌、肺癌和肝细胞癌的荷瘤动物模型中显示出抗肿瘤活性,但要达到最佳的抗肿瘤效果,仅阻断TGF-β信号通路是不足够的,加尼舍替联合程序性的细胞死亡受体-配体1(PD-L1)可提高结肠癌模型的肿瘤生长抑制效果,显示出联合靶向TGF-β和PD-1/PD-L1通路的潜在协同作用。加尼舍替是一种化疗药物具有一定的毒副作用,其毒性会造成一系列的并发症,如低白细胞计数或心脏衰竭,持续长期服用加尼舍替会导致动物心脏毒性,可能损害其他器官的生理功能。为解决此问题,可用纳米载体对加尼舍替进行包裹从而降低其毒性,增加了药物的递送量,继而使加尼舍替的临床转化成为可能。
肝细胞癌(Hepatocellularcarcinoma,HCC)是一种常见的致死性癌症,在世界范围内发病率呈上升趋势,占全球发病率第6位恶性肿瘤。虽然已经开发了许多治疗方法,但这些治疗方法的总体反应不足,且复发率高,肝癌患者的长期预后仍然很差。对于巴塞罗那临床肝癌(BarcelonaClinicLiverCancer,BCLC)分期0~C期肝癌,消融治疗是最常用的策略。单发肝癌病灶<2cm的患者消融后总生存率与手术切除术相比无显著差异,但消融总体获益优于外科切除,因此推荐为一线治疗。在消融大肝癌(>5cm)或外形极不规则病灶后残留的活性肿瘤组织是微波消融(MWA)术后复发的主要原因,因此迫切需要有效的辅助治疗。其中,纳米载药是一种新兴的肿瘤靶向给药技术,脂质体药物载体具有特异性高、载药效果好、释药速率适中以及稳定性好的优点,而且,脂质体药物载体制备方法简便,成本低。本研究旨在调控肿瘤微环境的智能型纳米药物增敏肝癌微波消融治疗的基础研究。
转化生长因子-β(TGF-β)是慢性肝病的调节因子,参与了从最初肝损伤、炎症和纤维化到肝硬化和肝细胞癌的所有疾病进展阶段。在肝癌中,TGF-β具有较强的侵袭性和侵袭性表型,触发癌细胞的上皮-间充质转化,肝纤维化沉积,基质金属蛋白酶-2、α-平滑肌肌动蛋白、胶原增多。此外,TGF-β信号通路在促进肿瘤生长中发挥重要作用,因此,阻断该通路可抑制肿瘤的生长。疏水性药物加尼舍替是一种新型的口服TGF-βRII小分子抑制剂,可特异性下调SMAD2和SMAD3的磷酸化,阻止SMAD2和SMAD3与SMAD4形成三聚体复合物,下调复合体在细胞核中的聚集,降低纤维化相关基因的表达。据报道加尼舍替在乳腺癌、结肠癌、肺癌和肝细胞癌的荷瘤动物模型中显示出抗肿瘤活性,但要达到最佳的抗肿瘤效果,仅阻断TGF-β信号通路是不足够的,加尼舍替联合程序性的细胞死亡受体-配体1(PD-L1)可提高结肠癌模型的肿瘤生长抑制效果,显示出联合靶向TGF-β和PD-1/PD-L1通路的潜在协同作用。加尼舍替是一种化疗药物具有一定的毒副作用,其毒性会造成一系列的并发症,如低白细胞计数或心脏衰竭,持续长期服用加尼舍替会导致动物心脏毒性,可能损害其他器官的生理功能。为解决此问题,可用纳米载体对加尼舍替进行包裹从而降低其毒性,增加了药物的递送量,继而使加尼舍替的临床转化成为可能。
