CN105412936A - 一种刺激响应型聚吡咯纳米管靶向药物载体及制备方法 - Google Patents
一种刺激响应型聚吡咯纳米管靶向药物载体及制备方法 Download PDFInfo
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- CN105412936A CN105412936A CN201510974522.6A CN201510974522A CN105412936A CN 105412936 A CN105412936 A CN 105412936A CN 201510974522 A CN201510974522 A CN 201510974522A CN 105412936 A CN105412936 A CN 105412936A
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- polypyrrole nanotube
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Abstract
一种刺激响应型聚吡咯纳米管靶向药物载体及制备方法,以二氧化钛纳米管阵列或多孔阳极氧化铝阵列为模板通过化学气相沉积制备聚吡咯纳米管;通过β-环糊精和聚吡咯纳米管管口之间用酰腙键、二硫键等刺激响应型敏感键连接,可以将药物阻挡在纳米管内并且在弱酸性及还原性环境将药物释放出来;将聚乙二醇链一端连接叶酸靶向分子另一端连接金刚烷头基,金刚烷头基通过主客包络与β-环糊精疏水空腔衔接,叶酸分子通过受体-配体介导识别肿瘤细胞。该方法制备的刺激响应型聚吡咯纳米管肿瘤靶向药物载体,粒径大小分布均匀,形貌可控,产品稳定,合成工艺简单,成本较低,适于大量生产。
Description
技术领域
本发明涉及靶向药物载体纳米材料领域,具体涉及一种刺激响应型靶向药物载体,及制备方法。
背景技术
近年来癌症是严重影响人类健康的疾病,传统抗癌药物在杀死肿瘤细胞同时也攻击正常细胞。如何使抗癌药物只在肿瘤组织部位释放,而不影响正常的细胞是一个亟需解决的热点问题。聚吡咯是一种C,N五元杂化共轭型导电高分子,通常为无定型黑色固体。聚吡咯无毒,生物相容性好,在刺激神经细胞生长、骨细胞再生、细胞行为控制、血管移植、生物支架、蛋白质分离和DNA吸附、生物传感等生物组织工程领域有重要应用(GeorgePM,LyckmanAW,LaVanDA,etal.Fabricationandbiocompatibilityofpolypyrroleimplantssuitableforneuralprosthetics[J].Biomaterials,2005,26(17):3511-3519.)。通常以化学或电化学氧化聚合制备,得到的一般为纳米颗粒,很难形成独立的纳米管状结构。空心管状的纳米结构其比表面积大,对药物具有较大的吸附容量,可以实现很好的载药量,可以保持药物稳定性,由于其无毒,生物相容性好,可以作为纳米药物载体,其具有导电性能可以通过微弱的的电场脉冲维持药物持续释放,达到缓控释效果,并且具有包封性好、药物不易泄露(GeJ,NeofytouE,CahillIIITJ,etal.Drugreleasefromelectric-field-responsivenanoparticles[J].ACSnano,2011,6(1):227-233.)。大量研究的嵌段共聚物形成的胶束、泡囊、纳米凝胶容易产生漏药、泄药,并且粒径大小不均一等问题。
发明内容
