CN113679662A - 微环境响应型聚合物前药共递送凝胶系统的制备方法及用途 - Google Patents
微环境响应型聚合物前药共递送凝胶系统的制备方法及用途 Download PDFInfo
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- CN113679662A CN113679662A CN202111000067.1A CN202111000067A CN113679662A CN 113679662 A CN113679662 A CN 113679662A CN 202111000067 A CN202111000067 A CN 202111000067A CN 113679662 A CN113679662 A CN 113679662A
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Abstract
本发明公开了微环境响应型聚合物前药共递送凝胶系统的制备方法及用途,通过迈克尔加成反应由双巯基或多巯基小分子对酸响应型聚合物前药中的双键进行巯基化修饰,再通过迈克尔加成反应由两端连有双键的肿瘤微环境响应型交联剂交联,最后通过溶剂交换法制备纳米凝胶并载入可调节肿瘤微环境的药物。本发明通过对化疗药物结构修饰、交联载药,实现对不同药物逐级定点的释放,减小了药物的全身毒副作用,改善了不同药物的协同作用。
Description
技术领域:
本发明涉及高分子材料学和药物制剂制备方法及用途,特别涉及微环境响应型聚合物前药共递送凝胶系统的制备方法和应用。
背景技术:
当今,化疗药已被广泛用于防止癌细胞的增殖、渗透和转移。然而,由于许多化疗药往往选择性较低且水溶性较差,大大限制了它们的临床应用。而在过去的几十年中,人们尝试了许多方法来改善这一类化疗药物的应用,各种载药系统如聚合物前药、脂质体、聚合物胶束等也被研发,用于这类化疗药物的可控释放。而基于两亲性聚合物-药物偶联物形成的微环境响应型聚合物前药共递送凝胶系统结合了聚合物前药与聚合物胶束的优点,通过对化疗药物进行结构修饰,改善了化疗药物的水溶性,并能够利用肿瘤微环境和正常组织中的一些特殊差异,如pH、氧化还原、酶等环境的不同,在特定刺激下进行酶和/或化学转化以释放活性药物发挥所需的药理活性,提高药物靶向到肿瘤组织与细胞的选择性,降低了药物的毒副作用。
据研究,人体血液正常pH值为7.35-7.45,实体肿瘤间质pH值为6.5-7.2,肿瘤细胞内涵体中pH值为5.0-6.0,溶酶体中pH值为4.5-5.0。这是由于肿瘤细胞的增殖速度过快,实体瘤内部的缺氧状态使得肿瘤细胞通过无氧呼吸代谢,产生了大量乳酸,且由于肿瘤内部血管系统缺乏,难以将这些乳酸排出蓄积在肿瘤部位,从而导致肿瘤组织形成酸性环境。因此,肿瘤中的这些酸性环境可以作为信号用于触发聚合物前药的断裂释放。
此外,肿瘤组织中往往具有较高的活性氧(ROS)水平、高含量的谷胱甘肽(GSH),某些酶(如基质金属蛋白酶、肿瘤白蛋白代谢蛋白酶、溶酶体酶、磷酯酶A2等)的过度表达等,故可以以此为刺激信号,设计肿瘤微环境响应型聚合物前药共递送凝胶药物系统,实现药物在肿瘤微环境的靶向释放,减少药物的副作用。
发明内容
本发明的目的是提供一种微环境响应型聚合物前药共递送凝胶系统的制备方法和用途。
技术方案:本发明所述微环境响应型聚合物前药共递送凝胶系统的制备方法,是通过迈克尔加成反应由双巯基或多巯基小分子对酸响应型聚合物前药中双键进行巯基化修饰,随后通过迈克尔加成反应由两端连有双键的肿瘤微环境响应型交联剂交联,再通过溶剂交换法制备纳米凝胶并载入可调节肿瘤微环境的药物制备得到。