以细胞因子诱导杀伤细胞(Cytokine-InducedKiller,CIK)为基础的免疫治疗在早期肝细胞癌中是有效的辅助治疗,但在晚期肝细胞癌中缺乏疗效。大量数据表明,肿瘤进展与骨髓源性抑制细胞(Myeloid-derivedsuppressorcells,MDSCs)的积累有关,MDSCs可诱导局部甚至全身免疫抑制。此外,肝癌患者中高MDSCs亚群与早期复发相关并被证明是接受根治性切除、放疗、肝动脉灌注化疗的HCC患者预后不良的一个预测因子,MDSCs已被证明通过多种直接或间接机制抑制CD8+和CD4+T细胞以及NK细胞。近年来,大量证据支持MDSCs在肿瘤免疫抑制中的关键作用,以及在肿瘤血管生成、耐药和促进肿瘤转移中的重要作用。他达拉非是MDSCs抑制剂,可减少MDSCs细胞在HCC中的富集,恢复CIK细胞活性,达到杀伤肿瘤的作用,因此,发明一张包载加尼舍替与他达拉非的酶响应杂化纳米粒势在必行。
发明内容
针对上述情况,为解决现有技术之缺陷,本发明之目的就是提供一种包载加尼舍替与他达拉非的酶响应杂化纳米粒及其制备方法和应用,可有效对加尼舍替进行包裹从而降低其毒性,增加了药物的递送量,继而使加尼舍替的临床转化成为可能的问题。
本发明解决的技术方案是,该纳米粒包括两亲性聚合物纳米粒子和包裹于两亲性聚合物纳米粒子外层的一种酶响应两亲性多肽的脂质体,还有包埋于所述的两亲性聚合物纳米粒子膜上的疏水性药物他达拉非以及包埋于外层的一种酶响应两亲性多肽的脂质体膜上的疏水性药物加尼舍替。
所述的一种酶响应两亲性多肽是可与基质金属蛋白酶2(MMP-2)响应的多肽MRP,MRP序列为SDK(C18)SGPLGIAGQSK(C18)DS,两亲性多肽含有特异性切割序列GPLG-IAGQ为MMP-2酶切识别位点,可切割为SDK(C18)SGPLG和IAGQSK(C18)DS两段,此外含有两个亲水性氨基酸天冬氨酸(D)和丝氨酸(S)可增加亲水性,两个连接在赖氨酸(K)侧链的十八烷(C18)构成了两亲性分子的疏水部分,它可以通过疏水作用力与脂质体主要成分之一的磷脂的尾部相互作用。
该纳米粒的制备方法为:先制备酶响应两亲性多肽-脂质体-药物组合物,所使用的方法为薄膜分散法;再制备聚合物-药物组合物时,所使用的方法为复乳法;最后通过脂质体挤出器将两种纳米粒包裹在一起,具体步骤如下:
(1)用聚合物-药物组合物水溶液水合酶响应两亲性多肽-脂质体-药物组合物薄膜至悬液;
(2)将步骤(1)液体悬液用400、200、100nm的聚碳酸酯膜挤出;
(3)将步骤(2)液体悬液用离心机高速离心后用去离子水重悬,得到最终包载加尼舍替与他达拉非的酶响应杂化纳米粒溶液。
进一步的,所述的步骤(1)中,用超声波细胞破碎仪进行超声水合5min,直至双分子层彻底水合下来。
进一步的,所述的步骤(2)中,离心转速为14000rpm,20min。
所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒粒径在50-200nm。
所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的分散性在0.2以下。
所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒在制备治疗肝癌术后残余的肿瘤组织进行杀伤及调控肿瘤微环境药物中的应用。
所述的酶响应两亲性多肽-脂质体-药物组合物制备方法为:
(1)将MMP-2响应性的两亲性多肽MRP、卵磷脂、DSPE-PEG(2000)、胆固醇、疏水性药物,分别溶于有机溶剂,制成溶液;
(2)将上述溶液置于蒸馏瓶中通过旋蒸仪旋蒸成为分散良好的薄膜直至除尽有机溶剂,即得。
所述的步骤(1)中各物质加入有机溶剂后,用超声波细胞破碎仪超声2分钟,使其充分溶解。
所述的卵磷脂为大豆卵磷脂、氢化大豆卵磷脂或蛋黄卵磷脂,优选为氢化大豆卵磷脂;所述的有机溶剂为二氯甲烷、三氯甲烷、甲醇、无水乙醇、丙酮、二甲基亚砜任意一种或者两种以上的混合,优选为无水乙醇。