本发明的目的在于提供一种载药量大,无毒,生物相容性好,纳米粒子大小均一,结构大小可控,能够很好的控制药物的释放,成本低廉、适合工业化生产的刺激响应型聚吡咯纳米管靶向药物载体。
本发明的另一目的在于提供一种的方法可行、步骤简单、成本低廉、适合工业化生产的刺激响应型聚吡咯纳米管载体药物的合成方法。
本发明的技术方案如下:
一种刺激响应型聚吡咯纳米管药物载体,该载体的聚乙二醇链一端连接叶酸靶向分子,另一端连接金刚烷基,金刚烷基通过主客包络与巯基化β-环糊精的疏水空腔衔接,并由β-环糊精上巯基与载药的聚吡咯纳米管上的巯基氧化形成二硫键组装而成;所述的聚吡咯纳米管是由吡咯单体与端基二卤素取代直链烷烃发生氮取代反应得到1-(ω-卤代烷基)吡咯,以二氧化钛纳米管阵列或多孔阳极氧化铝阵列为模板,在所述的阵列内表面经化学气相沉积聚合后,再进行聚吡咯纳米管酰腙化、硫醇化得到含酰腙基和巯基的聚吡咯纳米管。
所述的端基二卤素取代直链烷烃的优选的碳原子数为2~10。
所述的金刚烷基来源于1-金刚烷甲酸或1-金刚烷乙酸。聚乙二醇分子量为200~10000。
本发明的1-(ω-卤代烷基)吡咯中ω为不定数,优选为2~10。
本发明的一种刺激响应型聚吡咯纳米管载体药物的制备方法,包括以下步骤:
(a)吡咯单体的修饰
将吡咯单体与氢化钠在–10~+10℃的低温条件下,N2或Ar保护下反应完全后加入端基二卤素取代直链烷烃,反应完后抽滤,经萃取,洗涤,旋干溶剂,分离纯化得1-(ω-卤代烷基)吡咯;
或是将吡咯单体于氢氧化钠水溶液中,加入相转移催化剂,直接在端基二卤素取代直链烷烃溶液中回流,反应完后用水稀释,二氯甲烷萃取,水洗有机相,除水,旋干溶剂即得1-(ω-卤代烷基)吡咯。
(b)聚吡咯纳米管的制备
在沉积了Fe3+的纳米管阵列模板上,将(a)制得的1-(ω-卤代烷基)吡咯于真空,温度150~280℃下化学气相沉积反应聚合得到经修饰的聚吡咯纳米管;用酸或碱溶液溶解分散后,离心将所述的经修饰的聚吡咯纳米管分离,清洗数次,干燥;所述的纳米管阵列模板二氧化钛纳米管阵列模板或多孔阳极氧化铝模板;
(c)将(b)步得到的聚吡咯纳米管进行酰腙化、硫醇化处理得到含酰腙基和巯基;
(d)聚吡咯纳米管载药
将经(c)步得到含酰腙基和巯基的聚吡咯纳米管分散在药物溶液中进行药物负载,得到的负载药物的聚吡咯纳米管再离心分离;
(e)叶酸-聚乙二醇-金刚烷-β-环糊精的制备
双端氨基聚乙二醇和叶酸分子、金刚烷基化合物分别通过缩合反应,得一端修饰叶酸分子,另一端连接修饰有金刚烷基的聚乙二醇链;巯基化β-环糊精与所述的聚乙二醇链的金刚烷基端通过主客包络结合得到叶酸-聚乙二醇-金刚烷-β-环糊精;
(f)刺激响应型聚吡咯纳米管药物载体的组装
负载药物的聚吡咯纳米管上巯基与叶酸-聚乙二醇-金刚烷-β-环糊精上巯基氧化形成二硫键,组装成刺激响应型聚吡咯纳米管载体药物。
所述的(a)步的相转移催化剂为四丁基溴化铵或四丁基硫酸氢铵,吡咯与相转移催化剂比例为1:0.003~0.1。
所述的(b)步的化学气相沉积真空度为5~50Pa,化学气相沉积时间为1~5h。
所述的(b)步的制备是将二氧化钛纳米管阵列模板于Fe3+溶液中,在20~60℃下浸泡24~72h,得到表面沉积一层Fe3+的二氧化钛纳米管阵列模板,将模板45~80℃真空干燥6~10h,将沉积了Fe3+的二氧化钛纳米管阵列模板和1-(ω-卤代烷基)吡咯单体置于真空装置,真空度10~50Pa,加热温度150~250℃,反应时间1~5h,1-(ω-卤代烷基)吡咯单体在Fe3+氧化作用下形成阳离子自由基,在二氧化钛纳米管内表面引发聚合;用酸或碱溶液溶解二氧化钛模板24~48h,得到分散的聚吡咯纳米管,通过离心将聚吡咯纳米管从酸或碱溶液分离,然后用乙醇清洗数次,真空干燥备用。
