CN114377144A - pH/活性氧双重响应性超分子聚肽前药纳米粒子 - Google Patents
pH/活性氧双重响应性超分子聚肽前药纳米粒子 Download PDFInfo
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- CN114377144A CN114377144A CN202210105633.3A CN202210105633A CN114377144A CN 114377144 A CN114377144 A CN 114377144A CN 202210105633 A CN202210105633 A CN 202210105633A CN 114377144 A CN114377144 A CN 114377144A
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- Prior art keywords
- poly
- lysine
- polypeptide
- active oxygen
- prodrug
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Abstract
本发明公开了一种pH/活性氧双重响应性超分子聚肽前药纳米粒子,属于生物医药技术领域。所述超分子聚肽前药纳米粒子由聚乙二醇‑聚(L‑赖氨酸)‑二茂铁‑柱芳烃和吡啶‑聚(L‑赖氨酸)负载葡萄糖氧化酶制成。本发明的超分子聚肽前药纳米粒子通过聚合物‑前药的形式,增加了载药效率,减少了纳米药物的毒副作用,提高了稳定性,并且通过将化疗和化学动力治疗、饥饿疗法相结合的三重联合疗法,大大提高了抗肿瘤治疗的效果。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种pH/活性氧双重响应性超分子聚肽前药纳米粒子及其制备方法和应用。
背景技术
目前,聚肽的合成方法主要是通过一级胺或碱性引发剂引发单体α-氨基酸-N-羧基酸酐(NCA)的开环聚合法(ROP),其功能化则是利用具有功能基团的氨基酸单体(如半胱氨酸、天冬氨酸、谷氨酸等),对聚肽的侧链进行功能化修饰。而席夫碱则是含有亚胺或甲亚胺特性基团 (C=N)的一类有机化合物,通常席夫碱由胺和有活性羰基的化合物(醛、酮等)缩合而成,改变连接的取代基及其位置,变化给电子基团的位置,形成席夫碱配体。在药物输送方面的应用,科研工作者主要是合成两亲性聚肽共聚物,利用其自组装形成囊泡、胶束、纳米管和纳米线等纳米载体来负载一种或多种药物,同时,席夫碱的一步反应也给反应过程降低不少难度。然而,传统的两亲性聚肽是通过共价键链接亲疏水链段,其合成过程复杂且分子量也难以精确调控,从而影响其组装体的形貌和尺寸,而这又对纳米药物的抗肿瘤效果有着十分重要的影响。为了充分发挥刺激响应性聚肽纳米药物输送体系的潜力,急需一种高效简洁的方法来制备多功能两亲性聚肽。因此,通过在聚肽的侧链中引入大环化合物,如环糊精、杯芳烃、葫芦脲、柱芳烃等,利用一锅法快速反应并通过主客体识别作用进一步构建刷型的两亲性超分子聚肽,不仅简化了合成步骤,缩短了制备过程和成本,还使得组装体的尺寸和形貌更易于预测和调控,有利于实现纳米药物在肿瘤部位的富集和肿瘤细胞内药物的可控释放。该合成策略同时也具有易于功能化和结构多样性的优点,为设计多功能聚肽纳米药物输送体系提供了良好的技术途径。
此外,传统的聚肽纳米药物输送体系大多是将化疗药物包封在纳米载体内部,利用EPR效应将药物输送到肿瘤部位。该方法虽然在一定程度上改善了抗肿瘤的效果,但存在载药率低、药物过早泄露、稳定性差等问题。为此,将小分子药物通过刺激响应性化学键链接在聚肽侧链或末端上,制备出聚肽-药物缀合物(简称聚肽前药),不仅提高了载药效率,增强了药物的溶解性和稳定性,降低了药物的系统毒性,而且链接的化学键在内部或外部刺激源的作用下,可以响应性地释放出药物,实现对药物的控制释放,提高治疗效果。因此,将刺激响应性、聚肽前药和纳米药物输送体系相结合,设计制备刺激响应性的聚肽前药体系,对癌症治疗领域具有重要的研究意义以及实用价值。
文献检索发现,我国中国科学技术大学葛治伸课题组在题目< Ferrocene-containing polymersome nanoreactors for synergistically amplified tumor-specific chemodynamic therapy >(协同放大肿瘤特异性化疗的含二茂铁聚合物纳米反应器)论文中(Yuheng Wang et al. Journal of Controlled Release 2021, 333, 500-510)报道了关于三嵌段聚肽纳米药物的制备、其性能的研究及其在肿瘤治疗中的应用。但是,上述体系中的化疗药物是通过物理包埋的作用负载在纳米粒子内部,在体内血液循环过程中,仍存在药物过早泄露等问题,影响纳米药物的抗肿瘤效果,并带来毒副作用。
发明内容
本发明的目的是提供一种pH/活性氧双重响应性超分子聚肽前药纳米粒子及其制备方法和应用。
为了实现上述目的,本发明采用以下技术方案:
一种pH/活性氧双重响应性超分子聚肽前药纳米粒子,由聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃和吡啶-聚(L-赖氨酸)负载葡萄糖氧化酶制成;