所述的疏水性药物他达拉非与两亲性聚合物的质量比为1:2-40。
进一步的,所述的步骤(1)中,氢化大豆卵磷脂、胆固醇、DSPE-PEG(2000)的摩尔比是56.5:38.5:5;氢化大豆卵磷脂、胆固醇、DSPE-PEG(2000)摩尔比为55:40:3.2;氢化大豆卵磷脂、胆固醇、DSPE-PEG(2000)摩尔比为111.6:32.3:3.6;更优选的氢化大豆卵磷脂、胆固醇、DSPE-PEG(2000)的摩尔比是56.5:38.5:5。
进一步的,所述的步骤(1)中,氢化大豆卵磷脂、DSPE-PEG(2000)、胆固醇总质量为1.2mg。
进一步的,所述的步骤(1)中,MMP-2响应性的两亲性多肽MRP:脂质体的质量比为1:(3-10),最终优选的多肽MRP:脂质体的质量比为1:5。
进一步的,所述的步骤(1)中,疏水性药物加尼舍替配置成母液,浓度为1mg/ml。
进一步的,所述的步骤(1)中,加尼舍替与酶响应两亲性多肽-脂质体质量比为1:2-40,加尼舍替用量为0.5-10重量份,磷脂用量为0.1-40重量份;投入不同量的加尼舍替,比如0.5mg、1mg、1.2mg、1.5mg,最后可检测酶响应两亲性多肽-脂质体-药物组合物对加尼舍替的包封率。
进一步的,所述的步骤(2)中,旋蒸时水浴加热,温度为5-45℃,更优选的温度为37℃;旋蒸除去有机时间为1~3h,直至无水乙醇彻底挥发。
所述的步骤(2)中,酶响应两亲性多肽-脂质体-药物组合物粒径在80-200nm。
所述的步骤(2)中,酶响应两亲性多肽-脂质体-药物组合物分散度(PDI)在0-0.2。
所述的聚合物-药物组合物制备方法为:
(1)将两亲性聚合物与疏水性药物他达拉非分别溶于有机溶液中,再加入水,探头超声形成第一乳液;
(2)将第一乳液与高浓度表面活性剂水溶液混合,然后超声处理形成第二乳液;
(3)将第二乳液加入低浓度表面活性剂水溶液,搅拌均匀后旋蒸去除有机溶剂;
(4)将步骤(3)剩下的溶液高速离心后用去离子水重悬得到聚合物-药物组合物纳米粒。
进一步的,所述的步骤(1)中,两亲性聚合物选用mPEG-PLGA,mPEG分子量为5000,mPEG-PLGA是聚乙二醇-聚乳酸-羟基乙酸共聚物,聚乳酸:羟基乙酸配比为75:25。
进一步的,所述的步骤(1)中,将mPEG-PLGA溶于二氯甲烷中,配置成20ml mg/ml的母液。
进一步的,所述的步骤(1)中,将疏水性药物他达拉非配置成1mg/ml的母液。
进一步的,所述的步骤(1)中,取1ml的mPEG-PLGA母液,取200μl的水和1ml他达拉非混于EP管中,构成水油混合物,用探头超声形成第一乳液。
进一步的,所述的步骤(1)中,他达拉非与两亲性聚合物的质量比为1:2-40;投入不同量的他达拉非,比如0.5mg、1mg、1.2mg、1.5mg,最后可检测聚合物对他达拉非的包封率。
进一步的,所述的步骤(1)中,探头超声的功率为30%,时间为3min,工作时间1s,暂停工作2s。
进一步的,所述的步骤(2)中,表面活性剂为胆酸钠或聚乙烯醇,更优选的表面活性剂为胆酸钠。
进一步的,所述的步骤(2)中,胆酸钠的浓度为(0-5)wt%,胆酸钠的浓度会影响聚合物纳米粒子的粒径和分散性,更优选的胆酸钠的浓度为2%。
进一步的,所述的步骤(2)中,第二次超声功率为35%,时间为5min,工作时间1s,暂停工作2s。
