CN114246861B - 一种具有剪切应力响应的载药纳米粒子的制备方法 - Google Patents
一种具有剪切应力响应的载药纳米粒子的制备方法 Download PDFInfo
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- Medicinal Preparation (AREA)
Abstract
本发明的一种具有剪切应力响应的载药纳米粒子的制备方法属于纳米材料制备技术领域,包括辛伐他汀酸的合成、PEI‑SH的合成、SA PEI的制备、SA PEI@RBCs的制备等步骤。本发明制备的纳米粒子吸附在红细胞表面使其具有良好的生物相容性,既可以实现体内的长效循环又具有剪切应力敏感的特点,保证药物在动脉粥样硬化部位释放,提高动脉粥样硬化治疗的效果。
Description
技术领域
本发明属于纳米材料制备技术领域,具体涉及一种具有剪切应力响应的载药纳米粒子系统的制备与应用。
背景技术
动脉粥样硬化是一种慢性炎症性疾病,其特征是内皮功能发生障碍,脂质在动脉壁大量沉积,使得单核细胞不断进入动脉壁并分化为巨噬细胞,吞噬大量脂质而形成泡沫细胞,脂质、泡沫细胞及巨噬细胞在动脉壁内膜的积聚形成斑块,斑块的突起所带来的剪切应力的变化显著异于正常部位。据报道,动脉粥样硬化的剪切应力是健康血管的100多倍,巨大的剪切应力落差使斑块处具有特殊的微环境。
辛伐他汀属于羟甲基戊二酰辅酶A(HMG-COA)还原抑制剂,主要通过抑制HMG-COA还原酶活性来增加低密度脂蛋白(LDL)受体基因的转录,抑制内源性胆固醇的生成。辛伐他汀因具有降低胆固醇水平和消耗活性氧(ROS)的作用而广泛应用于心血管疾病的一级和二级防治,但由于其横纹肌溶解的副作用而迫使治疗戒断的发生,因此寻找新的药物递送方式已迫在眉睫。
近年来,纳米医学的快速发展为药物递送提供了理想的途径,它可以有效地提高治疗效果,改善生物分布,降低药物毒性。其中,刺激响应性纳米载体受到广泛青睐,可以根据病灶部位的特殊微环境进行响应性设计,这保证了药物在病灶部位的集中释放,既显著提高了治疗效果,又能有效降低药物对健康部位的毒性。考虑AS斑块处高的剪切应力微环境,可以设计具有剪切应力响应的药物递送系统用于AS的治疗。
将广泛用于基因转染的阳离子聚合物PEI作为载体,在其末端修饰巯基,通过静电吸附与负电性辛伐他汀酸(SA)进行自组装交联得到载药纳米粒子(SA PEI),SA PEI易与红细胞膜(RBCs)上的负电性蛋白聚糖和唾液酸发生静电吸附,形成SAPEI@RBCs仿生药物递送系统。SAPEI@RBCs可响应剪切应力而使SA PEI在斑块处富集,进而提高治疗效果。SA PEI@RBCs仿生药物递送系统为动脉粥样硬化的治疗开发了新的方向。
发明内容
本发明的目的在于,开发一种新型的具有响应剪切应力的载药系统SA PEI@RBCs,同时还提供该载药体系的制备方法及其在制备抗血栓纳米粒子方面的应用。
本发明的技术方案如下:
一种具有剪切应力响应的载药纳米粒子的制备方法,具有以下步骤:
1)辛伐他汀酸的合成
首先,将辛伐他汀在乙醇中搅拌至完全溶解后加入0.1M NaOH,在50℃下反应2h,随后,将反应溶液的pH用盐酸调节至中性,利用旋转蒸发仪除去反应液中的乙醇,加入正丁醇萃取辛伐他汀酸,其中,辛伐他汀、乙醇、NaOH和正丁醇的质量比为30~90:800~1500:1:500~5000,有机相经旋转蒸发和真空干燥后得到辛伐他汀酸,记为SA。
2)PEI-SH的合成