所述聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃的结构式如下式所示:
上述pH/活性氧双重响应性超分子聚肽前药纳米粒子的制备方法,是将聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃、吡啶-聚(L-赖氨酸)和葡萄糖氧化酶溶于N,N-二甲基甲酰胺中,再滴加去离子水,搅拌后,经透析得到超分子聚肽前药纳米粒子。
进一步地,聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃的浓度为0.9 mg/mL,吡啶-聚(L-赖氨酸)的浓度为9.1 mg/mL,葡萄糖氧化酶的浓度为1 mg/mL。
进一步地,N,N-二甲基甲酰胺和去离子水的体积比为1.5:10。
上述pH/活性氧双重响应性超分子聚肽前药纳米粒子在制备抗肿瘤药物中的应用。
本发明的超分子聚肽前药纳米粒子为化疗-化学动力治疗-饥饿疗法一体化治疗体系提供了一种简单而有效的途径。
与现有技术相比,本发明的更优效果如下:
(1)高效合成了一种超分子聚肽前药纳米粒子。
(2)该超分子聚肽前药纳米粒子在正常生理环境中,具有很好的稳定性。
(3)该超分子聚肽前药纳米粒子在肿瘤细胞内的酸性环境中,能够快速的解组装,从而加速药物的释放。
(4)该超分子聚肽前药纳米粒子负载的葡萄糖氧化酶能够催化肿瘤细胞内的葡萄糖分解,产生过氧化氢,阻断肿瘤细胞的能量供给,实现饥饿治疗。
(5)该超分子聚肽前药纳米粒子中的二茂铁成分,能够与过氧化氢反应生成羟基自由基,能够杀死肿瘤细胞,实现化学动力学治疗。
(6)该超分子聚肽前药纳米粒子在羟基自由基作用下,能够释放出化疗药物阿霉素,从而杀死肿瘤细胞,实现化疗。
(7)该化疗-化学动力治疗-饥饿疗法一体化治疗技术操作简单,仅需要两次静脉注射,便可实现肿瘤的有效治疗,具有重要的临床应用前景。
(8)本发明为制备超分子聚肽前药纳米粒子提供了一种简单而有效的途径,为获得具有pH/活性氧双重响应性的化疗-化学动力治疗-饥饿疗法一体化治疗的超分子聚肽前药纳米粒子提供了很好的实验平台。
与现有技术相比,本发明的超分子聚肽前药纳米粒子通过聚合物-前药的形式,增加了载药效率,减少了纳米药物的毒副作用,提高了稳定性,并且通过将化疗和化学动力治疗、饥饿疗法相结合的三重联合疗法,大大提高了抗肿瘤治疗的效果。
附图说明
图1为聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃的制备流程图。
图2为聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃的核磁图谱。
图3为超分子聚肽前药纳米粒子的制备原理图。
图4为超分子聚肽前药纳米粒子的动态光散射图谱。
图5为超分子聚肽前药纳米粒子的透射电镜图。
图6为超分子聚肽前药纳米粒子对宫颈癌细胞的细胞活性测试结果。
图7为超分子聚肽前药纳米粒子对HeLa肿瘤生长影响的结果。
具体实施方式
下面结合附图和具体实施例对本发明作进一步详细说明,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
本发明中,吡啶-聚(L-赖氨酸)参照专利CN113694211A公开的方法合成得到。
实施例1
聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃的制备如图1所示。
步骤一:参考已有文献得到单氨基柱[5]芳烃和ε-苄氧羰基-L-赖氨酸酸酐,在手套箱中,取氨基聚乙二醇200 mg,溶3 mL无水的N,N-二甲基甲酰胺中,再加入ε-苄氧羰基-L-赖氨酸酸酐147 mg,室温反应48 h后,将反应液沉降在16 mL无水乙醚中,再离心,反复3次,真空干燥24 h得到白色固体聚乙二醇-聚(L-赖氨酸)259.6 mg。产率80.5~82.1%。
步骤二:取步骤一得到的白色固体100 mg溶解在10 mL冰醋酸/三氟乙酸(体积比为1: 1)的混合溶剂中,于0 oC下加入1.1 mL氢溴酸/冰醋酸(33 wt%)混合溶液,继续反应1.5 h。反应结束后,将反应液沉降在80 mL无水乙醚中,再离心,反复3次,最后置于真空烘箱中干燥,得到淡黄色固体粉末46.3 mg,产率是 87.6-90.6%。
步骤三:将1,1-二醛基二茂铁58.74 mg和单氨基柱[5]芳烃169.62 mg溶于2 mL二甲亚砜中,于100 oC下反应12 h。取步骤二的产物100 mg 加入上述反应溶液,于100 oC继续反应12 h。反应结束后,将反应液用截留分子量为3500的透析袋透析,去离子水500 mL×1次/8 h,透析24 h。最后冷冻干燥,得到灰色固体粉末聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃230.27 mg,产率是76.7~80.1%。