进一步的,所述的步骤(3)中,低浓度胆酸钠表面活性剂水溶液的浓度为(0.5-0.6)wt%,更优选为0.6%。
进一步的,所述的步骤(3)中,搅拌的时间为10-20min,使得纳米粒均匀分散。
所述的聚合物纳米粒子的粒径为100nm以下。
所述的聚合物纳米粒子的分散性在0.2以下。
本发明以酶响应两亲性多肽-脂质体-聚合物为载体将两种疏水性药物整装到一个纳米体系中,实现了对肿瘤微环境的调控和对肿瘤细胞的杀伤作用,从而实现了药物载体对药物逐级递送的效果,即对肿瘤微环境中过表达的MMP-2的响应性,一方面TGF-β抑制剂加尼舍替对肿瘤微环境进行调控,抑制肝星状细胞激活、促进胶原降解,另一方面PDE5抑制剂,调节HCC微环境的负向免疫,提高HCC对免疫治疗的敏感性作用,对MDSC细胞进行杀伤,达到对肿瘤细胞的杀伤作用,是纳米药物上的创新。
附图说明
图1为本发明的酶响应两亲性多肽MRP序列图。
图2为本发明酶响应两亲性多肽MRP与MMP-2孵育前后MALDITOFMS图(a为孵育前,右b孵育后)。
图3为本发明酶响应两亲性多肽-脂质体-药物组合物酶切前后的形貌TEM图(a为孵育前,b孵育后TEM图)。
图4为本发明酶响应多肽-脂质体-药物组合物透射电镜图,疏水性药物为加尼舍替。
图5为本发明聚合物-药物组合物透射电镜图,疏水性药物他达拉非。
图6为本发明包载加尼舍替与他达拉非的酶响应杂化纳米粒TEM图。
图7为本发明酶响应两亲性多肽-脂质体-药物组合物粒径图。
图8为本发明聚合物-药物组合物粒径图,其中疏水性药物为他达拉非粒径图。
图9为本发明包载加尼舍替与他达拉非的酶响应杂化纳米粒粒径图。
图10为本发明纳米粒稳定性测定粒径图。图11为本发明不同时间点pH为7.4与4.4条件下的他达拉非药物释放曲线。
图12为本发明通过QPCR验证Galunisertib对纤维化的影响图。
图13为本发明通过免疫细胞化学检测HSC分泌的多种染色细胞外基质(ECM)成分表达量图。
具体实施方式
以下结合附图和实施例对本发明的具体实施方式作进一步详细说明。
实施例1
本发明在具体实施时,酶响应两亲性多肽-脂质体-药物组合物的制备方法具体包括以下步骤:
(1)取两亲性多肽5mg溶于5ml无水乙醇中配制成母液、氢化大豆卵磷脂14.67mg溶于1ml无水乙醇中配制成母液、DSPE-PEG(2000)4.67mg溶于1ml无水乙醇中配制成母液、胆固醇4.96mg溶于1ml无水乙醇中配制成母液、疏水性药物加尼舍替5mg溶于5ml无水乙醇中配制成母液;
(2)取MRP母液200μl、氢化大豆卵磷脂母液50μl、DSPE-PEG(2000)母液50μl、胆固醇母液50μl、疏水性药物加尼舍替母液500μl于10ml的茄型瓶中,再加入1.15ml的无水乙醇,即共2ml的体系。
(3)将茄型瓶在条件为温度37℃下,用旋蒸仪缓慢旋蒸,除去无水乙醇直至成分散良好的薄膜,即得。
实施例2
本发明在具体实施时,聚合物-药物组合物制备方法具体包括以下步骤:
(1)取mPEG-PLGA84mg溶于4.2ml二氯甲烷中配制成母液,取疏水性药物他达拉非5mg溶于5ml二氯甲烷中配制成母液,取800mg的胆酸钠溶于40ml的去离子水中配制成2%的母液,取15ml的2%的胆酸钠溶液稀释至浓度为0.6%的胆酸钠溶液;取mPEG-PLGA母液1ml,取他达拉非母液0.5ml,取200μl的去去离子水于10mlEP管中;在条件为探头超声的功率为30%,时间为3min,工作时间1s,暂停工作2s,探头超声形成第一乳液;
