CN111603568A - 电荷反转型聚肽复合纳米药物及其制备方法和应用 - Google Patents
电荷反转型聚肽复合纳米药物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种电荷反转型聚肽复合纳米药物及其制备方法和在制备抗肿瘤药物中的应用。所述电荷反转型聚肽复合纳米药物由电荷反转型聚肽复合纳米粒子包载活性药物制成;所述电荷反转型聚肽复合纳米粒子是将电荷反转型聚肽共聚物修饰在聚多巴胺纳米粒子表面后得到,所述活性药物包载在聚多巴胺纳米粒子内;所述电荷反转型聚肽共聚物为聚乙二醇‑b‑聚(L‑赖氨酸)‑b‑聚(L‑半胱氨酸)。本发明的电荷反转型聚肽复合纳米药物,一方面在将近红外光转换成热量的同时,能够释放出一氧化氮气体,从而实现逆转肿瘤耐药性的作用;同时能在癌细胞内释放出抗癌药物阿霉素,实现对肿瘤的治疗。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种电荷反转型聚肽复合纳米药物及其制备方法和在制备抗肿瘤药物中的应用。
背景技术
多药耐药性是导致肿瘤化疗失败的重要原因之一,而刺激响应性聚合物纳米药物能够在进入细胞后刺激响应性地释放出抗癌药物,在一定程度上能避免多药耐药性的作用。此外,根据与正常组织的中性环境不同,肿瘤组织的表现为弱酸性,通过弱酸性的pH值使纳米药物载体的表面电荷发生变化,使其在中性的呈负电而稳定存在于血液循环中,在酸性肿瘤组织中,电荷反转成正电荷,使其与带负电的细胞膜具有较高的亲和力,从而增强细胞的内化。因此,开发一种电荷反转型逆转肿瘤耐药性的抗癌纳米药物具有重要的临床应用前景。
此外,一氧化氮气体是一种具有多种生理功能的内源性气体,能够降低肿瘤细胞的P-gp表达水平和逆转肿瘤细胞的多药耐药性。因此,研发具有响应性释放NO气体的功能型聚合物纳米载体可以进一步提高抗肿瘤治疗的效果。其中,通过光控制NO释放的体系由于能够精确的控制释放位置、时间和剂量而最具吸引力。但是大多数光响应体系是基于紫外或可见光,其治疗效果受到组织浅层穿透和短波长光引起的副作用的影响较大。因此,基于近红外光激发的NO释放体系是一个更合适的选择,其可以穿透更深的组织,同时对周围的组织造成更小的损伤。同时,近红外光(NIR, 650 – 900 nm)响应性聚合物纳米药物可以针对肿瘤部位进行精准的光热疗法,光热疗由于其微创性和高选择性成为了癌症治疗中的高效新型技术, 还可以大大增强药物在肿瘤细胞的积累和亚细胞器的转运,并对多药耐药性起到一定的抑制作用。因此,开发一种具有光热疗-NO气体-化疗三重联合疗法一体化的抗癌纳米药物为实现无创、高效地治疗肿瘤(特别是耐药肿瘤)提供了一条切实有效的途径,具有重要的临床应用前景。
Ming Su等人在Polydopamine Nanoparticles for Combined Chemo- andPhotothermal Cancer Therapy(化疗-光热疗一体的聚多巴胺纳米粒子)论文中(ZhijunZhu and Ming Su*,Nanomaterials 2017, 7, 160)报道了关于聚多巴胺纳米粒子的制备、其性能的研究及其在肿瘤治疗中的应用。但是,上述体系中负载顺铂药物的聚多巴胺纳米粒子仅仅将化疗和光热疗相结合,并且结构单一,只局限于无耐药性的肿瘤治疗,不能实现对耐药肿瘤的有效治疗,在临床中很难转化和应用。
发明内容
针对上述现有技术的不足,本发明提供了一种电荷反转型逆转肿瘤多药耐药性的聚肽复合纳米药物的制备与抗肿瘤应用,以解决原有技术中肿瘤对阿霉素抗癌药物的多药耐药性问题,以及化疗与光热疗法、NO气体治疗的一体化治疗等问题。
为了实现上述发明目的,本发明采用以下技术方案:
电荷反转型聚肽复合纳米药物,由电荷反转型聚肽复合纳米粒子包载活性药物制成;
所述电荷反转型聚肽复合纳米粒子是将电荷反转型聚肽共聚物修饰在聚多巴胺纳米粒子表面后得到,所述活性药物包载在聚多巴胺纳米粒子内;
所述电荷反转型聚肽共聚物为聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸),结构式如式Ⅰ所示:
进一步地,所述活性药物为阿霉素。
上述电荷反转型聚肽复合纳米药物的制备方法,包括以下步骤:
步骤1,制备电荷反转型聚肽共聚物聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸);
步骤2,制备聚多巴胺纳米粒子;