本实施例制得的聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃如图2所示,详细峰位置归属:1H NMR (400 MHz, DMSO-d 6 , TMS), δ (ppm) = 6.77-6.63 (d, 180H, OPh,(CHN)30), 5.28-5.22 (d, 120H, (CFe)30), 4.49-4.31 (s, 15H, (NHCOCH)15), 3.98-3.74 (m, 270H, (NCH 2 CH 2 NH)15, (OCH 2 CH3)45, (CH 2 Ph)75), 3.73-3.24 (s, 456H, CH3O(CH 2 CH 2 O)113CH 2 CH 2 ), 3.08-2.99 (s, 3H, OCH 3 ), 2.79-2.62 (m, 30H, (CH 2 N)15), 1.49-1.13 (m, 225H, (OCH2CH 3 )45, (NCH2CH 2 CH 2 CH 2 )15).。
实施例2
超分子聚肽前药纳米粒子的制备如图3所示:
取0.9 mg聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃、9.1 mg吡啶-聚(L-赖氨酸)和1mg葡萄糖氧化酶溶解于1.5 mL N,N-二甲基甲酰胺中,搅拌12 h后,向其中滴加10 mL去离子水,再搅拌12 h。结束后,将溶液置于分子量3500的透析袋中,用500 mL去离子水透析2天,中间每8小时换一次去离子水,透析结束后,冷冻干燥得到超分子聚肽前药纳米粒子,收率为78.5%~83.8%。
本实施例制得的超分子聚肽前药纳米粒子的动态光散射图谱如图4所示,其数均粒径为212.7 ± 5.2 nm,PDI为0.23 ± 0.02;其透射电镜图如图5所示,为均匀的球形胶束结构。
实施例3
超分子聚肽前药纳米粒子对宫颈癌细胞的影响
将实施例2中制备得到的超分子聚肽前药纳米粒子(PFW-DOX/GOD)、阿霉素(DOX)和对照组PFW-DOX、PFW/GOD分别用细胞培养液配制成阿霉素浓度分别为 0.2、0.5、1、2、4、8µg/mL,对应的葡萄糖氧化酶的浓度分别为0.74、1.85、3.7、7.4、14.8、29.6 mU/mL。然后分别跟HeLa细胞(宫颈癌腺癌)培养48 h。采用MTT方法进行细胞活性测试,结果如图6所示。图6中,横坐标DOX指代的是阿霉素的浓度, GOD指代的是葡萄糖氧化酶的浓度。图6中,DOX是指单使用阿霉素的实验组,PFW-DOX是指聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃与吡啶-聚(L-赖氨酸)组装形成的纳米粒子的实验组,PFW/GOD是指单用聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃负载葡萄糖氧化酶的纳米粒子的实验组,PFW-DOX/GOD是指pH/活性氧双重响应性超分子聚肽前药纳米粒子的实验组。未负载葡萄糖氧化酶的纳米粒子PFW-DOX,只表现出很小的毒性;没有阿霉素前药的纳米粒子PFW/GOD,表现出的细胞毒性比PFW-DOX组稍高一些;只有pH/活性氧双重响应性超分子聚肽前药纳米粒子表现出相比于阿霉素对照组而言更高的细胞毒性。说明该pH/活性氧双重响应性超分子聚肽前药纳米粒子相对于其他对照组,表现出更好的抗肿瘤效果。
实施例4
超分子聚肽前药纳米粒子对HeLa肿瘤生长的影响实验
将接种了HeLa荷瘤的小鼠分别分为五组:生理盐水、阿霉素、纳米粒子PFW-DOX、纳米粒子PFW/GOD、pH/活性氧双重响应性超分子聚肽前药纳米粒子PFW-DOX/GOD。第0天通过尾静脉注射一次,在21天将小鼠进行安乐死后,将肿瘤部位解剖出来,如图7所示。图中,PBS是指注射生理盐水对照组,DOX是指注射阿霉素实验组,PFW-DOX是指注射聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃与吡啶-聚(L-赖氨酸)组装形成的纳米粒子的实验组,PFW/GOD是指注射单用聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃负载葡萄糖氧化酶的纳米粒子的实验组,PFW-DOX/GOD是指注射pH/活性氧双重响应性超分子聚肽前药纳米粒子的实验组。相比于其他对照组,PFW-DOX/GOD实验组对组内所有小鼠肿瘤表现出更强的抑制作用。
Claims (5)
2.权利要求1所述的pH/活性氧双重响应性超分子聚肽前药纳米粒子的制备方法,其特征在于:将聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃、吡啶-聚(L-赖氨酸)和葡萄糖氧化酶溶于N,N-二甲基甲酰胺中,再滴加去离子水,搅拌后,经透析得到超分子聚肽前药纳米粒子。
3.根据权利要求2所述的制备方法,其特征在于:聚乙二醇-聚(L-赖氨酸)-二茂铁-柱芳烃的浓度为0.9 mg/mL,吡啶-聚(L-赖氨酸)的浓度为9.1 mg/mL,葡萄糖氧化酶的浓度为1mg/mL。
4.根据权利要求2所述的制备方法,其特征在于:N,N-二甲基甲酰胺和去离子水的体积比为1.5:10。
5.权利要求1所述的pH/活性氧双重响应性超分子聚肽前药纳米粒子在制备抗肿瘤药物中的应用。
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