CN114377142A - 一种以pH响应和逐级靶向实现深层递送的ROS响应型前药 - Google Patents
一种以pH响应和逐级靶向实现深层递送的ROS响应型前药 Download PDFInfo
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- CN114377142A CN114377142A CN202111472081.1A CN202111472081A CN114377142A CN 114377142 A CN114377142 A CN 114377142A CN 202111472081 A CN202111472081 A CN 202111472081A CN 114377142 A CN114377142 A CN 114377142A
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Abstract
本发明涉及一种以pH响应和逐级靶向实现深层递送的ROS响应型前药。本发明涉及该前药的制备方法:①以对苯二甲醛与N‑苄氧羰基‑1,2‑二氨基乙烷反应,制备化合物(A),(A)在钯碳氢气条件下反应制备(B);②将二甲基二硫代丙酸基甲烷和二氯亚砜反应制备(C),(C)与喜树碱反应制备(D),(D)与乙二胺反应制备(E);③以单端马来酰亚胺功能化的聚乙二醇和4‑硝基苯基氯甲酸酯反应制备(F),(F)与(B)反应制备(G),(G)引发N6‑苄氧羰基‑L‑赖氨酸环内酸酐开环聚合制备(H),往(H)中依次加入对氨基苯磺酰胺、(E)反应制备聚合物前药(I)。本发明还公开了该聚合物前药制备纳米药物的方法。
Description
技术领域
本发明涉及一种聚合物前药,尤其涉及一种用于提高实体瘤肿瘤渗透和治疗效果的聚合物前药,本发明还涉及由该聚合物前药获得的纳米药物及其制备方法。
背景技术
实体瘤占人类肿瘤的85%以上,手术切除、化疗、放疗等治疗方式效果有限。静脉注射的的纳米药物能富集到肿瘤部位的纳米药物大约只有注射剂量的0.7%[NatureReviews Materials:2016,1(5):16014.],并且大多数纳米粒子只能扩散到离肿瘤血管一个或两个细胞层的距离,只能到达实体瘤的表层细胞,难以到达远离血管的低氧肿瘤区[ACS Nano:2018, 12(8):8423-8435.]。肿瘤处亚致死浓度的药物刺激诱发癌细胞的耐药性,导致化疗抗性、肿瘤复发和最终死亡[Nature Communications:2017,8,15884;ActaBiomaterialia:2018,71,351- 362.]。肿瘤渗透性能差是纳米粒子肿瘤富集少的关键原因,构建具有肿瘤深层渗透性能的纳米药物可以有效提高纳米粒子的肿瘤富集[AdvancedMaterials:2020,32(16):e1906745.]。因此,提高纳米药物的肿瘤富集和渗透性能是降低化疗药物耐药性和提高实体瘤治疗效果的重要方法。