步骤3,将聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)加至溶剂中,溶解后加至聚多巴胺纳米粒子的水溶液中,搅拌反应,得到电荷反转型聚肽复合纳米粒子;
步骤4,向步骤3得到的电荷反转型聚肽复合纳米粒子中加入活性药物,搅拌反应,得到电荷反转型聚肽复合纳米药物。
上述电荷反转型聚肽复合纳米药物在制备逆转肿瘤多药耐药性的抗肿瘤药物中的应用。
本发明设计合成了一种肿瘤微环境pH和近红外光双重响应的电荷反转型聚肽共聚物聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)(PLC),其侧链含2,3-二甲基马来酸酐(DMMA)和S-亚硝基(SNO),将该聚合物修饰在聚多巴胺纳米粒子(PDA)的表面,得到复合纳米粒子PDA-PLC。负载阿霉素(DOX)后的复合载药纳米粒子PDA-PLC/DOX 在正常生理环境中带负电荷,而在肿瘤组织的弱酸性环境中,负电荷转变为正电荷,与带负电荷的细胞膜具有较高的亲和力,从而增强了细胞的内摄,提高了化疗的疗效。此外,加上近红外光的照射后,触发SNO基团断裂释放出的NO 气体,能抑制P-gp 糖蛋白的表达,逆转MCF-7/ADR 的多药耐药性,并且PDA 的光热转换性能能协同DOX 的化疗,表现出更好的抗肿瘤活性。
有益效果:
1、该电荷反转型聚肽复合纳米药物,在近红外区有强吸收,在温和的光照条件下(光强1.6 W/cm2、波长808 nm、光照时间5 min),实现了温和的光热治疗作用。
2、该电荷反转型聚肽复合纳米药物,在将近红外光转换成热量的同时,能够释放出一氧化氮气体,从而实现逆转肿瘤耐药性的作用。
3、该电荷反转型聚肽复合纳米药物能在癌细胞内释放出抗癌药物阿霉素,实现对肿瘤的治疗。
4、该逆转肿瘤耐药性的光热疗-NO气体-化疗一体化技术操作简单,仅需要一次静脉注射和一次光照,便可实现耐药肿瘤的完全消融和无痕治疗,具有重要的临床应用前景。
5、本发明为制备用于电荷反转型逆转肿瘤多药耐药性的载药纳米粒子提供了一种简单而有效的途径,为获得具有pH响应性电荷反转功能、近红外光吸收性、光热治疗、NO气体治疗与化疗一体化的聚肽复合纳米药物提供了很好的实验平台。
附图说明
图1为本发明中制备电荷反转型聚肽复合纳米药物的示意图。
图2为实施例1中聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)的合成路线图。
图3为实施例1中聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)的氢谱。
图4为实施例1中电荷反转型聚肽复合纳米粒子的动态光散射图谱。
图5为实施例1中电荷反转型聚肽复合纳米药物的动态光散射图谱。
图6为实施例2中电荷反转型聚肽复合纳米药物对MCF-7肿瘤细胞生长抑制作用的示意图。
图7为实施例2中电荷反转型聚肽复合纳米药物对MCF-7/ADR肿瘤细胞生长抑制作用的示意图。
图8为实施例3中电荷反转型聚肽复合纳米药物对MCF-7/ADR耐药肿瘤生长抑制作用的示意图。
图5-图8中,PDA指代聚多巴胺纳米粒子,DOX指代阿霉素,PDA-PLC指代电荷反转型聚肽纳米粒子,PDA-PLC/DOX指代电荷反转型聚肽复合纳米药物,NIR指代近红外激光,统计显著性数据:***P < 0.001。
具体实施方式
如图1所示,本发明设计合成了一种含有热敏性S-亚硝基供体的肿瘤微环境pH敏感性电荷反转型聚肽共聚物(PLC),制备出具有近红外和肿瘤微环境pH双重刺激响应性的电荷反转型聚肽复合纳米粒子(PDA-PLC),用于实现光热疗-NO 气体-化疗的联合治疗来克服肿瘤细胞的多药耐药性作用。PDA-PLC 复合纳米粒子的制备方法如下:首先制备出粒径约140 nm 的聚多巴胺纳米粒子(PDA),再将双亲性聚合物PLC 修饰到PDA 的表面,得到NIR与pH 双重刺激响应性的电荷反转型聚肽复合纳米粒子。其中,PDA 内核能够吸收近红外光,并把它转化为热能来加速S-NO 键的断裂,从而能够利用NO 气体来逆转肿瘤细胞的MDR效应。此外,带负电的复合纳米粒子在中性的血液循环中能稳定存在,当到达肿瘤组织的弱酸性环境中,表面的负电荷会转变成正电荷,从而增强细胞的内化。
以下实施例进一步说明本发明的内容,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。
实施例1
电荷反转型聚肽复合纳米药物的制备