步骤(b)中,所述的酸为硫酸、盐酸、硝酸、磷酸或氢氟酸,所述的碱为氢氧化钠、氢氧化钾中的一种或几种。所述的酸或碱溶液的质量百分数为1~10wt%。所述的Fe3+为氯化铁、硫酸铁、硝酸铁、溴化铁、高氯酸铁的一种或几种。Fe3+溶液浓度为0.05~0.5mol/L。
所述的步骤(c)中,聚吡咯纳米管酰腙化、硫醇化是将对羟基苯甲醛与无水碳酸钾于干燥的N,N-二甲基甲酰胺溶剂中N2保护下反应,然后加入(b)制备得到的经修饰的聚吡咯纳米管,搅拌反应完全后洗涤离心,得黑色固体;3-巯基丙酸甲酯与水合肼加热回流反应得3-巯基丙酸酰肼,再与所述的黑色固体常温下反应,反应完全后用洗涤离心得经硫醇化、酰脘化的聚吡咯纳米管黑色固体;
所述(c)步还可以于干燥的N,N-二甲基甲酰胺溶剂中加入相转移催化剂如碘化钾或碘化亚铜等。
所述的(e)步的制备是双端氨基聚乙二醇和叶酸分子通过1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺盐酸盐(EDCI)和N-羟基琥珀酰亚胺(NHS)缩合,得一端修饰叶酸分子的聚乙二醇链,即叶酸-聚乙二醇,采用葡聚糖凝胶LH-60分离纯化;将叶酸-聚乙二醇链与1-金刚烷甲酸或1-金刚烷乙酸通过1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺盐酸盐(EDCI)和N-羟基琥珀酰亚胺(NHS)缩合,得到叶酸-聚乙二醇-金刚烷链,采用葡聚糖凝胶G-25或LH-60纯化。β-环糊精与三苯基膦、单质碘反应,得6位伯醇被碘取代的β-环糊精(6-碘-β-环糊精),然后与硫脲反应,碱水解,酸化得巯基化β-环糊精(6-巯基-β-环糊精),巯基化β-环糊精与叶酸-聚乙二醇-金刚烷链通过主客包络结合。
步骤(e)中,叶酸-聚乙二醇中的聚乙二醇分子量为200~10000,叶酸与聚乙二醇的摩尔比为1:1~1.5,溶剂为干燥的二甲亚砜,反应温度为室温;
步骤(e)中,金刚烷基可为1-金刚烷甲酸或1-金刚烷乙酸其中的一种,叶酸-聚乙二醇与金刚烷基的摩尔比为1:1~1.5,溶剂为干燥的二甲亚砜,反应温度为室温。
步骤(c)中,对羟基苯甲醛与无水碳酸钾的摩尔比为1:1~1.05,相转移催化剂为四丁基溴化铵、四丁基硫酸氢铵的一种或几种,巯基丙酸甲酯与水合肼的摩尔比为1:2.3~3,加热回流反应所用的溶剂为甲醇、乙醇中的一种,反应时间为10-24h。
步骤(d)中所述的药物为5-氟尿嘧啶、盐酸阿霉素、羟基喜树碱、长春新碱、紫杉醇抗癌药物中的一种或几种。
本发明的载体药物优选的制备步骤为:
(a)将吡咯单体于50%氢氧化钠水溶液中,加入相转移催化剂,然后加入过量的端基二卤素取代直链烷烃X(CH2)nX,反应完后加入水,用二氯甲烷萃取,合并有机相,用水洗涤,无水硫酸钠干燥,旋干溶剂,得氮取代的直链卤代烃吡咯单体1-(ω-卤代烷基)吡咯。
(b)采用阳极氧化法制备二氧化钛纳米管阵列模板;将二氧化钛纳米管阵列模板用浓度为0.05~0.5mol/L的FeCl3溶液,在20~60℃下浸泡24~48h,得到表面沉积一层Fe3+的二氧化钛纳米管阵列模板,将模板45~80℃真空干燥6~10h,将沉积了Fe3+的二氧化钛纳米管阵列模板和1-(ω-卤代烷基)吡咯100~1000μl置于真空装置,真空度10~50Pa,加热温度150~250℃,反应时间1~5h,所述的吡咯单体在Fe3+氧化作用下形成阳离子自由基,在二氧化钛纳米管内表面引发聚合。用质量分数1~10%的稀HF溶液溶解二氧化钛模板24~48h,得到分散的聚吡咯纳米管,通过离心将聚吡咯纳米管从HF溶液分离,然后用乙醇清洗数次,真空干燥备用。