进一步地,所述酸响应型聚合物前药主要是由包含丙烯双键单元的乙烯基醚丙烯酸酯及其衍生物与含羟基化疗药物通过酸响应型缩醛键连接,形成药物-小分子复合物,然后再通过迈克尔加成反应与巯基化PEG或带其他配体的巯基化PEG连接,即得所述酸响应型聚合物前药。
进一步地,所述包含丙烯双键单元的乙烯基醚丙烯酸酯及其衍生物选自乙烯基乙醚丙烯酸酯(VEA)或乙烯基乙醚甲基丙烯酸酯(VEMA)。
进一步地,所述含羟基化疗药物选自紫杉醇、多西紫杉醇、羟基喜树碱或雌二醇。
进一步地,所述聚乙二醇的PEG分子量为0.5~20kDa。
进一步地,所述带配体修饰的PEG为巯基化PEG。
上述技术方案中,所述迈克尔加成反应,是将酸响应型聚合物前药溶于有机溶剂中,加入双巯基或多巯基小分子,在惰性气体保护下,进行迈克尔加成反应,制备巯基化酸敏感聚合物前药。
作为优选,所述有机溶剂选自N,N-二甲基甲酰胺、二甲亚砜、四氢呋喃或二氯甲烷;酸响应型聚合物前药与双巯基或多巯基小分子的摩尔比为1∶(3~6)。
上述技术方案中,酸敏感药物-小分子复合物作为疏水链段引入亲水聚合物PEG的末端,得到酸敏感两亲性聚合物前药,所述的酸敏感聚合物前药可以在水溶液中自组装形成纳米粒子,该纳米粒子的外层亲水层由PEG构成,内层疏水层由药物-丙烯酸酯-巯基构成,其中,水溶液可选自:纯水,磷酸盐缓冲溶液(PB),4-羟乙基哌嗪乙磺酸(Hepes)缓冲溶液等。所述纳米粒子的粒径为10~300nm。尺寸稳定,分布均一。
该两亲性聚合物可以通过迈克尔加成反应由两端连有双键的肿瘤微环境响应型交联剂交联,随后通过自组装得到交联纳米粒子,这样可增加纳米粒子的稳定性,并实现微环境响应断裂。
上述技术方案中,所述的交联可采用下列方法:将巯基化酸响应型聚合物前药溶于有机溶剂中,加入至两端连有双键的肿瘤微环境响应型交联剂的有机溶液中,在惰性气体保护下,进行迈克尔加成反应,制备交联型巯基化酸响应型聚合物前药。作为优选,所述有机溶剂选自N,N-二甲基甲酰胺、二甲亚砜、四氢呋喃或二氯甲烷;巯基化酸响应型聚合物前药与双巯基或多巯基小分子的摩尔比为1∶(0.5~0.6)。
进一步地,所述两端连有双键的肿瘤微环境响应型交联剂选自但不局限于:基质金属蛋白酶9(MMP-9)酶敏感多肽、基质金属蛋白酶2(MMP-2)敏感多肽、基质金属蛋白酶1(MMP-1)敏感多肽、基质金属蛋白酶7(MMP-7)敏感多肽、肿瘤白蛋白代谢蛋白酶敏感多肽、溶酶体酶(组织蛋白酶B)敏感多肽、磷酯酶A2(sPLA2)敏感多肽,
上述技术方案中,交联型酸敏感药物-小分子复合物作为疏水链段引入亲水聚合物PEG的末端,得到微环境敏感的两亲性聚合物前药,可以在水溶液中自组装形成纳米粒子,该纳米粒子的外层亲水层由PEG构成,内层疏水层由药物-丙烯酸酯-交联剂-丙烯酸酯-药物构成,其中,水溶液可选自:纯水,磷酸盐缓冲溶液(PB),4-羟乙基哌嗪乙磺酸(Hepes)缓冲溶液等。所述纳米粒子的粒径为10~300nm。尺寸稳定,分布均一。
上述交联型两亲聚合物的疏水层可以负载小分子药物,通过肿瘤微环境响应型交联剂交联,增加纳米粒子的稳定性的同时实现微环境响应释放药物,所以可选择包载可调节肿瘤微环境的药物,调节肿瘤微环境,协同增强聚合物前药的作用。所以本发明还公开了上述交联型两亲性聚合物在制备药物载体中的应用。
上述技术方案中,所述包载药物可采用下列方法:将可调节肿瘤微环境的药物溶解于有机溶剂中,加入至微环境响应型聚合物前药凝胶水溶液中,交替进行涡旋和超声,得到载药的交联纳米粒子。