(2)加2ml的2%的胆酸钠溶液于第一乳液中,在条件为探头超声的功率为35%,时间为5min,工作时间1s,暂停工作2s,探头超声形成第二乳液;
(3)将第二乳液逐滴加入到含有10ml 0.6%的胆酸钠溶液的圆底烧瓶中,在搅拌的条件下分散15分钟;将分散好的溶液用旋蒸仪除去有机溶剂二氯甲烷,然后转移至15ml的EP管中;
(4)将步骤(3)所得溶液高速离心,离心转速为14000rpm,20min,室温,用2ml的去离子水重悬,得到聚合物-药物组合物水溶液。
实施例3
本发明在具体实施时,包载加尼舍替与他达拉非的酶响应杂化纳米粒制备方法具体包括以下步骤:
(1)用聚合物-药物纳米粒组合物水溶液水合酶响应两亲性多肽-脂质体-药物组合物薄膜至悬液;用超声波细胞破碎仪进行超声水合5min,直至酶响应两亲性多肽-脂质体-药物组合物的薄膜彻底水合下来;
(2)将步骤(1)所得溶液使用400、200、100nm的聚碳酸酯膜挤出;
(3)将步骤(2)所得溶液高速离心,离心转速为14000rpm,20min,室温(23±2℃)即可,离心后再用1ml去去离子水重悬,最终得到包载加尼舍替与他达拉非的酶响应杂化纳米粒。
本发明包载加尼舍替与他达拉非的酶响应杂化纳米粒经试验证明,可用于杀伤肝癌术后残余的肿瘤组织及调控肿瘤微环境,相关试验资料如下:
由图1可以看出:MMP-2响应两亲性多肽MRP序列为SDK(C18)SGPLG-IAGQSK(C18)DS。
图2为酶响应两亲性多肽MRP与MMP-2孵育前后MALDITOF MS图,图(a,b)可明显看到当MRP与MMP-2孵育3h后,在2101处的分子离子峰消失,图(b)中可见1098与1048两个主峰,1048对应多肽序列IAGQSK(C18)DS,1098对应多肽序列SDK(C18)SGPLG,酶切后多肽分子量与预测一致,证明MRP可被MMP-2酶切开。
图3为酶响应两亲性多肽-脂质体-药物组合物被MMP-2酶切前后透射电镜图。通过电镜图(a)也可观察到没有孵育前酶响应两亲性多肽-脂质体-药物组合物是一个光滑的球形,与MMP-2孵育3h后,酶响应两亲性多肽-脂质体-药物组合物可见边缘为不光滑的球形结构,MMP-2响应引起脂质体膜的扰动,进而引发内部药物的快速释放。
图4为酶响应两亲性多肽-脂质体-药物组合物透射电镜图,其中疏水性药物为加尼舍替。
图5为聚合物-药物组合物透射电镜图,其中疏水性药物为他达拉非。
图6为包载加尼舍替与他达拉非的酶响应杂化纳米粒透射电镜图。
图7为酶响应两亲性多肽-脂质体-药物组合物粒径图。
图8为聚合物-药物组合物粒径图,其中疏水性药物为他达拉非。
图9为包载加尼舍替与他达拉非的酶响应杂化纳米粒粒径图。
图10为纳米粒稳定性测定粒径图,其中,图(a)为酶响应两亲性多肽-脂质体-药物组合物在第1、3、5天的粒径图,药物为疏水性药物加尼舍替,粒径变化小,其具有良好的稳定性;图(b)为聚合物-药物组合物在第1、3、5天的粒径图,疏水性药物为他达拉非,其粒径变化小,其具有良好的稳定性;图(c)包载加尼舍替与他达拉非的酶响应杂化纳米粒在第1、3、5天的粒径图,粒径变化小,其具有良好的稳定性。
图11为不同时间点pH为7.4和4.4的条件下的他达拉非药物释放曲线,模拟他打拉菲在活体的药物释放,聚合物-药物组合物,其中疏水性药物为他达拉非,放在恒温摇床37℃48h,每隔一段时间取1ml样品用HPLC测其释放的他达拉非的量,pH 7.4模拟的是正常体内环境的pH,pH 4.4模拟的是肿瘤微环境的pH,结果显示不同pH药物释放量均达到80%以上,即在体内他打拉非可对肝癌细胞达到杀伤作用。
