CN114344476B - 一种聚合物前药修饰的配位纳米化学动力载体的制备及其应用 - Google Patents
一种聚合物前药修饰的配位纳米化学动力载体的制备及其应用 Download PDFInfo
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Abstract
本发明属于纳米医学抗肿瘤前药及递药载体设计领域,主要涉及一种聚合物前药修饰的配位纳米化学动力载体的制备及其在制备抗肿瘤药物中的应用。本发明的聚合物前药修饰的配位化学动力载体的构建方式为聚合物前药以物理或配位作用修饰在纳米配位载体表面,经体内外药效实验证明,可同步增加肿瘤组织中的过氧化氢源和铁源,并通过芬顿反应产生高活性活性氧实现化疗‑化学动力学治疗的协同。
Description
技术领域
本发明属于纳米医学抗肿瘤前药及递药载体设计领域,主要涉及一种聚合物前药修饰的配位纳米化学动力载体的制备及其在制备抗肿瘤药物中的应用。
背景技术
随着科学技术的进步,以往许多致命性疾病均得到了有效的治疗,但恶性肿瘤依然是导致人类死亡的主要原因之一。在人口趋于老龄化的今天,人们对生命健康越来越重视,对癌症患者的治疗需求日益迫切。临床上对癌症患者的主要治疗方法有手术治疗、放化疗和免疫疗法等。其中,早期肿瘤手术治疗能取得良好的效果,但由于国内癌症患者早期检出率较低,手术治疗对于国内大部分的晚期癌症患者都存在高复发,疗效差的问题,而仅有少部分患者能获益于免疫治疗。因此,化疗依旧是肿瘤治疗的主要手段,但其依旧存在全身毒副作用高,疗效较差的问题。开发新型高效低毒的肿瘤治疗手段是临床之急需。
化学动力学疗法(CDT),主要通过亚铁离子等催化剂将低活性的过氧化氢通过芬顿反应转化为高细胞毒性的羟自由基,进而对肿瘤细胞进行杀伤的治疗方法,其被证明是一种切实有效的肿瘤特异性氧化治疗方式。相较于需要借助外源性能量触发的光动力疗法与声动力疗法,CDT疗法利用肿瘤细胞内源性高过氧化氢环境,具有先天的肿瘤选择性,并且治疗不受肿瘤位置局限,在肿瘤治疗领域具有极大的潜力。但是,如何提高细胞内的过氧化氢浓度和亚铁离子的浓度,以及如何提高药物在肿瘤部位的蓄积,是CDT疗法治疗的难点。
有研究报导通过向肿瘤部位递送四氧化三铁纳米粒用于肿瘤的CDT治疗,但是该含铁无机纳米载体需要在pH 2~4的酸性条件下才能释放游离铁离子,因而其增加肿瘤组织中游离铁离子的浓度效果十分有限,仅能在载体表面产生芬顿反应,极大影响了其在肿瘤CDT疗法中的应用。也有研究通过直接递送葡萄糖氧化酶作为过氧化氢源来达到饥饿疗法和化学动力学疗法***的目的,但是直接递送葡萄糖氧化酶存在稳定性差以及肿瘤靶向效果差的问题。为了提高化学动力学疗法的治疗效果,研究者们专注于通过药物载体来同步递送过氧化氢源和亚铁源,以期实现强效的CDT治疗效果。但以上载体在制备过程中不可避免引入有机溶剂,过程复杂,且由于亚铁离子易被氧化,难以向肿瘤组织的稳定递送足量亚铁源。此外,过氧化氢源及铁源在血循环及正常组织的不可控释放,也导致对正常组织的毒副作用。因此,开发一种可于肿瘤组织中响应释放药物,并可稳定递送足量亚铁源及过氧化氢源的递药载体是目前CDT疗法面临的技术难题之一。
发明内容
