CN112402620A - 肿瘤微环境还原响应性的纳米药物及其制备方法 - Google Patents
肿瘤微环境还原响应性的纳米药物及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种肿瘤微环境还原响应的纳米药物及其制备方法,所述药物为纳米尺度的单甲氧基聚乙二醇和雷公藤红素化合物(MPEG2k‑SS‑Cel)药物以安全无毒的分子量约为2000的单甲氧基聚乙二醇(MPEG2k)为亲水性材料,通过二硫键化学键连疏水的天然抗肿瘤药物雷公藤红素,MPEG2k‑SS‑Cel可自组装为140nm左右的纳米胶束,单甲氧基聚乙二醇作为亲水段在胶束外将雷公藤红素包埋在内。药物通过亲水的单甲氧基聚乙二醇键连雷公藤红素以克服其疏水性使其难以在体内有效利用的缺点,并且通过中间的二硫键使纳米胶束具备在肿瘤微环境中在高浓度谷胱甘肽(GSH)情况下断裂响应使胶束崩解释放药物的特点。通过细胞实验检测该纳米药物具有高效的治疗效果。
Description
技术领域
本发明涉及一种肿瘤微环境还原响应性的纳米药物及其制备方法,它是还原响应型抗癌纳米药物的制备方法。
背景技术
根据统计,每年有接近430万人被诊断为癌症,也就是说,在中国每分钟就有超过8人被确诊为癌症。另外,癌症也是死亡率非常高的一个病种,每年有超过280万,平均每分钟有5人死于癌症。现在癌症治疗的主要手段是手术切除,化疗以及放射性治疗。虽然这些治疗手段在临床上发挥了重要的治疗效果,但也不能彻底治疗癌症。比如,手术虽然能切除大部分的肿瘤组织,但是没有切除的少部分的肿瘤组织依然可能复发。化疗药物在治疗癌症的同时,也对人体的正常细胞产生毒副作用,比如肝肾损伤,以及心脏毒性,并且在长期应用化疗药物后,肿瘤也会对化疗药物产生耐药性,从而降低化疗药物的治疗效果。
雷公藤红素(Celastrol,Cel),分子式 C29H38O4,是雷公藤的重要活性成分,又名南蛇藤素,为三萜类化合物,红色针状结晶,难溶于水,可溶于甲醇,乙醇,二氯甲烷等有机溶剂。它主要来源于中药雷公藤的根皮,具有多种生物活性,在一些炎症和肿瘤治疗中具有重要的研究价值。Cel 的抗癌机制为芳香酮基团上的 C2 和 C6 具有很强的亲核活性,可与蛋白酶体 5 亚基上苏氨酸-N 端的氢反应形成共价键,抑制癌细胞的蛋白酶体糜蛋白酶样活性,从而诱导癌细胞凋亡,被称为有效的天然蛋白酶体抑制剂。研究发现 Cel 可通过下调 microRNA-21,阻滞 PI3K/Akt-NF-κB 信号通路。尽管 Cel 具有较好的抗癌作用,但Cel为难溶性抗癌药物,口服生物利用度较低,且自身毒性较大,容易对机体产生全身性的毒副作用,其物理化学性质限制了它在临床上的应用。
抗癌纳米药物利用生物相容性好的材料负载药物,得到纳米尺度的药物可通过实体瘤的高通透性和滞留效应被肿瘤摄取,从而降低了药物在正常细胞内释放的概率,减弱了对正常组织的损伤。且肿瘤细胞生命活动旺盛,增殖频繁,快速的新陈代谢导致肿瘤细胞附近的微环境和正常细胞不一样。如肿瘤细胞内的还原物质谷胱甘肽(GSH)浓度2-10 mM,约为正常细胞和血液中GSH 浓度(2-20μM)的数千倍。利用肿瘤细胞内外巨大的还原环境的差异可以设计出还原响应型纳米药物。还原响应型纳米药物结构中常见的还原敏感化学键主要是二硫键(-SS-)和二硒键(-SeSe-)。还原响应型聚合物胶束一般都是通过-SS-或-SeSe-两端分别连接亲水性和疏水性链端,双亲性聚合物在水中自组装成胶束,然后包载疏水性抗肿瘤药物,载药胶束结构中的-SS-或-SeSe-可在肿瘤细胞内还原环境刺激下断裂,实现药物的快速释放。