(c)将对羟基苯甲醛与无水碳酸钾于干燥的N,N-二甲基甲酰胺溶剂中N2保护下常温反应,然后将(b)步制备得到的经修饰的聚吡咯用干燥的的N,N-二甲基甲酰胺溶液分散加入其中(还可加入少量相转移催化剂)搅拌,反应完全后用水和乙醇交替洗涤离心,得黑色固体;3-巯基丙酸甲酯与水合肼以甲醇为溶剂,加热回流反应,反应完全后产物经硅胶柱纯化(乙醚:甲醇=19:1)得3-巯基丙酸酰肼,与经上述修饰的聚吡咯常温下经醋酸催化反应,反应完全后用乙醇洗涤离心得黑色固体。
(d)将修饰后的聚吡咯纳米管分散在含一定浓度5-氟尿嘧啶的PBS溶液中恒温振荡进行药物负载,负载药物的聚吡咯纳米管经离心分离。
(e)双端氨基聚乙二醇和叶酸分子通过1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺盐酸盐(EDCI)和N-羟基琥珀酰亚胺(NHS)缩合,得一端修饰叶酸分子的聚乙二醇链,采用葡聚糖凝胶LH-60分离纯化;将一端修饰叶酸分子的聚乙二醇链与金刚烷甲酸通过1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺盐酸盐(EDCI)和N-羟基琥珀酰亚胺(NHS)缩合,得到叶酸-聚乙二醇-金刚烷链,采用葡聚糖凝胶G-25或葡聚糖LH-60纯化。β-环糊精与三苯基膦、单质碘反应,得6位伯醇被碘取代的β-环糊精(6-碘-β-环糊精),然后与硫脲反应,碱水解,酸化得巯基化β-环糊精(6-巯基-β-环糊精),巯基化β-环糊精与叶酸-聚乙二醇-金刚烷链通过主客包络结合。
(f)将载药聚吡咯纳米管上巯基与叶酸-聚乙二醇-金刚烷-β-环糊精上巯基氧化形成二硫键,组装成刺激响应型聚吡咯纳米管药物载体。
本发明方法中所述步骤(a)中端基二卤素取代直链烷烃优选是二氯代烷烃、二溴代烷烃或二碘代烷烃,最优选为二氯代烷烃。
本发明方法中所述步骤(a)中,吡咯单体与相转移催化剂的摩尔比为1:0.003~0.1,所用溶剂为端基二卤素取代直链烷烃。
本发明方法中所述步骤(b)中阳极氧化为以钛片为阳极,其他惰性电极为阴极,电解液为质量分数0.3~0.7wt%的氟化铵,体积分数0~10vol%的水,体积分数0~0.9volH2SO4,阳极氧化电压40~150V,阳极氧化时间5min~2h。
本发明方法中所述步骤(b)模板真空干燥温度为45~80℃,真空干燥时间为24~72h,真空度为5~50Pa,优选为20Pa,真空装置加热温度为150~280℃,优选为220℃,真空加热反应时间为0.5~5h,优选为2h。
本发明方法中所述步骤(b)中吡咯单体用量为100μl~10ml。
本发明方法中所述步骤(b)溶解模板的溶液为硫酸、盐酸、硝酸、磷酸、氢氟酸、氢氧化钠、氢氧化钾,优选为氢氟酸,溶解模板溶液浓度为1~10wt%。
所述步骤(e)中β-环糊精与三苯基膦、单质碘摩尔比为1:10~20:10~20,溶剂为干燥的N,N-二甲基甲酰胺,反应温度50~90℃;碘代β-环糊精与硫脲摩尔比为1:7~12,溶剂为干燥的N,N-二甲基甲酰胺,反应温度50~90℃。
所述步骤(e)中硫醇化β-环糊精与叶酸-聚乙二醇-金刚烷结合时间为12~36h,介质为水或乙醇。
本发明的有益效果