进一步地,所述可调节肿瘤微环境的药物选自,但不局限于:TGF-β抑制剂、吡非尼酮(PFD)、洛沙坦(Losartan)、松弛肽(Relaxin)、菠萝蛋白酶(Bromelain)、肿瘤坏死因子-α(TNF-α)和衍生品、血小板衍生的生长因子(PDGF)拮抗剂、血管内皮生长因子(VEGF)受体抑制剂、多激酶抑制剂索拉菲尼(Sorafenib)。
在本发明实施方案中,载药纳米粒子的粒径优选为10~300nm,粒径分布为0.02~0.30。
本发明特别合成了一种酸响应型聚合物前药,并由肿瘤微环境响应型交联剂交联后通过溶剂交换法组装,再包载可调节肿瘤微环境的药物,制备了粒径均一的微环境响应型聚合物前药共递送凝胶药物系统;此微环境响应型聚合物前药共递送凝胶药物系统在体内循环中具有较高的稳定性,并能在肿瘤部位大量富集,进而在肿瘤微环境下交联结构解离,释放出可调节肿瘤微环境的药物,调节肿瘤微环境,协同增强聚合物前药的作用,随后聚合物前药在肿瘤细胞酸性环境下裂解释放出键连药物,实现肿瘤的安全高效治疗。
因此,本发明最后公开和保护上述肿瘤微环境响应型聚合物前药共递送凝胶药物系统在制备抗肿瘤药物中的应用。
本发明公开的微环境响应型聚合物前药共递送凝胶药物系统的疏水末端为巯基,通过两端连有双键的肿瘤微环境响应型交联剂交联可以得到稳定的交联纳米粒子,且实现微环境响应释放可调节肿瘤微环境的药物,该纳米粒子在细胞外和血液中不易解离,从而保证纳米粒子包封的药物稳定,增加药物体内循环时间;克服了现有技术中药物在体内易被泄漏、运载效率低的缺陷;并且该纳米粒子具有肿瘤微环境敏感性和酸敏感性,可在肿瘤微环境中和肿瘤细胞酸性环境中依次断裂,逐级定点的释放两种药物,将药物有效递送至目标组织,减小了药物的全身毒副作用,并改善了不同药物的协同作用。
本发明公开的微环境响应型聚合物前药共递送凝胶药物系统,克服了聚合物前药与聚合物胶束合成过程复杂、载药量低、稳定性差、体内药物泄露等缺陷,保留了二者的优势,且合成过程简单、化合物结构明确、载药量高,在体内循环过程中也较为稳定,药物利用率高,具有良好的生物相容性。而且,通过肿瘤微环境敏感的交联剂交联不仅提高了凝胶的稳定性,而且实现了肿瘤微环境响应释放药物,所以在包载可调节肿瘤微环境的药物后,可对肿瘤微环境进行调控和改善,协同增强聚合物前药的作用,在肿瘤治疗方面具有较大的应用前景。
有益效果:与现有技术相比,本发明具有以下优点:
1.本发明公开的肿瘤微环境响应型聚合物前药共递送凝胶系统载药量高、体内循环稳定,药物利用率高,并且生物相容性好,副作用小。
2.本发明公开的凝胶系统,不仅可以共价偶联化疗药物,还可以通过疏水作用装载可调节肿瘤微环境的药物,极大改善了纳米载体对药物的包封效果。
3.本发明公开的凝胶系统克服了现有技术中药物在体内易被泄漏、运载效率低的缺陷;并且该系统具有肿瘤微环境敏感性和酸敏感性,可在肿瘤微环境中和肿瘤细胞酸性环境中依次断裂,逐级定点的释放两种药物,将药物有效递送至目标组织,减小了药物的全身毒副作用,并改善了不同药物的协同作用。
4.本发明公开的凝胶系统制备简单,结构明确,具有良好的生物相容性,代谢产物对人体无害,并且能分别在肿瘤微环境中和肿瘤细胞酸性环境中依次断裂,将药物释放出来,从而产生协同治疗作用,在药物控制释放领域具有巨大的应用前景。
附图说明
图1为实施例1中羟基喜树碱-乙烯基醚丙烯酸酯-(巯基)-聚乙二醇复合物[HCPT-VEA-(SH)-PEG]的氢核磁图谱;
图2为实施例2中MMP-9敏感的多肽(上)和MMP-9敏感的多肽与HCPT-VEA-(SH)-PEG交联反应后(下)的氢核磁图谱;
图3为实施例3中聚合物前药凝胶交联前后及交联并包载TGF-β抑制剂SB525334后的粒径图;
图4为实施例4中交联型聚合物前药凝胶系统在不同条件下(pH 7.4;pH 7.4+MMP-9酶;pH 5.0+MMP-9酶)的粒径图;
