CN113797351B - 一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束及其应用 - Google Patents
一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束及其应用 Download PDFInfo
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Abstract
本发明提供了一种一步法合成pH响应的靶向透明质酸‑鬼臼毒素前药胶束及应用。从透明质酸和鬼臼毒素为原料出发,以二环己基碳二亚胺为缩合剂、4‑二甲氨基吡啶为催化剂通过缩合反应获得含酯键的透明质酸‑鬼臼毒素前药(HA‑CO‑O‑PPT)。本发明所合成的前药可在水溶液自组装形成胶束,具有好的血液相容性,适用于静脉注射。本发明还提供上述透明质酸‑鬼臼毒素前药胶束在药物递送中的应用。该发明具有合成步骤简单,可控的药物释放行为,对肿瘤细胞的靶向能力,高效的抗肿瘤效果,为其向临床应用的转化提供了极大可能。
Description
技术领域
本发明公开了一种一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束及其应用,属于新型纳米药物载体技术领域。
背景技术
癌症仍然是世界范围内严重危害人类健康的重大疾病之一。尽管临床上有多种癌症治疗方法,但化疗一直是治疗恶性肿瘤最常用的方法之一。然而,目前化疗药物由于水溶性差、非靶向性、不可控释放、血液清除速率快、给药剂量大及严重的毒副作用等问题,限制了其在肿瘤化疗中的应用。在过去的几十年里,为了改善化疗的疗效,科学家们在开发聚合物前药方面做了大量的工作。聚合物前药是通过将疏水性药物与聚合物共价连接而成,并在水溶液中自组装形成具有疏水内核和亲水外壳的胶束。聚合物前药胶束不仅可以提高疏水性药物的水溶性、生物相容性和生物利用度,还可以延长其血液循环时间。此外,纳米级结构的胶束使它们能够通过高通透性和滞留效应(EPR)在肿瘤中积累。然而,聚合物前药胶束的被动靶向递送和不可控的药物释放往往导致疗效不佳,从而限制了他们的临床应用。因此,开发能够特异性靶向肿瘤并能可控释放药物的“智能”聚合物前药胶束对于提高癌症治疗效果至关重要。
为了实现可控的药物释放,利用肿瘤微环境的特异性(如pH、氧化还原、温度、特殊气体和酶),人们研究并开发了多种多样的刺激敏感型聚合物前药胶束。尤其是利用正常组织和肿瘤组织中pH值的差异(前者pH值约为7.4,而后者则为4.5~6.5),开发的pH响应型前药胶束在药物控释方面备受关注。此外,具有肿瘤主动靶向的聚合物前药用于特异性药物递送也成为人们研究的热点。透明质酸(HA)是一种天然的糖胺聚糖,在关节软骨、皮肤真皮等多种组织中含量丰富,具有优良的生物相容性、生物降解性和低免疫原性。HA可以特异性靶向CD44过表达的肿瘤细胞。近年来越来越多地研究关注在具有pH敏感的HA靶向前药胶束。尽管基于pH敏感的HA前药胶束在癌症治疗方面取得了极大进展,但前药胶束的合成过程繁琐,由此限制了他们的大规模生产和应用。因此,通过简单的合成步骤来构建肿瘤靶向和pH敏感的前药胶束用于癌症治疗显得尤为重要。
鬼臼毒素主要来源于小檗科的鬼臼属、八角莲属和山荷叶属等植物的根或茎,是一种具有天然活性的木质素类化合物。鬼臼毒素具有显著的抗肿瘤活性,可逆结合微管蛋白,抑制微管蛋白的合成以抑制细胞的有丝分裂活动,实现细胞增殖的抑制进而实现抗肿瘤活性。但因其水溶性差、毒副作用严重、体内代谢时间短等缺点,成为其临床应用的关键瓶颈。
