CN114106321B - 一种活性氧响应性材料pei-sh的制备方法与应用 - Google Patents
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Abstract
本发明的一种活性氧响应性材料PEI‑SH的制备方法与应用,属于纳米材料制备技术领域。步骤包括将PEI600用PBS溶解后,加入2‑亚氨基硫烷盐酸盐,室温搅拌过夜后加入DTT;待反应结束后,将反应液在去离子水中透析48h后用冻干机冻干,得到的粘稠状固体活性氧响应性材料PEI‑SH可用于制备具有特异性释放药物能力的纳米粒子。本发明制备的纳米粒子具有过氧化氢特异性响应释药的特点,既能降低辛伐他汀酸的毒性,同时辛伐他汀酸可以消耗细胞内活性氧而提高治疗效果。
Description
技术领域
本发明属于纳米材料制备技术领域,具体涉及一种具有活性氧(ROS)响应而特异性释放药物的纳米粒子的制备与应用。
背景技术
动脉粥样硬化(AS)是全球范围内引发人类死亡的主要原因,可引发动脉疾病、心绞痛、心肌梗死、中风、静脉血栓等致命疾病。AS发展的本质是炎症反应,虽然多余的胆固醇不再被认为是AS形成的唯一标准,但它对其发展起到不可忽视的作用,高脂血症可促使氧化应激发生,进而诱发炎症,推动AS的发展。众所周知,动脉粥样硬化部位的ROS水平显著高于正常生理条件下的水平。因此,可以利用斑块处高的ROS水平设计具有ROS响应的药物递送系统用于AS的治疗。
他汀类药物是针对AS的常规治疗药物,其中,辛伐他汀是抑制胆固醇生成最有效的药物之一,Ho-Jin Moon等人也证明了辛伐他汀具有消耗活性氧(ROS)的作用。虽然辛伐他汀是临床上十分有效的治疗药物,但由于其肝毒性的副作用降低了患者对药物的依从性,不得不寻求新的药物递送方式来降低自由给药带来的副作用。
近年来,纳米医学得到快速发展,纳米载体成为药物递送最理想的途径。阳离子聚合物PEI已经被广泛应用于基因转染和疫苗佐剂,因具有易修饰,价格低廉,易获得的优点而广受青睐。将负电性辛伐他汀酸(SA)通过静电吸附进入PEI内部,并利用在PEI末端修饰的巯基进行交联,形成稳定的阳离子型载药纳米粒子(SAPEI)。SAPEI可响应斑块处高水平的ROS而发生药物的集中释放,显著提高治疗效果,同时降低自由给药带来的毒性。
发明内容
本发明的目的在于,为解决传统响应性纳米粒子功能单一的局限,提供一种既能响应活性氧又能消耗活性氧的载药纳米粒子SA PEI,同时还提供该材料的制备方法及其在抗血栓方面的应用。
本发明的技术方案如下:
一种活性氧响应性材料PEI-SH的制备方法,具有以下步骤: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PEI-SH,并保存在-20℃。
作为优选,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。
一种活性氧响应性材料PEI-SH的应用,其特征在于,用于制备具有特异性释放药物能力的纳米粒子,步骤为: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,滴加含有抗血栓药物的DMSO(二甲基亚砜)溶液至反应液中,按质量计,抗血栓药物: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天得到具有特异性释放抗血栓药物能力的纳米粒子。
所述的抗血栓药物优选辛伐他汀酸。
所述的抗血栓药物优选按以下方法合成: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(SA)。
本发明在阳离子PEI600的末端引入了巯基,通过静电吸附与阴离子SA自组装,从而获得了交联型载药纳米粒子(SA PEI),既增强了纳米粒子的稳定性,又实现了在特定环境中释放药物的目的。SA的加入可以中和PEI600的部分正电荷。因此,本发明对基于动脉粥样硬化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、本发明将毒副作用较大的辛伐他汀酸通过用PEI-SH吸附自组装形成纳米粒子使其具有良好的生物相容性。
2、纳米粒子具有过氧化氢特异性响应的特点。
3、本发明的载药纳米粒子不仅具有过氧化氢响应的能力,还可以通过辛伐他汀酸消耗活性氧来提高治疗的效果。
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3中SA PEI的稳定性图。(a)为DLS图;(b)为zeta电位图。
图9是实施例4中SA PEI在含有不同浓度H2O2的PBS中的SA的体外累积释放曲线图。
图10是实施例5中PEI-SH、SA和SA PEI与RBC孵育后的溶血率。(a)为PEI-SH的溶血率;(b)为SA和SA PEI的溶血率。
图11是实施例6中PEI-SH、SA和SA PEI的MTT图。(a)为PEI-SH的MTT图;(b)为SA和SA PEI的MTT图。
图12是实施例7中SA、PEI-SH和SA PEI对RAW 264.7的细胞内ROS含量的影响图。
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SAPEI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的载药量及药物释放