图5为实施例5中载有TGF-β抑制剂SB525334的聚合物前药共递送凝胶药物系统对4T1细胞的细胞毒性。
具体实施方式
实施例1巯基化酸响应型聚合物前药的制备
将1,6-己二硫醇(22μL,0.143mmol)溶于N,N-二甲基甲酰胺(DMF)中,在氮气保护下逐滴加入羟基喜树碱-乙烯基醚丙烯酸酯-聚乙二醇复合物(100mg,0.0357mmol)的DMF溶液,再加入三乙胺(TEA),于室温搅拌反应过夜。反应结束后,反应液用冰乙醚沉淀,产率:93.24%。氢核磁图谱如图1所示。
实施例2微环境响应型聚合物前药的组装及交联
将聚合物前药(1.0mg,0.357μmol)溶于无水乙醇中,将溶液于超声条件下缓慢滴加于高纯水中,所得溶液继续超声,然后在高纯水中透析,得到酸响应型聚合物前药胶束。将聚合物前药(1.0mg,0.357μmol)溶于无水乙醇中,于氮气保护下与MMP-9敏感的多肽的乙醇溶液(0.208mg,0.214μmol)混合,再加入三乙胺,于室温下搅拌反应4h,将反应液于超声条件下缓慢滴加到高纯水中,所得溶液继续超声,然后在高纯水中透析,得到交联型肿瘤微环境响应型聚合物前药凝胶。
图2是MMP-9敏感的多肽(上)和其与HCPT-VEA-PEG-SH交联反应后(下)的氢核磁图谱。结果表明,交联反应后,MMP-9敏感的多肽中的双键消失,表明交联反应进行完全。
实施例3TGF-β抑制剂的包载
将2μl TGF-β抑制剂的乙醇溶液(5mg/mL)加入至2mL微环境响应型聚合物前药凝胶水溶液(0.5mg/mL)中,交替进行涡旋混合和超声各三次,完成载药。图3是聚合物前药凝胶交联前后及交联并包载TGF-β抑制剂SB525334后的粒径图。材料交联前的平均粒径为142nm,粒径分布为0.18;交联后的平均粒径为168nm,粒径分布为0.23;载入TGF-β抑制剂后的平均粒径变化不大,为165nm,粒径分布为0.24。
实施例4含酶条件及酸性条件使交联型聚合物前药凝胶系统解交联及释放
准备交联型聚合物前药凝胶系统溶液(0.5mg/mL),分别加入到3个EP管中,向其中一个EP管中加入pH5.0醋酸缓冲液及MMP-9酶溶液,使pH 5.0醋酸缓冲液终浓度为5mM,MMP-9酶的终浓度为1μg/mL;一个EP管中加入pH 7.4磷酸盐缓冲溶液及MMP-9酶溶液,使pH 7.4磷酸盐缓冲溶液终浓度为5mM,MMP-9酶的终浓度为1μg/mL;一个EP管中加入pH 7.4磷酸盐缓冲溶液,使其终浓度为5mM,将其用封口膜封口,摇晃均匀,置于37℃恒温摇床中(200rpm),在24h时,通过动态激光光散射(DLS)来测定颗粒的粒径变化。图4为交联型聚合物前药凝胶系统在不同条件下作用24h后的粒径图,结果表明,在pH 7.4及MMP-9酶条件下作用24小时的凝胶粒径相较于在pH 7.4但无酶条件下的凝胶而言,粒径变得不均一,且出现大粒径的粒子,而在pH 5.0酸性环境中及MMP-9酶条件下作用24h的凝胶已全部为大粒径粒子。
实施例5载有TGF-β抑制剂聚合物前药共递送凝胶药物系统对4T1细胞的细胞毒性测试(MTT)
载有TGF-β抑制剂聚合物前药共递送凝胶药物系统在4T1细胞中的毒性通过MTT法测定。首先将100μL含有4T1细胞的DMEM悬浮液(DMEM培养基中含10%胎牛血清、100IU/mL青霉素和100μg/mL链霉素)均匀铺于96孔培养板中,并置于37℃,5%二氧化碳条件下培养过夜使单层细胞的覆盖率达到50~60%。然后向每孔中加入10μL不同浓度的自由羟基喜树碱,TGF-β抑制剂以及未交联的聚合物前药凝胶溶液,未加酶和加酶的载有TGF-β抑制剂的交联型聚合物前药共递送凝胶溶液,使羟基喜树碱在细胞孔中的最终浓度为1、5、25、50μg/mL,TGF-β抑制剂在细胞孔中的最终浓度为0.1、0.5、2.5、5μg/mL,MMP-9浓度为10nmol/L。