本发明通过一步法合成了具有靶向的pH响应型的透明质酸-鬼臼毒素前药(HA-CO-O-PPT),可在水中自组装形成胶束,用于肿瘤治疗,为聚合物前药向临床应用转化提供了极大可能。
发明内容
为了克服现有技术中存在的缺点和不足,本发明的目的在于提供一种一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束及应用。
本发明的技术方案如下:
一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束的方法,步骤如下:
将透明质酸溶于甲酰胺和N,N-二甲基甲酰胺混合溶液中,然后加入缩合剂二环己基碳二亚胺(DCC)和催化剂4-二甲氨基吡啶(DMAP),该反应在冰浴中反应1-2小时以活化透明质酸的羧基,得到透明质酸溶液;随后将鬼臼毒素(PPT)溶于N,N-二甲基甲酰胺中,形成的溶液再缓慢滴加至上述透明质酸溶液中,混合物在25℃下反应24-72小时,反应结束后,将所得混合物放入透析袋中用去离子水透析;最后,将溶液过滤,冻干,以获得透明质酸-鬼臼毒素前药;将透明质酸-鬼臼毒素前药溶解在超纯水中,超声处理10-20分钟,使其均匀分散,静置3-6小时,即得透明质酸-鬼臼毒素前药胶束。
优选地,所述透明质酸分子量为3000-10000Da。
优选地,所述透析袋截留分子量为1000-2000Da。
优选地,所述甲酰胺和N,N-二甲基甲酰胺的体积比为0.5:1-1:1。
优选地,所述透明质酸和二环己基碳二亚胺、4-二甲氨基吡啶摩尔比为1:0.5:0.2-1:1.2:1。
优选地,所述透明质酸和鬼臼毒素的摩尔比为1:1-1:30。
优选地,所述缓慢滴加的速率为60-120滴/分钟。
优选地,将所得混合物放入透析袋中用去离子水透析48-72小时,每3-12小时更换去离子水。
本发明同时请求保护上述方法制备得到的透明质酸-鬼臼毒素前药胶束。
本发明同时还请求保护上述透明质酸-鬼臼毒素前药胶束在制备治疗癌症药物中的应用,所述癌症为乳腺癌、肺癌或肝癌。
本发明从透明质酸和鬼臼毒素为原料出发,以二环己基碳二亚胺为缩合剂、4-二甲氨基吡啶为催化剂通过缩合反应,一步法获得含酯键的两亲性透明质酸-鬼臼毒素前药(HA-CO-O-PPT)。该前药可在水溶液中自组装形成胶束,具有好的血液相容性,适用于静脉注射,并能靶向递送至肿瘤部位,在低pH环境下酯键发生断裂而释放药物,实现了高效、安全的药物递送和可控的药物释放。
与现有技术相比,本发明具有以下优点:
1.本发明采用一步法将透明质酸和鬼臼毒素进行耦合制备透明质酸-鬼臼毒素前药,合成方法简单,易于工业化。
2.本发明合成的透明质酸-鬼臼毒素前药提高了鬼臼毒素的水溶性、生物相容性和血液循环时间。
3.本发明通过酯键将透明质酸和鬼臼毒素进行连接,具有肿瘤微环境的pH敏感性,透明质酸介导的肿瘤靶向性,实现了高效的药物递送和可控释放药物,高效的抗肿瘤效果,为其向临床应用的转化提供了极大可能,具有广阔的应用前景。
附图说明
图1为透明质酸-鬼臼毒素前药的合成步骤;
图2为实施例5所制备的透明质酸-鬼臼毒素前药的FT-IR谱图;
图3为实施例5所制备的透明质酸-鬼臼毒素前药的1H NMR谱图;
图4为实施例5所制备的透明质酸-鬼臼毒素前药胶束的TEM照片;
图5为实施例6所制备的透明质酸-鬼臼毒素前药胶束的体外释药行为;