将PEI600(聚乙烯亚胺,分子量600)用PBS溶解后,加入2-亚氨基硫烷盐酸盐,反应在N2和黑暗条件下进行,室温搅拌过夜后加入DTT(二硫苏糖醇),继续反应3h,其中,PEI600、PBS、2-亚氨基硫烷盐酸盐与DTT的质量比为30~70:230~300:1:1~5;待反应结束后,将反应液移入透析袋,在去离子水中透析48h后用冻干机冻干,得到粘稠状固体活性氧响应性材料,记为PEI-SH,并保存在-20℃。
3)SA PEI的制备
按1:100~1000的质量比将PEI-SH完全溶解在去离子水中,加入0.1M的NaBH4并在N2保护下室温继续搅拌3h,PEI-SH与NaBH4的质量比按溶质计为1:500~1000,用0.1M的HCl将反应液调至中性,滴加含有SA的DMSO(二甲基亚砜)溶液至反应液中,按质量计,SA:DMSO:PEI-SH=1:2~10:0.1~2,室温反应5h,最后,将反应液移入透析袋,并用去离子水透析2天得到SA PEI。
4)SA PEI@RBCs的制备
将新鲜的动物全血离心除去血浆、血小板和白细胞,分离出RBCs(下层红细胞),用PBS洗涤后重悬于1~5倍RBCs体积的PBS中,再加入步骤3)制备的SA PEI并轻轻混合,其中RBCs重悬液与SA PEI的体积比为1~3:1,在室温下孵育0.5~5h后离心得到具有剪切应力响应的载药纳米粒子SA PEI@RBCs。
作为优选,步骤2)中所述的透析袋的截留分子量为0.5kDa;步骤3)中所述的透析袋的截留分子量为1.0kDa。
作为优选,步骤2)中所述的PBS是pH为8的磷酸缓冲液,含0.001M乙二胺四乙酸二钠;步骤4)中所述的PBS是0.01M的无菌等渗磷酸盐缓冲液。
作为优选,步骤4)所述的将新鲜的动物全血离心,是在4℃,2000r/min的条件下离心10min,以3.8%柠檬酸钠作为抗凝剂。
由于AS是一种血管内循环系统的疾病,因此本申请利用红细胞作为药物递送系统。由于唾液酸的存在使红细胞表面带负电,将带正电荷的SA PEI通过静电吸附装载到红细胞表面,而不破坏红细胞的完整结构。SA PEI@RBCs会在斑块处剪切应力的作用下迫使SAPEI从红细胞表面解吸附,实现SA在斑块处的富集,这样可以有效地治疗AS,减少自由给药引起的毒性和副作用。因此,本研究对基于动脉粥样硬化的治疗提供了一种有前途的方法。
综上,本发明有以下有益效果:
1、本发明的仿生载药系统可以响应斑块处高的剪切应力,实现SA PEI在斑块部位的富集,提高药物治疗效果。
2、本发明中的红细胞载体可实现SA PEI@RBCs的体内长效循环,降低机体对SAPEI的清除率。
3、本发明的仿生载药系统有效地降低了游离辛伐他汀酸的毒性,具有良好的生物相容性。
附图说明
图1是实施例1中辛伐他汀酸的合成路线图。
图2是实施例1中辛伐他汀酸和辛伐他汀的1H NMR图。
图3是实施例1中辛伐他汀酸(SA)和辛伐他汀(SV)的FTIR光谱图。
图4是实施例2中PEI-SH的合成路线。
图5是实施例2中PEI-SH的FTIR图。
图6是实施例2中PEI-SH的Ellman检测图及半胱氨酸标准曲线。
图7是实施例3中SA PEI的TEM图。
图8是实施例4中SA PEI@RBCs的制备示意图。
图9是实施例4中SA PEI@RBCs的SEM图。
图10是实施例4中SA PEI@RBCs的zeta电位。
图11是实施例5中PEI-SH对HUVECs的MTT图。
图12是实施例5中SA和SA PEI对HUVECs的MTT图
图13是实施例6中NR PEI@RBCs处理RAW 264.7细胞3h和12h的共聚焦图。
图14是实施例7中剪切应力诱导SA PEI@RBCs的体外解吸图。