本发明先通过对吡咯单体的有效修饰及改性,经化学气相沉积制备得到经修饰的聚吡咯纳米管,合成的聚吡咯纳米管管长管径以模板大小为准,因此可以通过控制模板大小来制备不同管长管径的聚吡咯纳米管,并使得聚吡咯自动形成完整的纳米管形貌。通过本发明特殊的结构控制,在聚吡咯纳米管管口修饰酰腙键和二硫键作为pH和氧化还原响应型敏感键如同一个分子开关,可以将药物阻挡在纳米管内,并在弱酸性及还原性环境下能够很好的控制药物在肿瘤细胞内释放,聚吡咯纳米管外表面修饰一层亲水型聚乙二醇链能够增加纳米管药物载体的稳定性和水溶性,提高其在血液中循环时间,聚乙二醇链上修饰叶酸靶向分子,通过叶酸受体-配给介导的靶向识别作用,达到靶向给药效果。本发明的药物载体,为均一粒径大小的纳米粒子,通过控制模板的大小来控制聚吡咯纳米管的大小,且制备方法具有可控性。制备的聚吡咯在其N原子上进行取代,对其改性增加其水溶性和对人体生理环境的适应性。本发明刺激响应型聚吡咯纳米管肿瘤靶向药物载体,粒径大小分布均匀,形貌可控,产品稳定,合成工艺简单,成本较低,适于大量生产。本发明可控的模板制备方法及吡咯聚合条件温和,通过负载于模板纳米孔内表面的Fe3+引发吡咯单体聚合,形成一套制备聚吡咯纳米管的有效手段。
附图说明
图1聚吡咯制备及刺激响应型聚吡咯纳米管靶向药物载体的制备示意图。
图2阳极氧化二氧化钛纳米管阵列模板正面图。
图3阳极氧化二氧化钛纳米管阵列模板侧面图。
图4多根聚吡咯纳米管透射电镜图。
图5单根聚吡咯纳米管透射电镜图(管径200nm左右,管长500nm左右,与二氧化钛纳米管的模板吻合。)。
图6聚吡咯纳米管红外光谱图(吡咯单体聚合后,3436cm-1为N-H伸缩振动;1643,1454cm-1C=C伸缩振动;1380cm-1C-N伸缩振动;620cm-1为C-Cl伸缩振动。而进过修饰后的吡咯单体聚合,在2925,2853cm-1为烷烃C-H的伸缩振动;572,692cm-1为C-Cl伸缩振动,证明了聚吡咯接枝上氯代烷烃,有利于聚吡咯下一步修饰。)。
图7刺激响应型聚吡咯纳米管靶向药物载体不同环境下药物控制释放的累积释放度图,从图可知,在pH4.5PBS+10mM二硫苏糖醇(DTT)溶液中,药物载体在酸性及还原性环境中,药物快速释放,酸性环境下,酰腙键断裂,还原性环境下,二硫键断裂;在10mMDTTpH7.4PBS溶液中,药物释放速度没有10mMDTT+pH4.5溶液中释放速度快;在pH4.5PBS溶液中,药物释放速度比上述两种环境下更慢,可能原因是酰腙键被环糊精包覆,阻碍与酸性介质接触,酰腙键不易断裂导致药物释放缓慢;在中性(pH7.4)及碱性(pH8)条件下,药物基本不释放,证明了药物载体的刺激响应性。
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。
实施例1
(一)将10ml吡咯单体和17.29g氢氧化钠水溶液中,四丁基溴化铵0.48g,16ml1,3-二溴丙烷,反应12h,反应完全后抽滤,加入少量二氯甲烷溶解,饱和食盐水洗涤,旋干溶剂,减压蒸馏得1-(3-溴丙基)吡咯。
(二)模板的制备
将钛片机械抛光,脱油脱脂,钛片为阳极,铂片为阴极,0.18gNH4F、3ml水、0.3mlH2SO4的乙二醇电解液,温度0℃,180V恒压直流电源阳极氧化8min,制备的好的二氧化钛纳米管用蒸馏水将其表面电解液冲洗干净备用,图2和图3为其扫描电镜图。
将钛片机械抛光,脱油脱脂,钛片为阳极,铂片为阴极,0.14gNH4F、1.3ml水、乙二醇电解液,温度15℃,120V恒压直流电源阳极氧化30min,制备的好的二氧化钛纳米管用蒸馏水将其表面电解液冲洗干净备用。
(三)吡咯聚合
将制备好的二氧化钛纳米管阵列模板浸入0.2MFeCl3溶液中,时间24h,60℃真空干燥6h,将0.5ml1-(2-氯乙基)吡咯单体、二氧化钛纳米管模板置入真空装置,真空度60Pa,200℃加热2h,聚合后的模板用5wt%的HF溶液腐蚀溶解,得到分散的聚吡咯纳米管分散液,离心分离的黑色的聚吡咯纳米管沉淀,乙醇清洗。图4和图5为其透射电镜图,图6为其红外光谱图。