近来一项研究表明大多数纳米粒子(达97%)是以主动转胞吞的方式跨越内皮细胞进入肿瘤,而不是靠EPR进入肿瘤[Nature Materials:2020,19(5):481-482.]。这种能量相关的主动传输可以克服纳米粒子的瘤内传输障碍(异质的肿瘤血管、升高的间隙液压力、浓密的细胞外基质等),促进纳米粒子的肿瘤渗透。细胞的转胞吞作用通常由肿瘤渗透肽(CRGDK, iRGD等)或电荷吸附介导的快速内吞启动,依靠小窝蛋白相关的内吞和外泌作用实现跨细胞传输[Biomaterials:2020,240,119902.]。肿瘤渗透肽通过靶向肿瘤表面特异性高表达的神经纤毛蛋白-1(NRP-1)受体启动转胞吞作用,提高纳米粒子的肿瘤富集和渗透。此外,肿瘤组织浓密的细胞外间质会阻碍纳米粒子在瘤内的扩散传输,降低纳米粒子的尺寸是提高纳米粒子瘤内扩散传输的重要方法。低氧的肿瘤微环境会抑制癌细胞小窝蛋白依赖性途径的内吞作用[Nature Communications:2016,7,11371.],进而抑制纳米粒子进入低氧癌细胞和在低氧肿瘤区的转胞吞渗透。碳酸酐酶IX(CAIX)是低氧肿瘤的标记物,专一性地在实体瘤低氧区癌细胞膜外过量表达。近来发现CAIX是低氧癌细胞膜上具有内吞活性的受体,在纳米粒子上修饰CAIX配体,靶向低氧癌细胞膜上的CAIX可以恢复低氧癌细胞小窝蛋白依赖性的内吞作用[Science Advances:2019,5(9):eaax0937],提高纳米粒子在低氧肿瘤区的入胞和渗透。因此,设计合成聚乙二醇-席夫碱-聚赖氨酸共聚物,在共聚物的主链上键合主动靶向癌细胞的NRP-1配体,在侧链上键合靶向低氧癌细胞和促进低氧癌细胞摄取的CAIX配体、以及键合酮缩硫醇共轭的喜树碱,构建一种以逐级靶向和pH响应实现深层递送的ROS响应型聚合物前药。先以NRP-1配体主动靶向肿瘤,起始的转胞吞渗透;进入肿瘤纳米粒子pH响应降解,减小尺寸和开启阳离子介导的转胞吞渗透;渗透到低氧区的纳米粒子靶向低氧癌细胞表面的CAIX促进低氧癌细胞的内吞和转胞吞作用,提高纳米粒子的肿瘤渗透;这种具有肿瘤深层递送性能的前药纳米粒子在转胞吞渗透过程中ROS响应地释放喜树碱杀死肿瘤表层和低氧肿瘤核的癌细胞,从而提高实体瘤的治疗效果。
发明内容
本发明所要解决的第一个技术问题是针对上述的技术现状而提供一种以pH响应和逐级靶向NRP-1/CAIX促进肿瘤深层递送的ROS响应型聚合物前药。
本发明所要解决的第二个技术问题是针对上述的技术现状而提供一种以pH响应和逐级靶向NRP-1/CAIX促进肿瘤深层递送的ROS响应型聚合物前药制备方法。
本发明所要解决的第三个技术问题是提供一种以pH响应和逐级靶向NRP-1/CAIX促进肿瘤深层递送的ROS响应型聚合物前药纳米粒子。
本发明所要解决的第四个技术问题是提供一种以pH响应和逐级靶向NRP-1/CAIX促进肿瘤深层递送的ROS响应型聚合物前药纳米粒子的制备方法。
本发明解决上述第一个技术问题所采用的技术方案为:设计一种一种以pH响应和逐级靶向NRP-1/CAIX促进肿瘤深层递送的聚合物前药,其特征在于该前药的结构式(I)如下:
结构式(I)中的n为43-22;2的整数,m为5-1000的整数。
本发明解决上述第二个技术问题所采用的技术方案为:提供一种以pH响应和逐级靶向 NRP-1/CAIX促进肿瘤深层递送的聚合物前药的制备方法,其特征在于包括小分子化合物的合成和聚合物前药的合成步骤:
(1)①往对苯二甲醛和N-苄氧羰基-1.2-二氨基乙烷中加入溶剂进行回流反应,将反应液后处理得结构式为(A)的产物;②将(A)溶液在钯碳和氢气条件下进行反应,处理反应液得结构式为(B)的产物;所述对苯二甲醛和N-苄氧羰基-1.2-二氨基乙烷的物质的量之比为1∶2~2.4。