1. 聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)的制备,方法如图2所示。
步骤一:参考已有文献得到ε-苄氧羰基-L-赖氨酸酸酐和S-邻硝基苄基-L-半胱氨酸,在手套箱中,取氨基聚乙二醇100 mg,溶于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73.5 mg,室温反应24 h后,再加入S-邻硝基苄基-L-半胱氨酸259.5 mg,继续反应48 h后,将反应液沉降在24 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。产率80.2~85.5%。
步骤二:取步骤一得到的白色固体50 mg溶解在100 mL N,N-二甲基甲酰胺/乙腈(体积比为4 : 1)的混合溶剂中,置于紫外灯(波长365 nm,功率150 W)下光照12 h。光照结束后,将溶液浓缩至3 mL左右,再沉降于25 mL的无水乙醚中,再离心,反复3次后,真空干燥得到黄色固体。再称取黄色固体30 mg溶解在2 mL N,N-二甲基甲酰胺中,然后加入20 µL亚硝酸叔丁酯,于室温避光搅拌反应24 h。反应结束后,将反应液沉降于16 mL的无水乙醚中,再离心,反复3次后,避光快速真空干燥得到黄色固体,产率81.3~84.6%。
步骤三:取步骤二得到的黄色固体100 mg溶于4 mL冰醋酸/三氟乙酸(体积比为1:1)的混合溶液中,于0℃下加入0.5 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,将反应液沉降在无水乙醚中,再置于25 ℃真空烘箱中快速干燥,得到黄色固体粉末82.9 mg,产率是89.2~91.6%。
步骤四:取步骤三得到的黄色固体粉末82.9 mg溶于10 mL水中,并用1 M氢氧化钠水溶液调节pH值为8.5,于室温下搅拌1 h,加入17.6 mg 2,3-二甲基马来酸酐,再用1 M氢氧化钠水溶液调节pH值,保持pH值在8~9之间,反应12 h后将反应液冻干,再用1 mL N,N-二甲基甲酰胺溶解,再于无水乙醚中沉降,反复3次,最后将所得产物置于25 oC真空烘箱中快速干燥,得到黄色固体粉末聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)79.5 mg,产率是87.3%。
制得的聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)核磁氢谱如图3所示,详细峰位置归属:1H NMR (400 MHz, DMSO-d 6 , TMS), δ (ppm) = 3.53-3.42 (m, 452H,(CH2CH2O)113), 3.44-3.39 (m, 20H, NHCH2(CH2)3), 3.22 (s, 3H, OCH3), 2.78-2.49(m, 80H, ONSCH2), 1.48-1.13 (m, 60H, NHCH2(CH2)3)。
2. 电荷反转型聚肽复合纳米粒子的制备
步骤一:在25 mL圆底烧瓶中加入410 mg三羟甲基氨基甲烷,20 mL蒸馏水,30 ℃下搅拌半小时后,再将0.04 g多巴胺盐酸盐溶于0.8 mL蒸馏水中,加入之前的反应液中,继续于30 oC下搅拌反应24 h。然后用蒸馏水透析(透析袋截留分子量3500)两天,1000 mL蒸馏水×8,得到聚多巴胺纳米粒子水溶液,收率为90%~94 %。
步骤二:取1 mg 聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)溶于0.1 mL N,N-二甲基甲酰胺中,将其加入到1 mL聚多巴胺纳米粒子水溶液中,搅拌反应24 h后,将反应液用17000 rpm高速离心半个小时,再分散于蒸馏水中,反复3次,得到电荷反转型聚肽复合纳米粒子,收率为87%~91 %。
制得的电荷反转型聚肽复合纳米粒子的动态光散射图谱如图4所示,其数均粒径为148 ± 4 nm,PDI为0.18 ± 0.04。
3. 电荷反转型聚肽复合纳米药物的制备
在25 mL圆底烧瓶中加入2 mL 浓度为1mg/mL制备得到的电荷反转型聚肽复合纳米粒子水溶液,然后加入3 ml 浓度为1.0 mg/mL 的阿霉素水溶液,室温避光搅拌反应24 h。结束后用17000 rpm的转速离心30 min,再加入10 mL蒸馏水,离心,反复3次,再冷冻干燥36小时。收率为83%~87%。