为了克服现有技术的不足,本发明提供了一种聚合物前药修饰的配位纳米化学动力载体,以氯化血红素(亚铁源)和锌离子形成配位纳米载体核心,同时将硼替佐米(过氧化氢源)以pH敏感硼酸酯键共价修饰到透明质酸长链上,最后将二者共组装,构建了pH响应硼替佐米透明质酸前药修饰的氯化血红素配位纳米载体,以期实现过氧化氢源和铁源在肿瘤部位的高效共递送,实现高效的化疗-化学动力学治疗的协同。该配位载体通过透明质酸介导的主动靶向作用聚集在肿瘤部位,肿瘤部位的偏酸性环境触发硼替佐米原形药释放,引起肿瘤部位大量的过氧化氢堆积,同时氯化血红素配位核心通过其优越的过氧化物酶活性将过氧化氢转化成强氧化活性羟自由基,从而实现高效的肿瘤杀伤作用。
本发明的目的在于克服现有技术的两大难点,一是实现CDT疗法中过氧化氢源和亚铁源在时空上的稳定共递送,提供高效治疗三阴性乳腺癌等实体瘤的治疗策略,二是通过高分子聚合物靶向、刺激敏感释药的手段提高药物在肿瘤部位的蓄积,降低对正常组织的毒副作用。
本发明的目的可以通过以下技术方案来实现:
一种聚合物前药修饰的配位纳米化学动力载体,其特征在于,包含聚合物前药以及配位纳米载体;所述配位纳米载体包含金属离子与有机药物配体;所述聚合物前药为共价药物偶连物,其偶联方式为“小分子药物-刺激响应敏感键-高分子聚合物”;所述聚合物前药修饰的配位化学动力载体的构建方式为聚合物前药以物理或配位作用修饰在纳米配位载体上。
在其中一些实施例中,所述金属离子包括但不限于以下一种或多种:钙离子、铜离子、锌离子、锰离子、钴离子或铁离子;所述有机药物配体包括但不限于血红素、二茂铁等含有羧基、氨基等可配位结构的有机分子;所述纳米配位载体通过金属离子与有机药物配体的配位作用制备。
在其中一些实施例中,所述纳米配位载体通过溶剂热法及高压均质制备;所述溶剂热法的溶剂包括但不限于去离子水、无水乙醇等;所述溶剂热法的反应温度可以是60~100℃,反应时间可以是4~48h;所述高压均质后得到的纳米配位载体的粒径为20~500nm。
在其中一些实施例中,所述聚合物前药中的小分子药物包括但不限于硼替佐米、伊沙佐米、丰加霉素、双氢青蒿素、喜树碱、肉桂醛或顺铂等能在细胞内产生过氧化氢的小分子。
在其中一些实施例中,所述聚合物前药中的刺激响应敏感键,可响应于肿瘤微环境或肿瘤细胞中的pH、谷胱甘肽、活性氧或高表达的酶;所述肿瘤组织高表达的酶包括但不限于基质金属蛋白酶、弗林蛋白酶、豆荚蛋白酶、FAP-α酶或组织蛋白酶等。
在其中一些实施例中,所述高分子聚合物包括但不限于透明质酸、岩藻多糖、聚乙二醇、海藻酸钠、壳聚糖、硫酸软骨素、聚乙烯醇、聚乳酸、右旋糖苷、聚乙烯吡咯烷酮或葡聚糖等;所述高分子聚合物的分子量为2k~50w。
本发明的另一个目的在于提供一种上述的聚合物前药修饰的配位纳米化学动力载体在制备用于实体肿瘤治疗药物中的用途。
在其中一些实施例中,所述的一种聚合物前药修饰的配位纳米化学动力载体可同步增加肿瘤组织中的过氧化氢源和铁源,并通过芬顿反应产生高活性活性氧实现化疗-化学动力学治疗的协同。
与现有技术相比,本发明具有以下有益效果:
本发明设计合成的一种聚合物前药修饰的配位纳米化学动力载体可通过透明质酸的主动靶向作用在肿瘤部位蓄积,在肿瘤部位刺激响应断键,释放硼替佐米原形药物,进而产生大量过氧化氢,同时氯化血红素-锌配位载体将过氧化氢转化成毒性更高的羟自由基,实现氧化应激的级联放大作用。本发明实现了过氧化氢源和铁源同步靶向递送于肿瘤部位问题,实现了对三阴性乳腺癌等实体瘤的高效、低毒的治疗策略。
附图说明
以下对本发明中的附图进行详细说明:
图1为实施例1中硼替佐米透明质酸前药的核磁氢谱图。
图2为实施例2或3中氯化血红素-锌的配位载体和载硼替佐米透明质酸前药氯化血红素-锌的配位载体的动态光散射粒径图和Zeta电位图;