(2)①往丙烷-2,2-二基双(硫)基]二乙酸中加入二氯亚砜室温进行反应,将反应液处理得结构式为(C)的产物;②将(C)和喜树碱反应,处理反应液得结构式为(D)的产物;③将(D)与乙二胺反应,处理反应液得结构式为(E)的产物;丙烷-2,2-二基双(硫)基]二乙酸与二氯亚砜的物质的量之比为1∶2~2.4,(C)与喜树碱的物质的量为1∶1~1.2,(E)与乙二胺的物质的量之比为1∶1~1.2。
(3)①往马来酰亚胺基单端功能化的聚乙二醇中加入4-硝基苯基氯甲酸酯进行反应,将反应液后处理得产物(F);②往聚合物(F)加入化合物(B)进行反应,处理反应液得结构式为(G)的产物;③往(G)中加入N6-苄氧羰基-L-赖氨酸环内酸进行反应,处理反应液得聚合物(H);④往聚合物(H)中依次加入对氨基苯磺酰胺、化合物(E)进行反应,处理反应液得聚合物前药(I);所述马来酰亚胺基单端功能化的聚乙二醇和4-硝基苯基氯甲酸酯的物质的量之比为1∶1~2;所述聚合物(F)与化合物(B)的的物质的量之比为 1∶1~1.5;所述聚合物(H)与N6-苄氧羰基-L-赖氨酸环内酸的物质的量之比为1∶ 100~5000;所述聚合物(H)与对氨基苯磺酰胺、化合物(E)的物质的量之比依次为1∶ 20~50∶20~50。
上述步骤涉及的各结构式如下:
上述步骤涉及的反应式如下:
作为优选,步骤(1)中第一步反应所述的溶剂为二氯甲烷、三氯甲烷、乙腈、四氢呋喃、N,N-二甲基甲酰胺,最优选N,N-二甲基甲酰胺;第二步和第三步反应的溶剂为二氯甲烷或三氯甲烷的一种。
作为优选,步骤(1)中各步反应所述溶剂的体积用量以反应物的物质的量计算为1~5 mL/mmol。
作为优选,步骤(1)中第一步和第二步所述反应液处理方式如下:浓缩反应后,柱层析得结构式为(A)和(B)产物。
作为优选,步骤(2)中第一步反应溶剂为二氯甲烷或三氯甲烷;第二步反应溶剂为为无水N,N-二甲基甲酰胺或无水二甲基亚砜的一种;第三步反应的溶剂为无水N,N-二甲基甲酰胺或无水二甲基亚砜的一种;第二步反应的碱为三乙胺、吡啶、N,N-二异丙基乙氨中的至少一种。
作为优选,步骤(2)中各步反应所述溶剂的体积用量以反应物的物质的量计算为1~5 mL/mmol。
作为优选,步骤(2)中第一步所述反应液处理方式如下:蒸馏得结构式为(C)的产物;第二步所述反应液的处理方式为:浓缩后,柱层析得结构式为(D)的产物;第三步所述反应液的处理方式为:浓缩后,柱层析得结构式为(E)的产物。
作为优选,步骤(3)中第一步反应溶剂为无水二氯甲烷或三氯甲烷;第二步反应溶剂为无水二氯甲烷、三氯甲烷或四氢呋喃;第三步反应的溶剂为无水N,N-二甲基甲酰胺或无水二甲基亚砜的一种;第四步反应的溶剂为二氯甲烷、三氯甲烷、四氢呋喃、水N,N-二甲基甲酰胺或无水二甲基亚砜的一种;第一步和第四步反应的碱为三乙胺、吡啶、N,N-二异丙基乙氨中的至少一种。
作为优选,步骤(3)中各步反应所述溶剂体积用量以反应物的物质的量计算为1~5 mL/mmol。