将冻干后的SAPEI粉末溶解在含有H2O2的去离子水中,终浓度为0.01mg/mL。高速离心后,将上清液转移到石英比色皿中,25℃条件下观察SA的紫外吸收峰,并根据已建立的标准曲线获得载药量为44.4%。使用透析袋进行了体外药物释放的研究。简而言之,将装在透析袋(MWCO 3.5kDa)中等量的SA PEI溶液浸入含不同浓度H2O2(0,2.5,5,7.5和10mM)的PBS(pH 7.4)中,每个样品的体积为68mL。将实验置于37℃黑暗环境中的摇床上轻轻晃动。在预定的时间点,取3mL透析袋外侧的溶液,同时加入等体积对应的透析液以保持体积恒定。SA的释放量用紫外分光光度计进行测定,并根据标准曲线进行分析。所有数据均以平均值表示,试验重复三次。图9是SA PEI在含有不同浓度H2O2的PBS(pH7.4)中的SA的体外累积释放曲线图,可以发现明显的H2O2依赖性药物释放曲线,说明SA PEI具有H2O2响应性释放药物的特性。
实施例5:SA PEI的血液相容性
将收集的9mL新鲜兔血装入含有1mL 3.8%柠檬酸钠的离心管中,离心(2000rpm,10min)后弃上清,收集底部红细胞,加入PBS洗涤三次,最后将红细胞重悬于10mL PBS中,4℃储存。取100μL红细胞悬液,加入不同浓度的SA PEI在37℃共孵育1h后,将混合液在2000rpm下离心10min,收集上清液,利用UV在540nm处检测上清液内血红蛋白的吸光度。分别研究了PEI-SH(0、2、4、6、8、16、24、32、38μg/mL)、SA(0、2、4、6、8、10、16、24μg/mL)和SAPEI(0、2、4、6、8、10、16、24μg/mL)在不同浓度下的溶血情况。图10说明当PEI-SH的浓度低于32μg/mL时,溶血率均低于公认的5%阈值。与游离SA相比,SA PEI的溶血率在设定的浓度范围内均低于5%,而游离SA的溶血率在浓度高于10μg/mL时就已经超过阈值,说明PEI-SH在一定范围内起到了降低SA溶血毒性的作用。
实施例6:SA PEI的细胞毒性
将RAW 264.7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中当PEI-SH浓度不超过16μg/mL时,细胞存活率均高于80%,表现出良好的细胞相容性。与游离SA相比,当SA PEI的浓度≤16μg/mL时,细胞的存活率表现出与PEI-SH相似的趋势,而游离SA的浓度超过4μg/mL时细胞存活率已经低于80%,表明SA PEI起到了显著降低SA细胞毒性的作用。
实施例7:细胞内ROS的水平
为了监测细胞内ROS的水平,采用了DCFH-DA检测法。DCFH-DA进入细胞后能够被细胞内ROS氧化形成具有绿色荧光的2',7'-二氯荧光素(DCF),已被广泛用作测定细胞内ROS的荧光探针。首先,将RAW 264.7(1×105细胞/孔)接种在激光共聚焦培养皿中,待细胞贴壁后加入LPS(4μg/mL),在37℃培养箱中培养36h。随后,用PBS洗去LPS,加入含有SA或SA PEI的新鲜培养基作用3h后,再次洗涤细胞3次,依次用10μM DCFH-DA和1mM Hoechst 33342分别培养30min和5min。最后,除去荧光探针溶液,用共聚焦激光扫描显微镜检测细胞内ROS水平。图12证明SA和SAPEI具有消耗ROS的作用,而PEI-SH的加入并未对细胞内ROS水平产生影响。同时,SAPEI消耗ROS的能力也再次证明SA PEI可以响应于细胞内ROS,实现药物的快速释放。
Claims (3)
1.一种活性氧响应性材料PEI-SH的制备方法,具有以下步骤:将分子量为600的聚乙烯亚胺用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二硫苏糖醇,继续反应3 h,其中,分子量为600的聚乙烯亚胺、PBS、2-亚氨基硫烷盐酸盐与二硫苏糖醇的质量比为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PEI-SH,并保存在-20 ℃;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。
2.一种按权利要求1的方法制备的活性氧响应性材料PEI-SH的应用,其特征在于,将所述的活性氧响应性材料PEI-SH用于制备具有特异性释放药物能力的纳米粒子,步骤为: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,滴加含有抗血栓药物的DMSO溶液至反应液中,按质量计,抗血栓药物: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天得到具有特异性释放抗血栓药物能力的纳米粒子。
3.根据权利要求2所述的一种活性氧响应性材料PEI-SH的应用,其特征在于,所述的抗血栓药物是辛伐他汀酸,按以下方法合成: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。
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