其中图2A是氯化血红素-锌的配位载体载药前后的动态光散射粒径分布图,图2B是氯化血红素-锌的配位载体载药前后Zeta电位变化示意图。载药后氯化血红素-锌的配位载体粒径略变大,负电势变强。
图3为实施例4中载硼替佐米透明质酸前药氯化血红素-锌的配位载体对MDA-MB-231肿瘤细胞毒性结果图。
图4为实施例5中载硼替佐米透明质酸前药氯化血红素-锌的配位载体胞内产生ROS流式结果图。
图5为实施例6载硼替佐米透明质酸前药氯化血红素-锌的配位递药***中肿瘤抑制效果图;
本发明的递药***对三阴性乳腺癌有明显的肿瘤治疗效果。
具体实施方式
下面对发明的优选实施例进行描述,以下优选实施例仅用于对本发明进行解释,本发明不限制于此,所用试剂浓度,体积,反应时间等可以根据具体情况进行调整。
实施例1:硼替佐米透明质酸前药(HA-DA-BTZ)的制备
称取2.00g透明质酸钠(1~10W),加入80ml无水乙醇中,搅拌下加入8ml浓盐酸,在室温条件下搅拌1小时。静置1小时,去除上清液。再加入80ml无水乙醇,在搅拌下加入8ml浓盐酸,在室温条件下搅拌1小时,静置后去除上清液,以上操作重复三次。第三次去除上清液后在4000rpm条件下离心7分钟,倒掉上清液,重复离心3次。将所得固体溶于100mL超纯水中,往溶液中滴加四丁基氢氧化铵调节pH到中性,冷冻干燥后既得产物HA-TBA。
称取1.00g HA-TBA溶于50mL DMF中,加入0.48g HDBT和0.32g DIC后充分搅拌,在氮气保护下于室温条件搅拌1小时。充分反应后,依次加入0.48g多巴胺(DA)、0.31g DMAP和1.62g DIPEA,在室温条件下搅拌4h。充分反应后在pH 4-5的氯化钠溶液中透析36小时,结束后再在纯水中透析36小时。透析结束后冷冻干燥得产物HA-DA。
称取0.20g HA-DA,溶于适量甲酰胺中,再称取0.29g硼替佐米(BTZ)溶于适量DMSO中,将BTZ溶液缓慢滴入HA-DA溶液中,在室温条件下搅拌24小时。充分反应后在纯水中透析24小时,冷冻干燥得到最终产物HA-DA-BTZ。
根据核磁共振结果显示(图1),合成产物在在1H-NMR 1.0~2.0ppm之间有透明质酸链上甲基上的特征峰,6.55-6.98ppm上有苯硼酸苯环上的特征峰,7.00~7.50ppm上有硼替佐米苯环上的特征峰,8.65~9.20ppm之间有硼替佐米吡嗪环基上的特征峰,表明硼替佐米透明质酸前药已成功合成。
实施例2:氯化血红素-锌配位载体的制备(Hemin-MOF)
称取适量氯化血红素(Hemin)溶于DMSO中,配制0.5mM浓度的氯化血红素PBS溶液,同时称取适量Zn(NO3)2·6H2O溶于超纯水中配制27mM浓度的锌离子水溶液。先取适量锌离子水溶液加入到圆底烧瓶中,在搅拌中缓慢滴加一半体积的氯化血红素PBS溶液,滴加完毕后继续搅拌15分钟至充分混合,转移到聚氟乙烯高压反应釜中后放入80℃烘箱反应过夜。待反应釜冷却至室温,将混合溶液在13000rpm条件下离心15分钟,收集得到黑褐色固体,用超纯水洗涤3~5次,于50℃烘箱中烘干得到微米级Hemin-MOF。通过反复高压均质和充分超声制备纳米级Hemin-MOF。
根据动态光散射粒径结果显示(图2A),高压均值后得到的Hemin-MOF的粒径约为150-180nm,粒径均一,Zeta电位测定结果表明(图2B)Hemin-MOF为Zeta电势为负。
实施例3:硼替佐米透明质酸前药的氯化血红素-锌的配位递药***的构建