作为优选,步骤(3)中第一步反应的反应液处理方式如下:旋干溶剂后,加入四氢呋喃溶解,过滤除去不溶物,滤液浓缩后,乙醚沉淀数次,收集固体,干燥后得结构式为 (F)的产物;第二步反应液的的后处理方式为:浓缩反应液后,乙醚沉淀数次,收集固体,干燥得结构式为(G)的产物;第三步反应液的后处理方式为:浓缩反应液后,乙醚沉淀数次,收集固体,将固体溶于二甲亚砜后滴加到水中自组装,随后透析冻干得结构式为 (H)的产物;第四步反应的后处理方式如下:浓缩后,滴加到水中搅拌自组装12h,随后透析72h,每6h换一次水,透析完后,离心,滤液冻干得结构式为(I)的产物。
本发明解决上述第三个技术问题所采用的技术方案为:一种以pH响应和逐级靶向NRP-1/CAIX促进肿瘤深层递送的两亲性聚合物前药,其特征在于设计合成聚乙二醇-席夫碱 -聚赖氨酸共聚物,在主链上键合主动靶向癌细胞的NRP-1配体,在侧链上键合靶向低氧癌细胞和促进低氧癌细胞摄取的CAIX配体、以及键合酮缩硫醇共轭的喜树碱。
本发明解决上述第四个技术问题所采用的技术方案为:一种聚合物前药纳米药物的制备方法,其特征在于包括如下步骤:往结构式(I)所示的聚合物中加入二甲基亚砜,超声溶解,缓慢滴加到去离子水或磷酸缓冲盐溶液溶液中,搅拌后转移至透析袋中透析,待透析干净后,离心收集上层清液,将上层清液冻干得逐级靶向促进肿瘤深层渗透的纳米药物。
与现有技术相比,本发明的优点在于:本发明是基于实体瘤外围肿瘤细胞的表面具有高表达的NRP-1、实体瘤内部低氧区癌细胞表面具有特异性高表达的CAIX以及癌细胞内具有高浓度活性氧的特点,构建了一种以逐级靶向肿瘤表面/低氧肿瘤核的ROS响应型聚合物前药纳米粒子。以马来酰亚胺单端功能化的聚乙二醇为亲水性链段,修饰上pH敏感的片段后,再引发NCA的开环反应制备聚乙二醇-聚氨基酸的嵌段共聚物,最后再依次修饰上CAIX配体、酮缩硫醇连接的喜树碱、NRP-1配体制备聚合物前药。纳米粒子通过EPR效应和主动靶向效应富集到肿瘤组织,与肿瘤外围癌细胞表面的神经纤毛蛋白-1受体结合促进纳米粒子入胞和渗透,渗透进入肿瘤组织的纳米粒子pH响应降解去PEG化减小纳米粒子的尺寸,同时质子化启动转胞吞促进纳米粒子的渗透;渗透到低氧区的纳米粒子靶向低氧癌细胞表面具有内吞活性的CAIX受体,实现纳米粒子在低氧肿瘤区的浸润;纳米粒子在转胞吞渗透过程中胞内ROS响应降解释放出喜树碱,从而杀死肿瘤表层和肿瘤核的癌细胞。
这种聚合物前药纳米药物具有体内传输稳定、以逐级靶向和转胞吞的方式实现肿瘤深层渗透、渗透过程中胞内ROS响应降解释放出喜树碱等优点。经实验证明共聚物前药(I) 具有靶向能力、pH/ROS响应降解性能、低的临界胶束浓度,在水中自组装可形成稳定的纳米粒子。
附图说明
图1为实施例3中纳米粒子的扫描电子显微镜照片。
具体实施方式
以下结合附图和实施例对本发明作进一步详细描述。
实施例1(聚合物前药(I))
(一)(1)①取100mL的圆底烧瓶加入30mL N,N-二甲基甲酰胺、3.35g(25mmol) 对二苯甲醛和10.68g(55mmol)N-苄氧羰基-1.2-二氨基乙烷进行回流反应24h。反应结束后用油泵浓缩有机溶剂,柱层析可得产物(A),产率82.5%。②将4.87g(10mmol)化合物(A)溶于30mL二氯甲烷后加入适量的钯碳,通入氢气,室温反应12h。浓缩反应液后,柱层析得产物得产物(B)。