图12为通过QPCR验证Galunisertib对纤维化的影响。当浓度为20μM时,Galunisertib可在HSC中降低COL1A1,αSMA的基因表达,达到了抗纤维化的作用。
图13为通过免疫细胞化学检测HSC分泌的多种染色细胞外基质(ECM)成分表达量。免疫细胞化学的方法检测了细胞外基质(ECM)成分表达量比如是I型胶原(CollagenI),纤维连接蛋白(Fibronectin)。从实验结果可以看出,孔空载体组与空白对照组(Control)蛋白表达量一致,说明空载体组本身不会引起细胞外基质水平的变化。Galunisertib与酶响应两亲性多肽-脂质体-药物组合物,其中疏水性药物为加尼舍替蛋白表达量一样,说明纳米组可与Galunisertib达到一样的抗纤维化作用。
表1为酶响应两亲性多肽-脂质体-药物组合物载药率测定,其中疏水性药物为加尼舍替。
表1脂质体在不同加尼舍替投入量下的载药效率(脂质体均为1.2mg)
表2为聚合物-药物组合物载药率测定,其中疏水性药物为他达拉非。
表2mPEG-PLGA投入他达拉非量下的载药效率(mPEG-PLGA均为20mg)
本发明用到的加尼舍替是一种新型的转化生长因子-β受体I型(transforminggrowthfactor-βreceptortypeI,TGF-βRI)小分子抑制剂,可抑制肝星状细胞激活、促进胶原降解。他达拉非是第五型磷酸二酯酶抑制剂(phosphodie-sterase5,PDE5),可上调肝癌细胞肿瘤微环境免疫反应,提高肝癌细胞对免疫治疗的敏感性。两个药物即加尼舍替与他达拉非联用的酶响应杂化纳米粒体系可靶向并杀伤肝癌术后残余的肿瘤组织,同时调控肿瘤微环境,降低肝纤维化。
本发明以酶响应两亲性多肽-脂质体-聚合物为载体将两种疏水性药物整装到一个纳米体系中,实现了对肿瘤微环境的调控和对肿瘤细胞的杀伤作用,从而实现了药物载体对药物逐级递送的效果,还提供了具有酶响应两亲性多肽-脂质体-聚合物杂化纳米粒子药物载体,其具有很好的稳定性、高特异性、良好的载药率,本发明纳米粒子具有多层结构,实现了药物在体内逐级递送,制备方法简单,条件温和,成本较低,具有良好的工业应用前景。
Claims (10)
1.一种包载加尼舍替与他达拉非的酶响应杂化纳米粒,其特征在于,该纳米粒包括两亲性聚合物纳米粒子和包裹于两亲性聚合物纳米粒子外层的一种酶响应两亲性多肽的脂质体,还有包埋于所述的两亲性聚合物纳米粒子膜上的疏水性药物他达拉非以及包埋于外层的一种酶响应两亲性多肽的脂质体膜上的疏水性药物加尼舍替。
2.根据权利要求1所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒,其特征在于,所述的一种酶响应两亲性多肽是可与MMP-2响应的多肽MRP,MRP序列为SDK(C18)SGPLGIAGQSK(C18)DS,两亲性多肽含有特异性切割序列GPLG-IAGQ为MMP-2酶切识别位点,此外含有两个亲水性氨基酸天冬氨酸和丝氨酸可增加亲水性,两个连接在赖氨酸侧链的十八烷构成了两亲性分子的疏水部分,它可以通过疏水作用力与脂质体主要成分之一的磷脂的尾部相互作用。