中国专利CN202010047522.2公开了一种塞来昔布胶束和和厚朴酚胶束药物联用控释***及其制备方法。该药物使用的载体包括单甲氧基聚乙二醇-外消旋聚乳酸嵌段共聚物中,聚乙二醇嵌段的分子量为1000~2000。其中单甲氧基聚乙二醇-外消旋聚乳酸嵌段共聚物为两性分子,即具有双亲性结构,可以在水溶液中自组装成纳米颗粒,提高了抗癌药物本身的溶解性。尽管单甲氧基聚乙二醇-外消旋聚乳酸嵌段共聚物药用高分子辅料属于低毒物质,但一般认为大量使用时具有一定的毒性作用。因此作药用高分子辅料时,需特别考虑其用量及其毒性大小,以确保新剂型的安全性。
发明内容
本发明的目的是提供一种肿瘤微环境还原响应性的纳米药物及其制备方法,具体为一种单甲氧基聚乙二醇-药物自组装构筑的还原响应型抗癌纳米药物的方法。本发明所提供的还原响应型抗癌纳米粒子对癌细胞微环境具有较强的响应性,能够特异性杀死癌细胞,且对癌细胞具有广泛的适用性。
本发明提供一种肿瘤微环境还原响应性的纳米药物(单甲氧基聚乙二醇-药物自组装构筑的还原响应型纳米抗癌药物)是以单甲氧基聚乙二醇(分子量约为2000)为载体,用具有还原响应性的二硫键键连抗癌药物雷公藤红素(Celastrol),通过溶剂蒸发法(或薄膜水化法)制得平均粒径为130-150nm的纳米药物。所述的还原响应型纳米抗癌药物MPEG2K-SS-CEL的结构表示为:
本发明提供的肿瘤微环境还原响应性的纳米药物的其制备方法包括的步骤:
1)将单甲氧基聚乙二醇-琥珀酰亚胺碳酸酯(MPEG2K-SC)、胱胺二盐酸盐、三乙胺按摩尔比1:3:7溶解于二氯甲烷/甲醇(v/v=1:1)混合溶剂中,室温反应12小时。反应完毕后用饱和NH4Cl溶液洗涤两次,有机相用无水硫酸钠干燥后减压浓缩,残液用甲基叔丁醚打浆。真空干燥后即得甲单甲氧基聚乙二醇-胱胺(MPEG2k-SS-NH2)。
2)将雷公藤红素(Cel)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、1-羟基苯并***(HOBT)按摩尔比1:3:3溶解于N,N-二甲基甲酰胺(DMF)中,零摄氏度活化2小时后,加入雷公藤红素三分之一当量的单甲氧基聚乙二醇-胱胺,室温避光反应24小时。反应结束后将上述有机溶液转移至截留分子量为2000的纤维素透析膜中,DMF中透析24小时后转移至蒸馏水中透析24小时;透析结束后将透析袋中水溶液置于-80℃冷冻4小时后用冷冻干燥机干燥24小时,即得橙红色絮状单甲氧基聚乙二醇-SS-雷公藤红素前药产品。
3)将单甲氧基聚乙二醇-SS-雷公藤红素前药10mg溶于1.5ml四氢呋喃中,超声振荡2min使其充分溶解;随后剧烈搅拌条件下,使用1 mL注射器将该溶液逐滴滴加至10ml蒸馏水中,室温搅拌30 min后,减压旋蒸除去体系中的四氢呋喃;将旋蒸处理过的溶液过0.22 μm滤膜即可得粒径在130-150nm的MPEG2K-SS-Cel胶束水溶液。
本发明是利用单甲氧基聚乙二醇与抗癌药物分子之间的共价结合,再通过自组装形成粒径在130-150nm的纳米胶束。在还原性环境中构成该纳米药物中间的二硫键断裂,纳米胶束分解,释放出抗癌药物。在体内,由于EPR效应,纳米药物易于富集在肿瘤组织,同时在肿瘤细胞过表达GSH的作用下,二硫键断裂,纳米胶束分解,快速释放药物并且大量积累在肿瘤细胞内,从而杀死癌细胞,达到治疗的目的。本发明中所用的抗癌药为抗炎类广谱抗癌药物,所适用的癌症包括乳腺癌、***、肺癌等。
本发明的特别突出的实质性特点如下:
1)本发明使用的单甲氧基聚乙二醇生物相容性好,生物毒性低,容易在体内降解。