将制备好的二氧化钛纳米管阵列模板浸入0.5MFeCl3溶液中,时间24h,60℃真空干燥6h,将0.5ml1-(3-溴丙基)吡咯单体、二氧化钛纳米管模板置入真空装置,真空度60Pa,220℃加热2h,聚合后的模板用5%的HF溶液腐蚀溶解,得到分散的聚吡咯纳米管分散液,离心分离的黑色的聚吡咯纳米管沉淀,并用乙醇清洗。
(四)聚吡咯纳米管酰腙化、硫醇化
3-巯基丙酸酰肼的制备:2ml3-巯基丙酸甲酯缓慢滴加至2.64ml的水合肼乙醇溶液中,氮气保护下加热回流24h,旋干溶剂,硅胶柱层析分离纯化(乙醚:甲醇=19:1)。
将0.261g对羟基苯甲醛与0.443g碳酸钾及相转移催化剂碘化钾于干燥的N,N-二甲基甲酰胺(4ml)N2保护下反应2h,然后将10mg聚吡咯溶于干燥的N,N-二甲基甲酰胺,注射器注入,反应6h。反应完成后离心分离,乙醇、水交替洗涤,干燥备用。修饰后的聚吡咯纳米管与3-巯基丙酸酰肼于干燥的N,N-二甲基甲酰胺溶液中加入微量醋酸催化反应24h,乙醇洗涤,离心分离。
(五)聚吡咯纳米管载药
取10mg经酰腙化、硫醇化的聚吡咯纳米管分散于含5.6mg/ml5-氟尿嘧啶pH为7.4的PBS溶液中,室温振荡24h,离心分离,平均载药量为6.5%。在纳米管类型药物载体,聚吡咯纳米管体现了高载药量,与无机介孔材料载药量相当(Zhang,Quan,etal."MultifunctionalMesoporousSilicaNanoparticlesforCancer‐TargetedandControlledDrugDelivery."AdvancedFunctionalMaterials22.24(2012):5144-5156.),与有机聚合物相比载药量略少(Han,Shi‐Song,etal."Dual‐pHSensitiveCharge‐ReversalPolypeptideMicellesforTumor‐TriggeredTargetingUptakeandNuclearDrugDelivery."Small(2015)).
(六)β-环糊精硫醇化
三苯基膦3.2354g、单质碘3.3543g、β-环糊精1g于单口圆底烧瓶中,加入50ml干燥的N,N-二甲基甲酰胺,N2保护80℃反应24h,反应完后减压蒸馏将溶剂除去,低温条件下加入甲醇钠调至pH为8-9除酯,然后于80ml甲醇溶液中分散沉淀,离心分离,采用甲醇索式提取回流24h洗掉杂质,真空干燥。取0.6104g碘代的β-环糊精和0.2799g硫脲于10mlN,N-二甲基甲酰胺溶液中70℃、N2氛围反应24h,反应完后溶剂减压蒸馏,然后加0.22g氢氧化钠水溶液加热回流碱水解90min,然后用硫酸氢钾酸化得白色固体沉淀,用大量水冲洗,干燥。
(七)叶酸-聚乙二醇-金刚烷制备
叶酸0.4g、EDCI0.208g和NHS0.1251g于5ml干燥的二甲亚砜中,N2保护常温活化1h,然后滴加3.62g氨基端聚乙二醇,常温反应24h,反应完后加入少量二氯甲烷溶解,用饱和NaCl洗涤,旋干溶剂,溶于少量水,用葡聚糖凝胶LH-60分离纯化。将1-金刚烷甲酸0.2g、EDCI0.255g和NHS0.154g于5ml干燥的二甲亚砜N2保护活化1h,然后滴加0.4g叶酸-聚乙二醇,反应24h,反应完后加入少量二氯甲烷,用饱和NaCl洗涤,旋干溶剂,溶于少量水,用葡聚糖凝胶LH-60分离纯化。
(八)叶酸-聚乙二醇-金刚烷-β-环糊精制备
0.4g叶酸-聚乙二醇-金刚烷与0.149g6-巯基-β-环糊精于10mlpH7.4PBS溶液中常温混合24h,N2氛围,离心分离。
(九)刺激响应型聚吡咯纳米管靶向药物载体组装