待继续培养48h后,向每孔中加入10μL3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(MTT)的PBS溶液(5mg/mL),并放入培养箱继续培养4h以使MTT与活细胞作用。随后移除含有MTT的培养液,向每孔中加入150μL DMSO以溶解活细胞与MTT产生的紫色甲瓒结晶,并使用酶标仪(SpectraMax i3x)测定每个孔在490nm处的吸收。细胞相对存活率通过与只有空白细胞的对照孔在490nm处的吸收相比得到。实验数据均是平行三组进行的。
细胞存活率(%)=(OD490样品/OD490对照)×100%
图5为聚合物前药共递送凝胶药物系统对4T1细胞的细胞毒性结果图。结果表明:未载药的聚合物前药凝胶系统随着浓度升高其细胞毒性也随之增强,说明该聚合物前药本身可以在胞内的酸性环境释放出羟基喜树碱从而一定程度上抑制小鼠乳腺癌4T1细胞的生长;载药的交联型聚合物前药共递送凝胶药物系统的细胞毒性强于未载药的聚合物前药凝胶系统,说明聚合物前药共递送凝胶药物系统可通过细胞本身分泌的MMP-9酶及酸性环境作用下释放出TGF-β抑制剂和羟基喜树碱,协同作用抑制4T1细胞的生长,且在加入MMP-9后,细胞毒性明显增加,说明聚合物前药共递送凝胶药物系统可通过MMP-9酶响应更快且更多地释放出TGF-β抑制剂,从而增强了细胞毒性。
Claims (10)
1.一种微环境响应型聚合物前药共递送凝胶系统的制备方法,其特征在于:先通过迈克尔加成反应由双巯基或多巯基小分子对酸响应型聚合物前药中的双键进行巯基化修饰,再通过迈克尔加成反应由两端连有双键的肿瘤微环境响应型交联剂交联,最后通过溶剂交换法制备纳米凝胶并载入可调节肿瘤微环境的药物即可。
2.根据权利要求1所述的微环境响应型聚合物前药共递送凝胶系统的制备方法,其特征在于:所述酸响应型聚合物前药由包含丙烯双键单元的乙烯基醚丙烯酸酯及其衍生物与含羟基化疗药物通过酸响应型缩醛键连接,形成药物-小分子复合物,然后再通过迈克尔加成反应与巯基化PEG或带其他配体的巯基化PEG连接,即得。
3.根据权利要求2所述的酸响应型聚合物前药,其特征在于:所述包含丙烯双键单元的乙烯基醚丙烯酸酯及其衍生物选自乙烯基乙醚丙烯酸酯(VEA)或乙烯基乙醚甲基丙烯酸酯(VEMA)。
4.根据权利要求2所述的酸响应型聚合物前药,其特征在于:所述含羟基化疗药物选自紫杉醇、多西紫杉醇、羟基喜树碱或雌二醇;所述聚乙二醇PEG分子量为0.5~20kDa;所述带其他配体的巯基化PEG包括NH2-PEG-SH、MAL-PEG-SH、NHS-PEG-SH或COOH-PEG-SH。
7.根据权利要求1所述的微环境响应型聚合物前药共递送凝胶系统的制备方法,其特征在于:所述调节肿瘤微环境的药物选自TGF-β抑制剂、吡非尼酮(PFD)、洛沙坦(Losartan)、松弛肽(Relaxin)、菠萝蛋白酶(Bromelain)、肿瘤坏死因子-α(TNF-a)和衍生品、血小板衍生的生长因子(PDGF)拮抗剂、血管内皮生长因子(VEGF)受体抑制剂或多激酶抑制剂索拉菲尼(Sorafenib)。
8.权利要求1-7任一项所述的微环境响应型聚合物前药制成的纳米粒子。
9.权利要求1-7任一项制备得到的微环境响应型聚合物前药共递送凝胶系统作为药物载体的应用。
10.权利要求1-7任一项制备得到的微环境响应型聚合物前药共递送凝胶系统在制备抗肿瘤药物中的应用。
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