图6为实施例6所制备的透明质酸-鬼臼毒素前药胶束的血液相容性;
图7为实施例7所制备的透明质酸-鬼臼毒素前药胶束的靶向性;
图8为实施例7所制备的透明质酸-鬼臼毒素前药胶束的细胞毒性。
具体实施方式
下面通过附图和具体实施例详述本发明,但不限制本发明的保护范围。如无特殊说明,本发明所采用的实验方法均为常规方法,所用实验器材、材料、试剂等均可从化学公司购买。
实施例1
将分子量为3000-10000Da的透明质酸(100mg,相当于-COOH基的0.26mmol)溶于甲酰胺(5mL)和N,N-二甲基甲酰胺(5mL)混合溶液中,然后加入缩合剂二环己基碳二亚胺(64mg,0.31mmol)和催化剂4-二甲氨基吡啶(6.40mg,0.052mmol),该反应在冰浴中反应1小时以活化透明质酸的羧基,得到透明质酸溶液。随后将鬼臼毒素(107.68mg,0.26mmol)溶于N,N-二甲基甲酰胺(10mL)中,缓慢滴加(120滴/分钟)至上述透明质酸溶液中。混合物在25℃下反应48小时。反应结束后,将所得混合物用去离子水透析(截留分子量为2000Da)72小时,每6小时更换去离子水。最后,将溶液过滤,冻干以获得透明质酸-鬼臼毒素前药。取透明质酸-鬼臼毒素前药(5mg)溶解在超纯水(1mL)中,超声处理10分钟,使其均匀分散,静置3小时,即得透明质酸-鬼臼毒素前药胶束。
实施例2
将分子量为3000-10000Da的透明质酸(100mg,相当于-COOH基的0.26mmol)溶于甲酰胺(5mL)和N,N-二甲基甲酰胺(5mL)混合溶液中,然后加入缩合剂二环己基碳二亚胺(64mg,0.31mmol)和催化剂4-二甲氨基吡啶(6.40mg,0.052mmol),该反应在冰浴中反应1小时以活化透明质酸的羧基,得到透明质酸溶液。随后将鬼臼毒素(538.73mg,1.3mmol)溶于N,N-二甲基甲酰胺(10mL)中,缓慢滴加(120滴/分钟)至上述透明质溶液中。混合物在25℃下反应48小时。反应结束后,将所得混合物用去离子水透析(截留分子量为2000Da)72小时,每6小时更换去离子水。最后,将溶液过滤,冻干以获得透明质酸-鬼臼毒素前药。取透明质酸-鬼臼毒素前药(5mg)溶解在超纯水(1mL)中,超声处理10分钟,使其均匀分散,静置3小时,即得透明质酸-鬼臼毒素前药胶束。
实施例3
将分子量为3000-10000Da的透明质酸(100mg,相当于-COOH基的0.26mmol)溶于甲酰胺(5mL)和N,N-二甲基甲酰胺(5mL)混合溶液中,然后加入缩合剂二环己基碳二亚胺(64mg,0.31mmol)和催化剂4-二甲氨基吡啶(6.40mg,0.052mmol),该反应在冰浴中反应1小时以活化透明质酸的羧基,得到透明质酸溶液。随后将鬼臼毒素(1077.47mg,2.6mmol)溶于N,N-二甲基甲酰胺(10mL)中,缓慢滴加(120滴/分钟)至上述透明质溶液中。混合物在25℃下反应48小时。反应结束后,将所得混合物用去离子水透析(截留分子量为2000Da)72小时,每6小时更换去离子水。最后,将溶液过滤,冻干以获得透明质酸-鬼臼毒素前药。取透明质酸-鬼臼毒素前药(5mg)溶解在超纯水(1mL)中,超声处理10分钟,使其均匀分散,静置3小时,即得透明质酸-鬼臼毒素前药胶束。
实施例4