(Hemin@HA-BTZ)
将实施例2中制备好的Hemin-MOF粉末超声分散在超纯水溶液中配制1mg/mL的Hemin-MOF溶液,将实施例1中制备好的HA-DA-BTZ材料超声分散在超纯水中配制2mg/mL浓度的HA-DA-BTZ溶液。将制备好的Hemin-MOF溶液1mL加入到4mL HA-DA-BTZ溶液中,在室温条件下低速搅拌4h。充分反应后在13000rpm条件下离心15分钟收集沉淀,用超纯水洗涤3~5次,于50℃烘箱中烘干得到载药纳米粒Hemin@HA-BTZ。
根据动态光散射粒径结果显示(图2A),所得载药纳米粒Hemin@HA-BTZ的粒径比未载药Hemin-MOF略大,约为150-200nm。Zeta电位测定结果表明(图2B),Hemin-MOF裹上硼替佐米前药后负电势变强,表明带负电的HA-DA-BTZ成功包裹在Hemin-MOF表面。
实施例4:Hemin@HA-BTZ体外细胞毒性实验
将5×104个/孔密度的MDA-MB-231细胞接种于96孔板中,在5%CO2细胞培养箱中养24h,加入含0、0.78、1.56、3.13、6.25、12.5、25μM Hemin(0、0.078、0.156、0.313、0.625、1.25、2.5μM BTZ)Hemin@HA-BTZ的培养液(89%DMEM培养基+10%胎牛血清+1%双抗)与细胞共孵育48h后,每孔加入20μL MTT(5mg/mL,PBS溶液),再避光孵育4h。吸走培养液后每孔加入100μL DMSO,震摇15min后立即用酶标仪测定其在490nm处各孔的吸光值。以不加药物组为对照组,不加细胞孔为空白组,按照以下公式计算细胞的存活率:细胞存活率(%)=(OD样品-OD空白)/(OD对照-OD空白)×100%。
如图3所示,在MDA-MB-231肿瘤细胞中,Hemin@HA-BTZ有明显的细胞毒性,其起效机制可能是硼替佐米前药HA-DA-BTZ在细胞内可引起过氧化氢的堆积,而Hemin-MOF具有过氧化物酶的作用,可以将细胞内的过氧化氢转化成杀伤效果更强的羟自由基,从而对肿瘤细胞其到化学动力学杀伤的效果。
实施例5:Hemin@HA-BTZ胞内ROS考察实验
将1×105个/孔密度的MDA-MB-231细胞接种于6孔板中,在5%CO2细胞培养箱中培养24h,加入含0、50μg/mL Hemin@HA-BTZ的培养液(89%DMEM培养基+10%胎牛血清+1%双抗)与细胞共孵育12h后,吸走培养液,每孔加入1ml DCFH-DA(10μM,DMEM溶液)在37℃培养箱中孵育20分钟。吸走探针,每孔用1mLPBS洗涤3次,消化收集细胞用流式细胞仪检测细胞内ROS生成。
如图4所示,MDA-MB-231细胞与Hemin@HA-BTZ共孵育后,细胞内能检测到明显的DCFH-DA探针的荧光,说明给药后细胞内ROS显著升高,证明Hemin@HA-BTZ可能通过提高细胞内ROS含量,造成线粒体损伤从而引起其对肿瘤细胞的杀伤。
实施例6:Hemin-MOF@HA-BTZ体内药效学评价
消化收集MDA-MB-231细胞配制成2×107个/mL的PBS细胞悬液,给裸鼠腋下皮下注射100μL细胞悬液构建MDA-MB-231裸鼠鼠皮下乳腺癌模型。观察裸鼠肿瘤状态,当裸鼠皮下肿瘤体积达到100mm3时,将小鼠随机分为2组(n=5),PBS组和Hemin@HA-BTZ组。根据分组分别给裸鼠注射不同的药物,在第1、3、5、7、9天进行给药,第一天给药后开始记录计算小鼠肿瘤体积和体重,每两天记录一次,17天后处死裸鼠。