(2)①取5.05g(20mmol)丙烷-2,2-二基双(硫)基]二乙酸中加入到100mL圆底烧瓶,加入30mL二氯甲烷后冷却到0℃,滴加3.48mL(48mmol)二氯亚砜,滴加完后撤去冰浴,室温进行反应12h。反应结束后,通过蒸馏收集产物(C),产率90.4%。②往5.23g (15mmol)喜树碱中加入30毫升N,N-二甲基甲酰胺,搅拌下滴加4.32g(15mmol)化合物(C),室温反应24h。反应结束后,浓缩反应液,柱层析得产物(D),产率86.3%。③往3.00g(5mmol)化合物(D)中加入30mL氯仿,搅拌下加入0.30g(5mmol)乙二胺进行室温反应24h。反应结束后,浓缩反应液,柱层析得产物(E),产率91.4%。
(3)①往100mL带支口的圆底烧瓶中加入8g(4mmol,Mw=2000g/mmol)单端马来酰亚胺功能化的聚乙二醇,于105℃真空除水3h,恢复至室温后加入30mL 4-硝基苯基氯甲酸酯(0.81g,4mmol)的二氯甲烷溶液于45℃氮气保护下反应72h。反应结束后,浓缩反应液,冰乙醚沉淀3次,收集固体,干燥得产物(F),产率90.1%。②将4g聚合物(F) 于105℃真空除水3h,恢复至室温后加入30mL化合物(B)的二氯甲烷溶液,于45℃氮气保护下反应72h。反应结束后,浓缩反应液,冰乙醚沉淀3次,收集固体,干燥得产物 (G),产率91.1%。③将2g(1mmol)聚合物(G)于105℃真空除水3h,加入30mL N6-苄氧羰基-L-赖氨酸环内酸酐(6.13g,20mmol)的二氯甲烷溶液于40℃反应48h。反应结束后,浓缩反应液,冰乙醚沉淀3次,收集固体,干燥得产物(H),产率94.1%。④往 1mmol聚合物(H)中加入30mL N,N-二甲基甲酰胺,随后加入1.72g(10mmol)对氨基苯磺酰胺于60℃反应24h,再加入6.24g(10mmol)化合物(E)于60℃反应24h,最后加入1mmol CRGDK于60℃反应24h。反应结束后,浓缩反应液,冰乙醚沉淀3次,将沉淀物质收集。用少量DMSO溶解后,搅拌下滴加到去离子水中自组装,再转移至透析袋中透析,透析结束后,将透析液冻干得聚合物前药(I),产率76.1%。
实施例2
将10mg嵌段共聚物(I)超声溶于1mL DMSO,搅拌下逐滴地滴加到7mL去离子水中,室温搅拌12h后转移至透析袋透析,待DMSO透析干净后,离心,过滤收集上层清液。定容至10mL后,涡旋混匀,即制备1mg/mL的前药纳米粒子溶液。
实施例3
取1滴制备的前药纳米粒子溶液(1mg/mL)置于硅片上,室温静置挥干后,用扫描电子显微镜观察纳米粒子的微观形貌,结果如附图所示,说明我们制备得到粒径比较均一的球形纳米粒子,粒径在50nm左右。
Claims (9)
2.一种权利要求1所述具有深层递送和响应释放性能聚合物前药的制备方法,其特征在于包括如下步骤:
(1)、①往对苯二甲醛中加入N-苄氧羰基-1,2-二氨基乙烷进行反应,将反应液处理得结构式为(A)的产物,所述对苯二甲醛与N-苄氧羰基-1.2-二氨基乙烷的物质的量之比为1∶2~2.4;②往(A)溶液中加入钯碳通入氢气进行反应,将反应液处理得结构式为(B)的产物,所述钯碳的量为催化量,(A)与氢气的物质的量之比为1∶2~4;
(2)、①往二甲基二硫代丙酸基甲烷的溶液中加入二氯亚砜进行反应,将反应液处理得结构式为(C)产物,所述二甲基二硫代丙酸基甲烷和二氯亚砜的物质的量之比为1∶2~2.4;②往(C)溶液中加入喜树碱进行反应,将反应液处理得结构式为(D)的产物,所述(C)与喜树碱的物质的量之比为1∶1~1.2;③往(D)的溶液中加入乙二胺进行反应,将反应液处理得产物(E),所述化合物(D)与乙二胺的物质的量之比为1∶1~1.2;