将载药聚吡咯纳米管与叶酸-聚乙二醇-金刚烷-β-环糊溶于水,溶液中鼓入氧气或加入少量双氧水,形成二硫键,组装成刺激响应型聚吡咯纳米管靶向药物载体,图1为刺激响应型聚吡咯纳米管靶向药物载体的制备示意图。
(十)刺激响应型聚吡咯纳米管靶向药物载体控释研究
将载好药的聚吡咯纳米管药物载体分别于pH4.5PBS+10mMDTT、pH7.4PBS+10mMDTT、pH4.5PBS、pH7.4PBS、pH8PBS溶液中进行控释研究,图7刺激响应型聚吡咯纳米管药物载体在不同介质中药物控释图。在酸性和还原性介质中,释药快速;在中性及碱性介质中,基本不释放,保证了药物载体对药物的控释性。
实施例2
(一)吡咯修饰
将10ml吡咯单体缓慢滴加至含35ml50%氢氧化钠的水溶液中,四丁基硫酸氢铵4.8g,1,2-二氯乙烷110ml,加热回流24小时,反应完后用水稀释,二氯甲烷萃取,合并二氯甲烷,用水洗涤3次,无水硫酸钠干燥,旋干溶剂得1-(2-氯乙基)吡咯。其它步骤同实施例1。
Claims (13)
1.一种刺激响应型聚吡咯纳米管药物载体,其特征在于,该载体的聚乙二醇链一端连接叶酸靶向分子,另一端连接金刚烷基,金刚烷基通过主客包络与巯基化β-环糊精的疏水空腔衔接,并由β-环糊精上巯基与载药的聚吡咯纳米管上的巯基氧化形成二硫键组装而成;所述的聚吡咯纳米管是由吡咯单体与端基二卤素取代直链烷烃发生氮取代反应得到1-(ω-卤代烷基)吡咯,以二氧化钛纳米管阵列或多孔阳极氧化铝阵列为模板,在所述的阵列内表面经化学气相沉积聚合后,再进行聚吡咯纳米管酰腙化、硫醇化得到含酰腙基和巯基的聚吡咯纳米管。
2.根据权利要求1所述的刺激响应型聚吡咯纳米管药物载体,其特征在于,所述的端基二卤素取代直链烷烃的碳原子数为2~10。
3.根据权利要求1所述的刺激响应型聚吡咯纳米管药物载体,其特征在于,所述的金刚烷基来源于1-金刚烷甲酸或1-金刚烷乙酸;聚乙二醇分子量为200~10000。
4.一种刺激响应型聚吡咯纳米管载体药物的制备方法,其特征在于,包括以下步骤:
(a)吡咯单体的修饰
将吡咯单体与氢化钠在–10~+10℃的低温条件下,N2或Ar保护下反应完全后加入端基二卤素取代直链烷烃,反应完后抽滤,经萃取,洗涤,旋干溶剂,分离纯化得1-(ω-卤代烷基)吡咯;
或是将吡咯单体于氢氧化钠水溶液中加入相转移催化剂条件下,直接在端基二卤素取代直链烷烃溶液中加热回流,反应完后用水稀释,二氯甲烷萃取,水洗有机相,干燥,旋干溶剂,得1-(ω-卤代烷基)吡咯;
(b)聚吡咯纳米管的制备
在沉积了Fe3+的纳米管阵列模板上,将(a)制得的1-(ω-卤代烷基)吡咯于真空,温度150~280℃下化学气相沉积反应聚合得到经修饰的聚吡咯纳米管;用酸或碱溶液溶解分散后,离心将所述的经修饰的聚吡咯纳米管分离,清洗数次,干燥;所述的纳米管阵列模板为二氧化钛纳米管阵列模板或多孔阳极氧化铝模板;
(c)将(b)步得到的聚吡咯纳米管进行酰腙化、硫醇化处理,得到含酰腙基和巯基的聚吡咯纳米管;
(d)聚吡咯纳米管载药
将经(c)步得到含酰腙基和巯基的的聚吡咯纳米管分散在药物溶液中进行药物负载,得到负载药物的聚吡咯纳米管再离心分离;
(e)叶酸-聚乙二醇-金刚烷-β-环糊精的制备
双端氨基聚乙二醇和叶酸分子、金刚烷基化合物分别通过缩合反应,得一端修饰叶酸分子,另一端连接修饰有金刚烷基的聚乙二醇链;巯基化β-环糊精与所述的聚乙二醇链的金刚烷基端通过主客包络结合得到叶酸-聚乙二醇-金刚烷-β-环糊精;
(f)刺激响应型聚吡咯纳米管药物载体的组装
负载药物的聚吡咯纳米管上巯基与叶酸-聚乙二醇-金刚烷-β-环糊精上巯基氧化形成二硫键,组装成刺激响应型聚吡咯纳米管载体药物。