如图5所示,PBS组裸鼠肿瘤生长迅速,Hemin@HA-BTZ组裸鼠肿瘤有明显抑制生长的作用。说明Hemin@HA-BTZ可通过同时提高裸鼠肿瘤内过氧化氢浓度和亚铁浓度产生大量ROS对肿瘤起到明显的抑制作用。
Claims (2)
1.一种聚合物前药修饰的配位纳米化学动力载体,其特征在于,由配位纳米载体以及聚合物前药制成;所述聚合物前药修饰的配位纳米化学动力载体的制备过程包括以下3个步骤:
a、合成硼替佐米透明质酸聚合物前药,其中聚合物与前药的偶连方式为小分子药物-硼酸酯键-透明质酸多巴胺衍生物;具体合成过程为称取2.00g透明质酸钠(1~10W),加入80mL无水乙醇中,搅拌下加入8mL浓盐酸,在室温条件下搅拌1小时,静置1小时,去除上清液,再加入80mL无水乙醇,在搅拌下加入8mL浓盐酸,在室温条件下搅拌1小时,静置后去除上清液,以上操作重复三次,第三次去除上清液后在4000rpm条件下离心7分钟,倒掉上清液,重复离心3次,将所得固体溶于100mL超纯水中,往溶液中滴加四丁基氢氧化铵调节pH到中性,冷冻干燥后既得产物透明质酸-四丁基氢氧化铵;接着,称取1.00g透明质酸-四丁基氢氧化铵溶于50mL N,N-二甲基甲酰胺中,加入0.48g N,N-二异丙基碳二亚胺和0.32g 1-羟基苯并***后充分搅拌,在氮气保护下于室温条件搅拌1小时,充分反应后,依次加入0.48g多巴胺、0.31g 4-二甲氨基吡啶和1.62g N,N-二异丙基乙胺,在室温条件下搅拌4h,充分反应后在pH 4-5的氯化钠溶液中透析36小时,结束后再在纯水中透析36小时,透析结束后冷冻干燥得产物透明质酸-多巴胺;最后,称取0.20g透明质酸-多巴胺,溶于适量甲酰胺中,再称取0.29g硼替佐米溶于适量二甲基亚砜中,将硼替佐米溶液缓慢滴入透明质酸-多巴胺溶液中,在室温条件下搅拌24小时,充分反应后在纯水中透析24小时,冷冻干燥得到最终产物硼替佐米透明质酸聚合物前药;
b、通过溶剂热法及高压均质制备锌离子与氯化血红素配位的纳米配位载体,具体制备过程为称取适量氯化血红素溶于二甲基亚砜中,配制0.5mM浓度的氯化血红素PBS溶液,同时称取适量Zn(NO3)2·6H2O溶于超纯水中配制27mM浓度的锌离子水溶液,先取适量锌离子水溶液加入到圆底烧瓶中,在搅拌中缓慢滴加一半体积的氯化血红素PBS溶液,滴加完毕后继续搅拌15分钟至充分混合,转移到聚氟乙烯高压反应釜中后放入80℃烘箱反应过夜,待反应釜冷却至室温,将混合溶液在13000rpm条件下离心15分钟,收集得到黑褐色固体,用超纯水洗涤3~5次,于50℃烘箱中烘干得到微米级配位载体,通过反复高压均质和充分超声制备纳米级配位载体;
c、将步骤b中制备好的纳米级配位载体粉末超声分散在超纯水溶液中配制1mg/mL的溶液,将步骤a中制备好的硼替佐米透明质酸聚合物前药材料超声分散在超纯水中配制2mg/mL浓度的硼替佐米透明质酸聚合物前药溶液,将制备好的纳米级配位载体溶液1mL加入到4mL硼替佐米透明质酸聚合物前药溶液中,在室温条件下低速搅拌4h,充分反应后在13000rpm条件下离心15分钟收集沉淀,用超纯水洗涤3~5次,于50℃烘箱中烘干即得上述聚合物前药修饰的配位纳米化学动力载体。
2.根据权利要求1所述的一种聚合物前药修饰的配位纳米化学动力载体在制备治疗实体肿瘤药物中的用途。
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