制得的电荷反转型聚肽复合纳米药物的动态光散射图谱如图5所示,其数均粒径为152 ± 3 nm,PDI为0.19 ± 0.04。
实施例2
电荷反转型聚肽复合纳米药物对乳腺癌细胞的影响
将实施例1中制备得到的电荷反转型聚肽复合纳米药物、阿霉素分别用细胞培养液配制成阿霉素浓度分别为 0.5、1、2、4、8、16、32、64 µg/mL,然后分别跟MCF-7细胞(乳腺癌)、MCF-7/ADR细胞(耐阿霉素的乳腺癌)培养48 h,此外,对于电荷反转型聚肽复合纳米药物需要另设一组,培养4 h后,再用近红外激光对其进行光照5 min (808nm,1.6W/cm2),继续培养48 h。采用MTT方法进行细胞活性测试,结果如图6和图7所示。图6和图7中,横坐标DOX指代的是阿霉素的浓度,图中,pH 7.4和pH 6.8是指电荷反转型聚肽复合纳米药物分别在pH7.4和pH 6.8条件下的实验组,pH 7.4+NIR和pH 6.8+NIR是指电荷反转型聚肽复合纳米药物分别在pH 7.4和pH 6.8条件下跟癌细胞培养4 h后,再用近红外激光对其进行光照的实验组,DOX是指单使用阿霉素的实验组。
由图6和图7 的结果可知,在普通的癌细胞(MCF-7细胞)上,电荷反转型聚肽复合纳米药物表现出相比于阿霉素而言极高的细胞毒性,而且针对于耐阿霉素的乳腺癌细胞(MCF-7/ADR细胞),阿霉素基本没有效果,但电荷反转型聚肽复合纳米药物显示了很强的杀死癌细胞的能力,并且在pH 6.8的弱酸性肿瘤微环境中,表现出更强的抗癌能力。说明该电荷反转型聚肽复合纳米药物在逆转肿瘤对阿霉素耐药性方面具有明显的效果,并且在pH6.8的弱酸性环境中,对多药耐药肿瘤细胞表现出更好的抗肿瘤效果。
实施例3
电荷反转型聚肽复合纳米药物对MCF-7/ADR肿瘤生长的影响实验
将接种了MCF-7/ADR荷瘤的小鼠分别分为七组:生理盐水、生理盐水+NIR、阿霉素(5mg/kg)、电荷反转型聚肽复合纳米药物 (2 mg/mL)、电荷反转型聚肽复合纳米药物+NIR (2mg/mL)。第0天注射一次,且注射12 h后对生理盐水+NIR和电荷反转型聚肽复合纳米药物+NIR进行光照5 min (808 nm, 1.6 W/cm2),同时每隔1天对小鼠进行称重并对肿瘤体积进行测量,结果如图8所示。
图8中,横坐标表示小鼠接受实验的天数,A图中纵坐标表示小鼠肿瘤体积,B图中纵坐标表示小鼠的体重。图中,PBS是指注射生理盐水对照组,PBS+NIR是指注射生理盐水12h后,再用近红外激光对其进行光照的实验组,DOX是指注射阿霉素实验组,PDA-PLC/DOX是指注射电荷反转型聚肽复合纳米药物的实验组,PDA-PLC/DOX+NIR是指注射电荷反转型聚肽复合纳米药物12 h后,再用近红外激光对其进行光照的实验组。
对于MCF-7/ADR肿瘤,游离的阿霉素对于该耐药肿瘤没有抑制的作用,而对于PDA-PLC/DOX+NIR组,第6天所有老鼠肿瘤完全消融并且没有结疤,而且在治疗的30天过程中并没有出现肿瘤的复发现象,且对小鼠体重几乎没有影响(图8A,B)。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (4)
2.根据权利要求1所述的纳米药物,其特征在于:所述活性药物为阿霉素。
3.权利要求1所述的电荷反转型聚肽复合纳米药物的制备方法,其特征在于:包括以下步骤:
步骤1,制备电荷反转型聚肽共聚物聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸);
步骤2,制备聚多巴胺纳米粒子;
步骤3,将聚乙二醇-b-聚(L-赖氨酸)-b-聚(L-半胱氨酸)加至溶剂中,溶解后加至聚多巴胺纳米粒子的水溶液中,搅拌反应,得到电荷反转型聚肽复合纳米粒子;
步骤4,向步骤3得到的电荷反转型聚肽复合纳米粒子中加入活性药物,搅拌反应,得到电荷反转型聚肽复合纳米药物。
4.权利要求1所述的电荷反转型聚肽复合纳米药物在制备逆转肿瘤多药耐药性的抗肿瘤药物中的应用。
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CN114712499A (zh) * | 2022-03-18 | 2022-07-08 | 南通大学 | 一种负载no的超分子聚肽纳米药物及其制备方法和应用 |
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