3.权利要求1所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的制备方法,其特征在于,先制备酶响应两亲性多肽-脂质体-药物组合物,所使用的方法为薄膜分散法;再制备聚合物-药物组合物时,所使用的方法为复乳法;最后通过脂质体挤出器将两种纳米粒包裹在一起,具体步骤如下:
(1)用聚合物-药物组合物水溶液水合酶响应两亲性多肽-脂质体-药物组合物薄膜至悬液;
(2)将步骤(1)液体悬液用400、200、100nm的聚碳酸酯膜挤出;
(3)将步骤(2)液体悬液用离心机高速离心后用去离子水重悬,得到最终包载加尼舍替与他达拉非的酶响应杂化纳米粒溶液。
4.根据权利要求3所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的制备方法,其特征在于,所述的酶响应两亲性多肽-脂质体-药物组合物制备方法为:
(1)将MMP-2响应性的两亲性多肽MRP、卵磷脂、DSPE-PEG(2000)、胆固醇、疏水性药物,分别溶于有机溶剂,制成溶液;
(2)将上述溶液置于蒸馏瓶中通过旋蒸仪旋蒸成为分散良好的薄膜直至除尽有机溶剂,即得。
5.根据权利要求3所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的制备方法,其特征在于,所述的聚合物-药物组合物制备方法包括以下步骤:
(1)将两亲性聚合物与疏水性药物分别溶于有机溶液中,再加入水,探头超声形成第一乳液;
(2)将第一乳液与高浓度表面活性剂水溶液混合,然后超声处理形成第二乳液;
(3)将第二乳液加入低浓度表面活性剂水溶液,搅拌均匀后用旋蒸仪除去有机溶剂;
(4)将步骤(3)所述液体用离心机高速离心后用去离子水重悬得到聚合物-药物组合物悬液。
6.根据权利要求4所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的制备方法,其特征在于,所述的卵磷脂为大豆卵磷脂、氢化大豆卵磷脂或蛋黄卵磷脂;所述的有机溶剂为二氯甲烷、三氯甲烷、甲醇、无水乙醇、丙酮、二甲基亚砜任意一种或者两种以上的混合。
7.根据权利要求4所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的制备方法,其特征在于,所述的加尼舍替与酶响应两亲性多肽-脂质体质量比为1:2-40,其中,加尼舍替用量为0.5-10重量份,磷脂用量为0.1-40重量份。
8.根据权利要求5所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的制备方法,其特征在于,所述的疏水性药物任意一种或者两种以上的混合他达拉非与两亲性聚合物的质量比为1:2-40。
9.根据权利要求5所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒的制备方法,其特征在于,所述的有机溶液为甲醇、无水乙醇、二氯乙烷、三氯乙烷的一种或者两种以上的混合;所述的表面活性剂为胆酸钠、聚乙烯醇、吐温80的任意一种或者两种以上的混合;所述的第一乳液水溶液中,高浓度表面活性剂的含量为2wt%;第二乳液水溶液中,低浓度表面活性剂的含量为0.6wt%。
10.权利要求1-9任一项所述的包载加尼舍替与他达拉非的酶响应杂化纳米粒在制备治疗肝癌术后残余的肿瘤组织进行杀伤及调控肿瘤微环境药物中的应用。
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