2)本发明所述药物中的二硫键对GSH响应灵敏,能够使药物在肿瘤部位快速释放,提高药物利用效率。
3)本发明所述药物与传统化疗药物相比具有更强的抗癌功效,能更有效杀灭和抑制癌细胞,起到很好的化疗效果。
4)本发明所述药物载体仅有单甲氧基聚乙二醇,无需引入疏水基团,合成简单,操作方便,产量较高,质量可控,易于放大制备。
附图说明
图1为所述药物前药的核磁共振氢谱(1HNMR)。
图2为纳米胶束在透射电子显微镜(TEM)下的形貌图。
图3为纳米胶束在马尔文纳米粒度电位仪测得的粒径和电位。
图4为所述前药和纳米胶束的对人乳腺癌(MCF-7)细胞毒性(MTT)实验结果。
具体实施方式
为了清楚阐述本发明的技术方案,下面结合具体实施例对本发明做进一步的详细描述。实施例中所使用的实验方法如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径获得。
实施例1(本部分操作全程避光)
1)准确称取单甲氧基聚乙二醇-琥珀酰亚胺碳酸酯(MPEG2K-SC)10.00g、胱胺二盐酸盐3.36g溶解于200ml二氯甲烷/甲醇(100ml/100ml)混合溶剂中,完全溶解后加入三乙胺3.54g,室温反应12小时。
2)反应完毕后的溶液用100ml饱和NH4Cl溶液洗涤两次,有机相用无水硫酸钠干燥后减压浓缩,残液用200ml甲基叔丁醚打浆。50℃真空干燥后即得MPEG2k-SS-NH2。
实施例2(本部分操作全程避光)
1)准确称取雷公藤红素135mg,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)172.5mg、1-羟基苯并***(HOBT)121.5mg,溶于3ml无水DMF中,完全溶解后,避光,零摄氏度反应2小时。
2)准确称取MPEG2k-SS-NH2 210 mg,加入1)中反应体系,避光,室温下继续反应24小时。
3)反应结束后将上述有机溶液转移至截留分子量为2000的纤维素透析膜中,在2L DMF中透析24小时(每4小时换一次透析液)后转移至蒸馏水中透析24小时(每2小时换一次蒸馏水)。
4)透析结束后将透析袋中水溶液转移至玻璃培养皿中,用保鲜膜覆盖皿口,针尖戳出数个气孔后置于-80℃冷冻4小时。
5)将培养皿中的冷冻样用冷冻干燥机干燥24小时,即得橙红色絮状单甲氧基聚乙二醇-SS-雷公藤红素前药产品。
实施例3
1)准确称取单甲氧基聚乙二醇-SS-雷公藤红素前药10mg溶于1.5ml的四氢呋喃中,超声振荡2 min使其充分溶解。
2)随后在剧烈搅拌条件下,将该溶液加至10 ml蒸馏水中,室温搅拌30 min。
3)减压旋蒸除去体系中的四氢呋喃。
4)将旋蒸处理过的溶液过0.22 μm滤膜即可得粒径在130-150nm的MPEG2K-SS-Cel胶束水溶液
应用效果测试结果:
以实施例1-3中所获得的纳米药物进行应用效果测试和评价:
图1为采用400MHz液体核磁共振谱仪对药物进行检测,以氘代氯仿为溶液,可在图谱中对应找到单甲氧基聚乙二醇、雷公藤红素和胱胺相关结构的特征峰,说明药物化合物成功合成。
图2为采用透射电子显微镜对制备的纳米药物进行检测,可见单甲氧基聚乙二醇与雷公藤红素自组装后形成平均直径约为130-150nm的纳米胶束,表明该纳米药物满足实体瘤EPR效应对纳米药物的粒径要求。
图3为纳米胶束在马尔文纳米粒度电位仪测得的粒径和电位,测得其平均粒径为142nm,其结果与透射电子显微镜测得的粒径结果相符,其zeta电位在水溶液中测得为-9.47mV。