将分子量为3000-10000Da的透明质酸(100mg,相当于-COOH基的0.26mmol)溶于甲酰胺(5mL)和N,N-二甲基甲酰胺(5mL)混合溶液中,然后加入缩合剂二环己基碳二亚胺(64mg,0.31mmol)和催化剂4-二甲氨基吡啶(6.40mg,0.052mmol),该反应在冰浴中反应1小时以活化透明质酸的羧基,得到透明质酸溶液。随后将鬼臼毒素(2154.93mg,5.2mmol)溶于N,N-二甲基甲酰胺(10mL)中,缓慢滴加(120滴/分钟)至上述透明质溶液中。混合物在25℃下反应48小时。反应结束后,将所得混合物用去离子水透析(截留分子量为2000Da)72小时,每6小时更换去离子水。最后,将溶液过滤,冻干以获得透明质酸-鬼臼毒素前药。取透明质酸-鬼臼毒素前药(5mg)溶解在超纯水(1mL)中,超声处理10分钟,使其均匀分散,静置3小时,即得透明质酸-鬼臼毒素前药胶束。
实施例5
将分子量为3000-10000Da的透明质酸(100mg,相当于-COOH基的0.26mmol)溶于甲酰胺(5mL)和N,N-二甲基甲酰胺(5mL)混合溶液中,然后加入缩合剂二环己基碳二亚胺(64mg,0.31mmol)和催化剂4-二甲氨基吡啶(6.40mg,0.052mmol),该反应在冰浴中反应1小时以活化透明质酸的羧基,得到透明质酸溶液。随后将鬼臼毒素(3232.40mg,7.8mmol)溶于N,N-二甲基甲酰胺(10mL)中,缓慢滴加(120滴/分钟)至上述透明质溶液中。混合物在25℃下反应48小时。反应结束后,将所得混合物用去离子水透析(截留分子量为2000Da)72小时,每6小时更换去离子水。最后,将溶液过滤,冻干以获得透明质酸-鬼臼毒素前药。取透明质酸-鬼臼毒素前药(5mg)溶解在超纯水(1mL)中,超声处理10分钟,使其均匀分散,静置3小时,即得透明质酸-鬼臼毒素前药胶束。
实施例6
将分子量为3000-10000Da的透明质酸(100mg,相当于-COOH基的0.26mmol)溶于甲酰胺(5mL)和N,N-二甲基甲酰胺(5mL)混合溶液中,然后加入缩合剂二环己基碳二亚胺(64mg,0.31mmol)和催化剂4-二甲氨基吡啶(6.40mg,0.052mmol),该反应在冰浴中反应1小时以活化透明质酸的羧基,得到透明质酸溶液。随后将鬼臼毒素(3232.40mg,7.8mmol)溶于N,N-二甲基甲酰胺(10mL)中,缓慢滴加(120滴/分钟)至上述透明质溶液中。混合物在25℃下反应24小时。反应结束后,将所得混合物用去离子水透析(截留分子量为2000Da)72小时,每6小时更换去离子水。最后,将溶液过滤,冻干以获得透明质酸-鬼臼毒素前药。取透明质酸-鬼臼毒素前药(5mg)溶解在超纯水(1mL)中,超声处理10分钟,使其均匀分散,静置3小时,即得透明质酸-鬼臼毒素前药胶束。
实施例7
将分子量为3000-10000Da的透明质酸(100mg,相当于-COOH基的0.26mmol)溶于甲酰胺(5mL)和N,N-二甲基甲酰胺(5mL)混合溶液中,然后加入缩合剂二环己基碳二亚胺(64mg,0.31mmol)和催化剂4-二甲氨基吡啶(6.40mg,0.052mmol),该反应在冰浴中反应1小时以活化透明质酸的羧基,得到透明质酸溶液。随后将鬼臼毒素(3232.40mg,7.8mmol)溶于N,N-二甲基甲酰胺(10mL)中,缓慢滴加(120滴/分钟)至上述透明质溶液中。混合物在25℃下反应72小时。反应结束后,将所得混合物用去离子水透析(截留分子量为2000Da)72小时,每6小时更换去离子水。最后,将溶液过滤,冻干以获得透明质酸-鬼臼毒素前药。取透明质酸-鬼臼毒素前药(5mg)溶解在超纯水(1mL)中,超声处理10分钟,使其均匀分散,静置3小时,即得透明质酸-鬼臼毒素前药胶束。