(3)①往马来酰亚胺基单端功能化的聚乙二醇中加入4-硝基苯基氯甲酸酯进行反应,将反应液后处理得产物(F),所述马来酰亚胺基单端功能化的聚乙二醇和4-硝基苯基氯甲酸酯的物质的量之比为1∶1~2;②往聚合物(F)中加入(B)进行反应,处理反应液得结构式为(G)的产物,所述聚合物(F)与(B)的的物质的量之比为1∶1~1.5;③往(G)中加入N6-苄氧羰基-L-赖氨酸环内酸酐进行反应,处理反应液得聚合物(H),所述聚合物(H)与N6-苄氧羰基-L-赖氨酸环内酸酐的物质的量之比为1∶100-5000;④往聚合物(H)中依次加入对氨基苯磺酰胺、化合物(E)进行反应,处理反应液得聚合物前药(I),所述聚合物(H)与对氨基苯磺酰胺、化合物(E)的物质的量之比依次为1∶20~50∶20~50;
上述步骤涉及的各结构式如下:
3.根据权利要求2所述的制备方法,其特征在于步骤(1)中第一步和第二步所述反应处理方式为浓缩滤液后,柱层析得结构式(A)、(B)产物。
4.根据权利要求2所述的制备方法,其特征在于步骤(2)第一步所述反应的处理方式为蒸馏得结构式(C)产物;第二步和第三步反应的处理方式为柱层析得结构式(D)、(E)产物。
5.根据权利要求2所述的制备方法,其特征在于步骤(3)中第一步和第二步反应所述反应液处理方式如下:浓缩反应液后,用冰乙醚沉淀数次,收集沉淀干燥后得结构式(F)、(G)所示产物;第三步反应液的后处理方式如下:浓缩反应液后,用冰乙醚沉淀数次,将沉淀干燥后得结构式(H)所示产物;第四步反应液的后处理方式如下:浓缩后用冰乙醚沉淀数次,收集沉淀,将沉淀溶于适量二甲亚砜后,滴加到水中进行自组装,透析除去二甲亚砜后,离心收集上层清液,冻干后得结构式(I)的前药。
6.根据权利要求2所述的制备方法,其特征在于步骤(3)中第一步和第三步反应中所述有机碱为三乙胺、吡啶或N,N-二异丙基乙氨中的至少一种。
7.一种具有权利要求1所述的聚合物前药,其特征在于在聚合物主链上键合主动靶向癌细胞表面的神经纤毛蛋白-1(NRP-1)配体,侧链上键合靶向低氧癌细胞和促进低氧癌细胞摄取的碳酸酐酶IX(CAIX)配体、以及键合酮缩硫醇共轭的喜树碱。
8.一种权利要求1所述聚合物前药制备纳米粒子的方法,其特征在于包括如下步骤:往结构式(I)所示的聚合物中加入二甲基亚砜,超声溶解后,缓慢滴加到去离子水或磷酸缓冲盐溶液溶液中,搅拌后转移至透析袋中透析,待透析干净后,离心,将上层清液冻干得逐级靶向具有深层递送性能的ROS响应型纳米药物。
9.一种权利要求8所述的前药纳米粒子,其特征在于该聚合物前药纳米粒子可以通过NRP-1配体主动靶向富集到肿瘤;渗透进入肿瘤的纳米粒子pH响应去PEG化,降低纳米粒子的尺寸促进纳米粒子的扩散渗透,同时质子化启动转胞吞作用进一步促进纳米粒子的渗透;渗透到肿瘤低氧区的纳米粒子通过靶向低氧区癌细胞表面的CAIX促进纳米粒子在低氧肿瘤的入胞和转胞吞渗透;纳米粒子在转胞吞渗透的过程中可以ROS响应的释放喜树碱杀死癌细胞。
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