图4为用MCF-7细胞(人乳腺癌细胞)检测实施例1-3中的纳米药物的抗癌活性。取对数生长期的细胞接种在无菌96孔板中,约10000细胞/孔,在含10%FBS的1640培养基中培养24小时,在细胞达到一个良好的贴壁状态后,将培养介质换成含不同浓度前药和胶束药物的培养液(前药和胶束浓度以Cel含量浓度计,分别为0、1、2、4、8、16、20、24、32、40、50μg/mL),每组分别设置5个孔。培养24小时后,每孔加入10μL 5μg/mL的MTT,继续培养4小时,除去培养液,加入150μL DMSO溶解形成的晶体,震荡10分钟保证晶体充分溶解形成均一的溶液。用多功能酶标仪在490 nm处检测样品的吸光度。可以看出,药物对MCF-7细胞具有明显的毒性,使用前药处理细胞时,当抗癌药物雷公藤红素浓度达到50μg/mL后,肿瘤细胞的存活率仅为9%,而使用纳米胶束处理细胞时,当抗癌药物雷公藤红素浓度仅为8μg/mL时,肿瘤细胞的存活率就已降至2%,说明纳米胶束更易于被细胞内吞,以达到更好的抗癌效果。
最后应说明的是:以上实施例仅用于本发明的技术方案而非对其限制,尽管参照上述实施例对本发明进行了详细的说明,本领域的技术人员依然可以对本发明的具体实施方式进行修改或等同替换,这些并未脱离本发明的精神和范围的任何修改或等同替换,均在申请的保护范围之内。
Claims (6)
2.权利要求1所述纳米药物的制备方法,其特征在于包括以下步骤:
1)将单甲氧基聚乙二醇-琥珀酰亚胺碳酸酯(MPEG2K-SC)、胱胺二盐酸盐、三乙胺按溶解于体积=1:1的二氯甲烷/甲醇混合溶剂中,室温反应12小时;反应完毕后用饱和NH4Cl溶液洗涤两次,有机相用无水硫酸钠干燥后减压浓缩,残液用甲基叔丁醚打浆;真空干燥后即得甲单甲氧基聚乙二醇-胱胺(MPEG2k-SS-NH2);
2)将雷公藤红素(Cel)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、1-羟基苯并***(HOBT)溶解于N,N-二甲基甲酰胺(DMF)中,零摄氏度活化2小时后,加入雷公藤红素三分之一当量的单甲氧基聚乙二醇-胱胺,室温避光反应24小时;反应结束后将上述有机溶液转移至截留分子量为2000的纤维素透析膜中,DMF中透析24小时后转移至蒸馏水中透析24小时;透析结束后将透析袋中水溶液置于-80℃冷冻4小时后用冷冻干燥机干燥24小时,即得橙红色絮状单甲氧基聚乙二醇-SS-雷公藤红素前药产品;
3)将单甲氧基聚乙二醇-SS-雷公藤红素前药10mg溶于1.5ml四氢呋喃中,超声振荡2min使其充分溶解;随后剧烈搅拌条件下,使用1 mL注射器将该溶液逐滴滴加至10ml蒸馏水中,室温搅拌30 min后,减压旋蒸除去体系中的四氢呋喃;将旋蒸处理过的溶液过0.22 μm滤膜即可得粒径在130-150nm的MPEG2K-SS-Cel胶束水溶液。
3.如权利要求1所述的制备方法,其特征在于所述的单甲氧基聚乙二醇-琥珀酰亚胺碳酸酯(MPEG2K-SC)、胱胺二盐酸盐、三乙胺按摩尔比1:3:7。
4.如权利要求1所述的制备方法,其特征在于所述的雷公藤红素(Cel)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、1-羟基苯并***(HOBT)的摩尔比1:3:3。
5.如权利要求1所述的制备方法,其特征在于所述的真空干燥温度为 50℃。
6.权利要求1所述的肿瘤微环境还原响应性的纳米药物在治疗乳腺癌、***、肺癌中的应用。
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