实施例8
将实施例5中制得的透明质酸-鬼臼毒素前药(1-2mg)与溴化钾固体粉末(100-200mg)混合研磨均匀、压片,在4000–500cm-1范围内扫描并进行红外表征。图2是实施例5所制备的透明质酸-鬼臼毒素前药的红外谱图,在1710cm-1(C=O)和1280cm-1(C-O)处出现酯键的特征信号峰,表明PPT成功接枝到HA上。
实施例9
将实施例5中制得的透明质酸-鬼臼毒素前药(5mg)溶在氘代水(0.5mL)进行核磁氢谱表征。图3是实施例5所制备的透明质酸-鬼臼毒素前药的核磁氢谱图,在化学位移5.8~6.8为PPT苯环上的氢的信号峰,说明PPT接枝到HA上。
实施例10
将实施例5中制得的透明质酸-鬼臼毒素前药胶束,用透射电镜表征形貌及粒径。图4是实施例5所制备的透明质酸-鬼臼毒素前药胶束的透射电镜图,该胶束的形态呈球形,胶束粒径在60-120nm,分布较均匀。
实施例11
采用透析法来研究透明质酸-鬼臼毒素前药胶束在不同pH条件下的释放行为。取2.0mL实施例6制得的透明质酸-鬼臼毒素前药胶束装入透析袋(截留分子量为2000Da)中,并将之分别浸入含有50mLpH 5.0和pH 7.4PBS溶液的离心管中,然后放置于恒温摇床中,振荡速度为200r/min,温度控制在37℃。在1h、2h、4h、6h、8h、10h、12h、24h、48h和72h时,从释放介质中取出2.0mL液体并用2.0mL相应pH的PBS替换以维持体积不变。用紫外分光光度计测量释放到PBS溶液中的鬼臼毒素的浓度。
图5是实施例6所制备的透明质酸-鬼臼毒素前药胶束的释药曲线,在pH 7.4下孵育72h后,大约29.9%的PPT缓慢释放,这表明胶束在到达肿瘤部位之前能够在正常生理环境中保持结构的完整性。相比之下,该胶束在pH 5.0下孵育72h后,PPT的累积释放量达到81.2%,这可能是由于酯键在酸性环境下断裂所致。总体而言,透明质酸-鬼臼毒素前药胶束可通过响应pH而控制药物释放。
实施例12
透明质酸-鬼臼毒素前药胶束的溶血实验:首先对新鲜的小鼠血浆进行脱纤维处理。取2mL的小鼠血液,用玻璃棒沿顺时针方向轻轻搅拌15min,除去血液中的纤维蛋白。然后加入8mL的PBS溶液,放入离心机中,以2500r/min离心10min,。撇去上清液,重复离心三次至上清液无色,得到血红细胞悬浮液。用PBS稀释该细胞悬浮液,旋涡振荡5min使悬液混合均匀,获得浓度约5%(v/v)的红细胞悬浮液。将红细胞悬浮液分别与实施例6制得的透明质酸-鬼臼毒素前药胶束(5mg/mL)、吐温80溶液(5mg/mL)混合,使混合物中透明质酸-鬼臼毒素前药胶束或吐温80的最终浓度范围为0.1至2mg/mL(分别为0.1、0.25、0.5、1、2mg/mL)。同时取1mL的红细胞悬液分别和超纯水、PBS等量混合作为阳性和阴性对照。在37℃恒温摇床上孵育4h后,以2500r/min离心10min。用酶标仪检测上清液在541nm处的吸光度,使用以下等式计算溶血程度:
其中Atest,Aneg,Apos分别是样品,阴性对照(PBS)和阳性对照(水)的吸光度值。
图6是实施例6所制备的透明质酸-鬼臼毒素前药胶束和Tween 80的溶血率,当浓度从0.1增加到2.0mg/mL时,吐温80诱导的溶血率从12.38%显著增加到74.79%。然而,透明质酸-鬼臼毒素前药胶束在相同浓度下表现出不超过5%的溶血率,其结果明显低于吐温80,这说明所制备的胶束具有好的血液相容性。
