CN112999359A - 肿瘤靶向的氧化还原响应前药纳米制剂及其制备方法、应用 - Google Patents
肿瘤靶向的氧化还原响应前药纳米制剂及其制备方法、应用 Download PDFInfo
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- CN112999359A CN112999359A CN202110234978.4A CN202110234978A CN112999359A CN 112999359 A CN112999359 A CN 112999359A CN 202110234978 A CN202110234978 A CN 202110234978A CN 112999359 A CN112999359 A CN 112999359A
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Abstract
本发明属于纳米药物制剂领域,涉及肿瘤靶向的氧化还原响应前药纳米制剂及其制备方法、应用。该制剂可以在体内有效和安全地递送化疗药物。为实现这一目标,首先将疏水性化疗药以氧化还原敏感键连接到聚乙二醇聚合物上,然后在表面修饰胆酸作为靶头。该聚合物可以自组装形成前药纳米粒,药物通过疏水作用包载于载体的疏水核心中。所形成的纳米前药递送系统可避免单核吞噬系统清除并循环到肿瘤部位,再通过主动靶向获得优先的肿瘤积累,并在肿瘤内部实现控释以快速有效的提高癌细胞内化疗药物浓度。
Description
技术领域
本发明属于纳米药物制剂领域,涉及肿瘤靶向的氧化还原响应前药纳米粒制剂及其制备方法、应用。
背景技术
据世卫资料,2020年全球罹患癌症的总人数达到1929万、死亡人数也增加至996万。全球五分之一的人在其一生中都会罹患癌症。国内数据显示,中国每分钟就有7.5人被确诊为癌症。在全球新发癌症病例中,中国以23.7%的占比,成为全球癌症新增人数最多的国家。随着全球人口增长,癌症将会更加常见,预计未来数年内,全球癌症发病人数仍将进一步加剧,2040年的新增患者数量可能将比2020年高出47%。与其他疾病相比,癌症具有发病速度快、易扩散、无固定发病部位等特征,这给癌症的治疗带来很大的困难。临床上常用于癌症的治疗,比如手术治疗,介入治疗、放射治疗、化学治疗、免疫治疗等手段,其中化疗是癌症治疗中较为常用的方式。而化学疗法是一种全身性的药物治疗手段,不可避免地存在着严重的毒副作用。目前临床使用的小分子抗癌药物虽然对癌细胞有较好的杀灭作用,但是由于其缺乏对肿瘤细胞的选择性,且在体内代谢速度快,半衰期较短,容易被排除出体外,血液中的药物浓度在短时间循环后会很快降低到有效治疗浓度以下,因此正常剂量给药无法达到理想的治疗效果。为达到消灭肿瘤的目的,往往采用加大给药剂量,但是这样会造成严重的系统毒性,引起腹泻、皮疹/脱屑、疲劳、手足部皮肤反应、脱发、恶心、瘙痒呕吐等毒副反应。因此,急需开发一种高效低毒的药物释放系统用于癌症的治疗。
靶向给药技术的诞生,为癌症的治疗开辟了新的领域和前景。从肿瘤治疗的发展趋势看,靶向给药为解决化疗药物的非选择性问题提供了巨大的空间,也成为肿瘤治疗领域一个非常重要的发展方向。在开发有效的癌症治疗方法中,纳米药物受到了广泛的关注。纳米基于的靶向药物递送系统可以靶向肿瘤中的恶性细胞,是一种非常有前景的癌症治疗手段。将化疗药物封装到纳米制剂中,可以使药物具有更长的体循环时间,更易于通过肿瘤部位增强的渗透和保留效应增加药物在靶细胞内的积聚。而且配体修饰的纳米制剂可通过识别某些在肿瘤细胞上表达的受体,定向将药物递送至肿瘤部位。然而,目前存在的一些肿瘤靶向制剂也存在一些缺陷,包括载体相关的毒性、载药能力有限,包裹药物的提前泄露等。因此,如何设计一种高效低毒的药物传递系统用于癌症治疗仍然是研究的热点。然而理想的纳米载体应该能够同时执行以下功能:①.逃避吞噬清除;②.靶向到病变部位(主动靶向);③进入靶细胞释放有效负载。目前纳米制剂在实现上述三种功能上,存在不同缺陷或不足,并不尽人意,因此有必要研发新的纳米制剂。