图15是实施例8中SA PEI@RBCs对FeCl3诱导兔颈动脉血栓形成的彩超图。
图16是实施例9中SA PEI@RBCs对KM小鼠的脏器的H&E染色。
具体实施方式
实施例1:辛伐他汀酸的合成
首先,在100mL单口瓶中加入含有1g辛伐他汀的10mL乙醇,搅拌至完全溶解后加入45mL 0.1M NaOH,反应在50℃下进行2h。随后,将反应溶液的pH用盐酸调节至中性。利用旋转蒸发仪除去反应液中的乙醇,加入正丁醇萃取SA,有机相经旋转蒸发和真空干燥后得到SA(0.882g,85%),合成路线如图1所示。图2和图3分别是辛伐他汀酸和辛伐他汀的1H NMR和FTIR图。1H NMR中可以看到由于内酯结构的开环,连接羟基的邻位H(e)的峰已经从原来的4.62ppm变为3.64ppm,连接羧基的邻位H(s)的峰从2.71ppm变为2.34ppm。FTIR中1583cm-1处的尖峰是羧酸基团(-COOH)中的-COO-不对称伸缩特征峰,而3363cm-1处的宽峰是由于氢键存在的原因,为羟基(-OH)的伸缩振动吸收峰。
实施例2:活性氧响应性材料PEI-SH的合成
将2mL PEI600加入到装有10mL PBS(pH 8,0.001M EDTA)的25mL单口瓶中,待完全溶解后,加入含有0.04g 2-亚氨基硫烷盐酸盐的5mL PBS(pH 8,0.001M EDTA)。反应在N2和黑暗条件下进行,室温搅拌过夜后加入0.14g DTT,继续反应3h。待反应结束后,将反应液移入透析袋(MWCO 0.5kDa),在去离子水中透析48h后用冻干机冻干,得到粘稠状固体(PEI-SH,0.05g),并保存在-20℃,合成路线如图4所示。图5中578cm-1处的峰代表-S-S-而不是-SH的吸收峰,这是因为不稳定的巯基很容易在空气中交联形成二硫键。我们利用Ellman试剂进一步对PEI-SH中的巯基进行了表征,如图6所示,加入Ellman试剂后的PEI-SH为亮黄色,而PEI600的溶液依然为透明色,说明PEI-SH中成功的引入了巯基,利用L-半胱氨酸的标准曲线计算得到PEI-SH的硫醇化程度为4.7%。
实施例3:SA PEI纳米粒子的制备
以PEI-SH与SA的质量比为10:10制备了SA PEI。首先,在25mL单口瓶中称取10mgPEI-SH,加入5mL去离子水,搅拌使之完全溶解,随后加入0.1M NaBH4并在N2保护下室温继续搅拌3h。用0.1M HCl将反应液调至中性,滴加含有10mg SA的2mL DMSO溶液至反应液中,室温反应5h。最后,将反应液移入透析袋(MWCO 1.0kDa),并用去离子水透析2天得到SA PEI。图7是SA PEI的TEM和DLS图,证实了SA PEI为球形纳米结构,粒径为160nm。图8的纳米粒子稳定性结果证明纳米粒子在一个月内非常稳定,粒径和zeta电位几乎保持不变。
实施例4:SA PEI@RBCs的合成
将新鲜采集的1mL新西兰大白兔全血加入到含有3.8%柠檬酸钠抗凝剂的离心管中,血液在4℃,2000r/min的条件下离心10min,以除去血浆、血小板和白细胞,分离出下层红细胞。用无菌等渗磷酸盐缓冲液(1×PBS)洗涤红细胞后再次离心弃上清,重复洗涤4次。将RBCs重悬于PBS后,在稀释的红细胞中加入一定量的SA PEI并轻轻混匀,室温孵育1h后离心得到SA PEI@RBCs。图8为SA PEI@RBCs的制备示意图。图9为SA PEI@RBCs的形貌,可以明显看到均匀吸附的纳米粒子,SA PEI的吸附并未引起膜损伤,这证明了方案的可行性,也为剪切应力响应性设计带来了希望。本发明进一步测试了RBC、SA PEI和SA PEI@RBCs的zeta电位,如图10所示,RBCs和SA PEI的Zeta电位分别为-31.5±0.2mV和42.4±5.6mV,而SAPEI@RBCs的Zeta电位介于两者之间(-14.9±2.5mV),说明RBCs的加入屏蔽了SA PEI的正电荷,这有利于实现SA PEI@RBCs在体内的长效循环。这些结果表明本申请成功的制备了SAPEI@RBCs药物递送系统。