实施例13
透明质酸-鬼臼毒素前药胶束的靶向性评估:将人类乳腺癌细胞(MCF-7)细胞以每孔6×104的细胞密度接种在12孔板上,孵育24h后,观察细胞约占瓶壁80%。加入10mg/mL透明质酸(分子量为3000-10000Da)培养2h,以不加透明质酸处理的作为对照。之后移去培养基(DMEM),加入新鲜含5μg/mL实施例6制得的透明质酸-鬼臼毒素前药胶束的DMEM,继续培养4h。用1×PBS(pH 7.4)洗涤细胞三次,通过胰蛋白酶消化,吹打并收集细胞,过筛。选择流式细胞仪进行检测。
图7是实施例6所制备的透明质酸-鬼臼毒素前药胶束的细胞靶向性研究,细胞摄取率从97.2%降低到30.7%,表明HA介导的特异性内吞作用。
实施例14
透明质酸-鬼臼毒素前药胶束的细胞毒性:通过CCK-8法测定透明质酸-鬼臼毒素前药胶束对人类乳腺癌细胞(MCF-7)的毒性。在96孔细胞培养板上种植细胞,平行5个孔,每孔种植5×104个细胞,在37℃,5%CO2细胞培养箱中培养至细胞密度达到80%以上。移去DMEM,分别加入新鲜含0.01,0.1,1,2,4,5,10和20μg/mL实施例6制得的透明质酸-鬼臼毒素前药胶束的DMEM,培养72h。加入10μL的CCK-8试剂,孵育1h,移至酶标仪测定各孔在450nm处的吸光度。计算细胞存活率(实验组的吸光度值占对照组吸光度值的百分比)。
图8是实施例6所制备的透明质酸-鬼臼毒素前药胶束对MCF-7细胞的毒性,与游离PPT相比,透明质酸-鬼臼毒素前药胶束显示出对MCF-7细胞更好的抑制效果。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一步法合成pH响应型的靶向透明质酸-鬼臼毒素前药胶束的方法,其特征在于,步骤如下:
将透明质酸溶于甲酰胺和N,N-二甲基甲酰胺混合溶液中,然后加入缩合剂二环己基碳二亚胺和催化剂4-二甲氨基吡啶,在冰浴中反应1-2小时,得到透明质酸溶液;随后将鬼臼毒素溶于N,N-二甲基甲酰胺中,滴加至上述透明质酸溶液中,在25℃下反应24-72小时,反应结束后,将所得混合物放入透析袋中用去离子水透析;最后,将溶液过滤,冻干,获得透明质酸-鬼臼毒素前药;将透明质酸-鬼臼毒素前药溶解在超纯水中,超声处理10-20分钟,静置3-6小时,即得透明质酸-鬼臼毒素前药胶束;
所述的透明质酸分子量为3000-10000Da。
2.根据权利要求1所述的方法,其特征在于,所述透析袋截留分子量为1000-2000Da。
3.根据权利要求1所述的方法,其特征在于,所述的甲酰胺和N,N-二甲基甲酰胺混合溶液的体积比为0.5:1-1:1。
4.根据权利要求1所述的方法,其特征在于,所述的透明质酸、二环己基碳二亚胺、4-二甲氨基吡啶摩尔比为1:0.5:0.2-1:1.2:1。
5.根据权利要求1所述的方法,其特征在于,所述透明质酸和鬼臼毒素的摩尔比为1:1-1:30。
6.根据权利要求1所述的方法,其特征在于,将所得混合物放入透析袋中用去离子水透析48-72小时,每3-12小时更换去离子水。
7.权利要求1-6中任意一项所述的方法制备得到的pH响应型的靶向透明质酸-鬼臼毒素前药胶束。
8.权利要求7所述的pH响应型的靶向透明质酸-鬼臼毒素前药胶束在制备治疗乳腺癌药物中的应用。
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