5.根据权利要求4所述的的制备方法,其特征在于,所述的(c)聚吡咯纳米管酰腙化、硫醇化处理是将对羟基苯甲醛与无水碳酸钾于干燥的N,N-二甲基甲酰胺溶剂中N2保护下反应,然后加入(b)制备得到的经修饰的聚吡咯纳米管,搅拌反应完全后洗涤离心,得黑色固体;3-巯基丙酸甲酯与水合肼加热回流反应得3-巯基丙酸酰肼,再与所述的黑色固体常温下反应,反应完全后洗涤离心得含酰腙基和巯基的聚吡咯纳米管黑色固体。
6.根据权利要求4所述的的制备方法,其特征在于,所述的(b)步的化学气相沉积真空度为5~50Pa,化学气相沉积时间为1~5h。
7.根据权利要求4所述的的制备方法,其特征在于,所述的(b)步的制备是将二氧化钛纳米管阵列模板在Fe3+溶液中,在20~60℃下浸泡24~72h,得到表面沉积一层Fe3+的二氧化钛纳米管阵列模板,将模板45~80℃真空干燥6~10h,将沉积了Fe3+的二氧化钛纳米管阵列模板和(a)制得的1-(ω-卤代烷基)吡咯置于真空装置,真空度10~50Pa,加热温度150~250℃,反应时间1~5h,1-(ω-卤代烷基)吡咯单体在Fe3+氧化作用下形成阳离子自由基,在二氧化钛纳米管内表面引发聚合;用酸或碱溶液溶解二氧化钛模板24~48h,得到分散的聚吡咯纳米管,通过离心将聚吡咯纳米管从酸或碱溶液分离,然后用乙醇清洗数次,真空干燥备用。
8.根据权利要求4或6或7所述的制备方法,其特征在于,步骤(b)中,所述的酸为硫酸、盐酸、硝酸、磷酸或氢氟酸,所述的碱为氢氧化钠、氢氧化钾中的一种或几种,所述的酸或碱溶液的质量百分数为1~10wt%;所述的Fe3+来源于氯化铁、硫酸铁、硝酸铁、溴化铁、高氯酸铁的一种或几种,Fe3+溶液浓度为0.05~0.5mol/L。
9.根据权利要求4所述的制备方法,其特征在于,步骤(e)中,双端氨基聚乙二醇中聚乙二醇的分子量为200~10000,叶酸与双端氨基聚乙二醇的摩尔比为1:1~1.5。
10.如权利要求4所述的制备方法,其特征在于,步骤(e)中,金刚烷基来源于1-金刚烷甲酸或1-金刚烷乙酸,其中,双端氨基聚乙二醇和叶酸分子形成的叶酸-聚乙二醇与金刚烷基的摩尔比为1:1~1.5。
11.根据权利要求4或9或10所述的的制备方法,其特征在于,所述的(e)步的制备是双端氨基聚乙二醇和叶酸分子通过1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺盐酸盐和N-羟基琥珀酰亚胺缩合,得一端修饰叶酸分子的聚乙二醇链,即叶酸-聚乙二醇,采用葡聚糖凝胶LH-60分离纯化;将叶酸-聚乙二醇与1-金刚烷甲酸或1-金刚烷乙酸通过1-乙基-3-(3-二甲基氨丙基)-碳化二亚胺盐酸盐和N-羟基琥珀酰亚胺缩合,得到叶酸-聚乙二醇-金刚烷链,采用葡聚糖凝胶G-25或LH-60纯化;β-环糊精与三苯基膦、单质碘反应,得6位伯醇被碘取代的β-环糊精,即6-碘-β-环糊精,然后与硫脲反应,碱水解,酸化得巯基化β-环糊精(6-巯基-β-环糊精),巯基化β-环糊精与叶酸-聚乙二醇-金刚烷链通过主客包络结合。
12.如权利要求5所述的制备方法,其特征在于,步骤(c)中,对羟基苯甲醛与无水碳酸钾的摩尔比为1:1~1.05,巯基丙酸甲酯与水合肼的摩尔比为1:2.3~3,加热回流反应所用的溶剂为甲醇、乙醇中的一种,反应时间为10-24h。
13.如权利要求4所述的制备方法,其特征在于,步骤(d)中所述的药物为5-氟尿嘧啶、盐酸阿霉素、羟基喜树碱、长春新碱、紫杉醇抗癌药物中的一种或几种。
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