实施例5:MTT
将人脐静脉内皮细胞(HUVECs)以5×103细胞/孔的密度接种于96孔板中,在恒温恒湿细胞培养箱中过夜培养,随后加入20μL不同浓度的SA PEI(0、0.125、0.25、0.5、1、2、4、8、16、32和64μg/mL)与细胞共培养24h。在避光条件下,向每个孔中加入20μL 1%MTT,继续在37℃培养箱中培养4h后小心吸弃DMEM培养基,每孔加入150μL DMSO溶解甲瓚。使用酶标仪检测每孔在492nm处的吸光度。图11和图12说明PEI-SH和SA PEI具有良好的细胞相容性。
实施例6:NR PEI@RBCs的细胞内吞
为了便于观察,将尼罗红(NR)代替SA进行了NR PEI@RBCs的体外细胞摄取研究。将RAW 264.7接种在6孔板(2.0×105个/孔)中,以DMEM为培养基在37℃培养箱中培养。待细胞贴壁后,分别加入NR PEI或NR PEI@RBCs(50μg/mL)共培养,3h和12h后吸弃培养基,用PBS洗去未结合的纳米粒子,用4%PFA固定细胞20min,并在黑暗环境中用DAPI对细胞核染色5min,洗去染料后用CLSM观察荧光分布。图13说明RBCs的加入阻碍了巨噬细胞对NR PEI的识别和内化,有利于延长NR PEI@RBCs的体内循环时间。
实施例7:体外剪切模型
为了验证SA PEI@RBCs是否具有剪切应力响应,同时便于观察剪切前后纳米粒子在红细胞表面的吸附情况,用FITC代替SA制备了FITC PEI@RBCs,其中,RBCs已用NR标记。首先,建立了一个可以模拟心脏产生脉动流的体外剪切循环系统,该循环系统由蠕动泵、医用硅胶管、管径控制器以及储液器组成。在该系统中,蠕动泵扮演了心脏的角色,可以为流体的流动提供脉动流,与心脏最大的区别在于,蠕动泵不与流体直接接触,最大程度降低了流体污染;医用硅胶管扮演血管的角色,与流体直接接触产生剪切应力;管径控制器扮演血管内血栓的角色,可通过调节管径的大小起到调节剪切应力大小的目的。
实验前,用75%乙醇对整个循环系统进行消毒,并用PBS冲洗5min。为了防止硅胶管对红细胞的粘附,用2%牛血清蛋白对整个系统孵育10min。将5mL FITC PEI@RBCs装入储液器内,37℃温育,根据Poiseuille定律设置泵参数。剪切应力(τ)为2Pa(20dynes/cm2)代表健康血管的剪切应力,10Pa(100dynes/cm2)代表血栓部位的剪切应力。循环一定时间后收集悬液,用CLSM观察纳米粒子在红细胞上的吸附情况。图14说明FITC PEI@RBCs在健康的血管内循环时FITC PEI很少发生脱落。而在100dynes/cm2的剪切应力作用下,大量的FITCPEI从红细胞表面脱落,进而实现了FITC PEI@RBCs在斑块处的剪切应力响应。
实施例8:FeCl3诱导的兔颈动脉血栓形成模型
体重约为2kg的雄性新西兰大白兔购自北京维通利华实验动物技术有限公司。所有动物的饲养及处理均按照《实验动物护理和使用指南》进行,经吉林大学动物伦理与实验委员会批准。已有文献报道,FeCl3可诱发颈动脉血栓的形成。利用戊巴比妥钠(3%,40mg/kg)对新西兰大白兔进行麻醉,暴露左侧颈总动脉,用浸有饱和30%FeCl3的滤纸包裹颈动脉诱发血栓形成,同时注射SA、SA PEI或SA PEI@RBCs。血管损伤后,除去滤纸,使用超声多普勒探头记录30min内的血流状态。图15中SA,SAPEI和SAPEI@RBCs组的血流信号依次增强,说明血栓程度依次降低,证实了SAPEI@RBCs组的治疗效果优于SAPEI组,表明剪切应力响应在血栓的治疗过程中起到了不可替代的作用,使SAPEI能够有效的在斑块处富集并抑制斑块的进一步发展。
实施例9:体内安全性评价
将生理盐水、SA、SA PEI或者SA PEI@RBCs(80mg/kg)通过尾静脉注射进入健康昆明小鼠,每三天给一次药。半个月后处死小鼠,收集主要组织(心、脾、肾、肝、肺)进行H&E染色。图16表明药物载体的加入未对小鼠的心肝脾肺肾产生可见的毒性,证明SAPEI和SAPEI@RBCs的体内安全性。
Claims (3)
1.一种具有剪切应力响应的载药纳米粒子的制备方法,具有以下步骤:
1)辛伐他汀酸的合成
首先,将辛伐他汀在乙醇中搅拌至完全溶解后加入0.1M NaOH,在50 ℃下反应2 h,随后,将反应溶液的pH用盐酸调节至中性,利用旋转蒸发仪除去反应液中的乙醇,加入正丁醇萃取辛伐他汀酸,其中,辛伐他汀、乙醇、NaOH和正丁醇的质量比为30~90:800~1500:1:500~5000,有机相经旋转蒸发和真空干燥后得到辛伐他汀酸,记为SA;
2)PEI-SH的合成
将PEI600用PBS溶解后,加入2-亚氨基硫烷盐酸盐,反应在N2和黑暗条件下进行,室温搅拌过夜后加入DTT,继续反应3 h,其中,PEI600、PBS、2-亚氨基硫烷盐酸盐与DTT的质量比为30~70:230~300:1:1~5;待反应结束后,将反应液移入透析袋,在去离子水中透析48 h后用冻干机冻干,得到粘稠状固体活性氧响应性材料,记为PEI-SH,并保存在-20 ℃;所述PEI600为分子量为600的聚乙烯亚胺,所述DTT为二硫苏糖醇,所述PBS是pH为8的磷酸缓冲液,含0.001M 乙二胺四乙酸二钠;
3)SA PEI的制备
按1:100~1000的质量比将PEI-SH完全溶解在去离子水中,加入0.1 M的 NaBH4并在N2保护下室温继续搅拌3 h,PEI-SH与NaBH4的质量比按溶质计为1:500~1000,用0.1M的HCl将反应液调至中性,滴加含有SA的DMSO溶液至反应液中,按质量计,SA:DMSO: PEI-SH=1:2~10:0.1~2,室温反应5 h,最后,将反应液移入透析袋,并用去离子水透析2天得到SA PEI;
4)SA PEI@RBCs的制备
将新鲜的动物全血离心除去血浆、血小板和白细胞,分离出RBCs,用PBS洗涤后重悬于1~5倍RBCs体积的PBS中,再加入步骤3)制备的SA PEI并轻轻混合,其中RBCs重悬液与SA PEI的体积比为1~3:1,在室温下孵育0.5~5 h后离心得到具有剪切应力响应的载药纳米粒子SAPEI@RBCs;所述PBS是0.01M的无菌等渗磷酸盐缓冲液。
2.根据权利要求1所述的一种具有剪切应力响应的载药纳米粒子的制备方法,其特征在于,步骤2)中所述的透析袋的截留分子量为0.5 kDa;步骤3)中所述的透析袋的截留分子量为1.0kDa。
3.根据权利要求1所述的一种具有剪切应力响应的载药纳米粒子的制备方法,其特征在于,步骤4)所述的将新鲜的动物全血离心,是在4 ℃,2000 r/min的条件下离心10 min,以3.8%柠檬酸钠作为抗凝剂。
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