胆酸是两亲性类固醇分子,调节脂溶性维生素,胆固醇和脂质的吸收,同时作为信号分子在调节上皮细胞增殖,基因表达和代谢方面也起着关键作用。研究表明,肝癌,胆管癌以及肠癌上均表达有胆酸转运蛋白,这些转运蛋白可识别胆酸,且与胆酸具有很高的亲和力1,2。此外,胆酸可以通过一系列复杂的机制与几种消化系统(主要是食道,胃,胰,结肠)和消化系统外器官(即前列腺,乳腺)的癌症联系起5。其中细胞内核受体法尼醇X受体(FXR)和跨膜G蛋白偶联受体(TGR5)是最常见的胆酸受体,胆酸及其类似物可通过调节这些胆酸受体位点来参与癌症的调控3,4。例如,FXR是一种胆酸激活的核受体,转录介导胆酸的信号传导活性,在乳腺癌,肠癌和肺癌组织中表达,胆酸配体修饰的药物可与通过调控FXR受体,使肿瘤抑制基因表达增加,用于治疗癌症。其他机制,比如直接氧化应激,促肿瘤DNA损伤,促肿瘤细胞凋亡,促进抑癌基因表达等多种作用都有利于癌症的治疗5。因此,胆酸作为配体的药物递送系统可以被认为是开发癌症靶向药物的有效转运途径。
为实现这一目标,首先将疏水性化疗药以氧化还原敏感键连接到聚乙二醇聚合物上,然后在表面修饰胆酸作为靶头。该聚合物可以自组装形成前药纳米粒,药物通过疏水作用包载于载体的疏水核心中。所形成的纳米前药递送系统可避免单核吞噬系统清除并循环到肿瘤部位,再通过主动靶向获得优先的肿瘤积累,并在肿瘤内部实现控释以快速有效的提高癌细胞内化疗药物浓度。该药物递送系统有望对特定部位的癌细胞进行定点打击,以实现高效精准的化疗药物递送。
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发明内容
本发明基于胆酸与癌症部位的高度亲和力以及肿瘤特异性的氧化还原微环境,本发明旨在构建一种肿瘤靶向的智能响应纳米载体及前药,以实现高效低毒的抗癌药物释放。本发明所构建的递送载体对肿瘤治疗以及其他疾病治疗策略的设计具有一定的指导意义。
技术方案
一种肿瘤靶向的氧化还原响应载体,其特征在所述的载体结构式如式I所示,
其中A为胆酸靶头,X—X为氧化还原敏感键,聚乙二醇分子量为1000-10000。
一种肿瘤靶向的氧化还原响应前药,其特征在于:所述的前药由抗肿瘤药物和聚乙二醇直接通过氧化还原敏感键连接,胆酸结合到聚乙二醇另一端作为靶向配体构成,其结构
式如下式II所示:
其中A为胆酸靶头,X—X为氧化还原敏感键,聚乙二醇分子量为1000-100000,黑色球体为化疗药物。
所述的载体或权利要求2所述的前药,其特征在于:所述的氧化还原敏感键为二硫键、硫醚键、二硒键、硒醚键、硫缩酮键或琥珀酰亚胺-硫醚键。
所述的前药,其特征在于:所述的化疗药物为紫杉醇、顺铂、阿霉素、多西紫杉醇、熊果酸。
所述的载体或权利要求2所述的前药,其特征在于:所述的胆酸为牛黄胆酸、胆酸、甘氨胆酸、去氧胆酸、猪去氧胆酸、熊去氧胆酸、鹅去氧胆酸或石胆酸。
所述的前药的纳米制备方法,其特征在于:所述的前药在水中自组装形成纳米颗粒。
所述的前药制成冻干粉、无菌分装产品、水针注射剂、片剂、散剂、颗粒剂、胶囊剂、凝胶剂或乳剂。
所述的前药在制备治疗肝癌、胆管癌、肠癌、乳腺癌、肺癌药物中的应用。
具体而言:本发明的技术方案如下:
一种具有肿瘤靶向的氧化还原响应前药纳米粒,其特征在于胆酸修饰作为主动靶向配体,同时氧化还原敏感作为肿瘤微环境响应靶向,该载体的化疗药物是共价结合到聚合物载体中的,以聚合物前药形式存在。其特征在于所述前药的结构式如式II。
其中A为胆酸靶头,X—X为氧化还原敏感键,n为聚合度,聚乙二醇分子量为1000-100000肿瘤靶向纳米前药结构通式II
本发明所述的肿瘤靶向的氧化还原响应前药载体制备中,所述的聚乙二醇的分子量为1000-100000,优选为2000-5000。其中化疗药物可以为紫杉醇,顺铂,阿霉素,多西紫杉醇,熊果酸等可用于癌症治疗的疏水性药物。其中涉及到的胆酸可以为甘氨胆酸,牛黄胆酸,熊脱氧胆酸,鹅脱氧胆酸,石胆酸等胆酸及其类似物。根据本发明优选的,将胆酸与聚乙二醇共价连接,所述连接键可以为酯键、酰胺键或者氨基酸作为连接键。化疗药物与聚乙二醇之间的所述的氧化还原敏感键可以为二硫键、硫醚键、二硒键、硒醚键、硫缩酮键和琥珀酰亚胺-硫醚键等。
本发明进一步提供了肿瘤靶向的氧化还原响应前药载体的制备方法,本发明以紫杉醇和阿霉素为例进行说明,具体如下:
胆酸-聚乙二醇-二硫键紫杉醇的制备
(1)二硫键紫杉醇的合成
将二硫代二丙酸和紫杉醇溶于二甲基甲酰胺/二氯甲烷混合溶剂中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和4-二甲氨基吡啶催化反应进行。将该混合物在室温下反应24h后,通过蒸发除去溶剂,加入适量的水以使产物沉淀并洗涤3次。粗产物通过硅胶柱色谱法纯化,干燥,残渣用无水乙醚重结晶得到连接二硫键的紫杉醇即化合物a。
(2)胆酸-聚乙二醇胺的合成
将胆酸和N3-PEG-NH2溶解在二甲基甲酰胺/二氯甲烷混合溶剂中,同时将N-羟基琥珀酰亚胺和1-羟基苯并三唑添加至反应混合物中。将混合物在室温下搅拌24h。反应后,乙醚沉淀,水透析24小时,然后冻干得到化合物b纯品,化合物b溶于四氢呋喃/水的溶剂中,使用三苯基膦还原化合物b的叠氮基团,透析纯化,冻干得到胆酸-聚乙二醇胺即化合物c。
(3)胆酸-聚乙二醇-二硫键紫杉醇的合成
化合物a和化合物c溶解在无水二氯甲烷中,同时将1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑添加至反应混合物中。将该混合物在室温搅拌下反应24小时后,蒸发除去有机溶剂,加入乙醚沉淀,将沉淀过滤,洗涤,干燥,之后用水透析24小时,然后冻干得到胆酸-聚乙二醇-二硫键紫杉醇即化合物d。
牛磺胆酸-聚乙二醇-二硒键阿霉素的制备
(1)二硒键阿霉素的合成
准确称取二硒代二乙酸和阿霉素溶于四氢呋喃中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和4-二甲氨基吡啶催化,同时加入少量三乙胺。将该混合物在室温下反应24h后,旋蒸除去溶剂,残余物溶于乙酸乙酯中,分别用水和碳酸氢钠洗涤,分离有机相。无水硫酸钠干燥后过柱分离,得到二硒键连接的阿霉素即化合物e。
(2)牛磺胆酸-聚乙二醇胺的合成
准确称取牛磺胆酸钠盐和对硝基氯甲酸苯酯溶于四氢呋喃中,然后加入三乙胺(0.1当量),室温下搅拌反应8小时后,萃取纯化得到3位甲酸修饰的牛磺胆酸钠粉末。之后,称取甲酸修饰的牛磺胆酸钠和N3-PEG-NH2溶于二甲基甲酰胺/二氯甲烷混合溶剂中,同时加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑催化反应。室温下搅拌反应24h后,纯化得化合物f纯品。化合物f溶于四氢呋喃/水的溶剂中,使用三苯基膦还原化合物f的叠氮基团,透析纯化,冻干得到牛黄胆酸-聚乙二醇胺即化合物g。
(3)牛磺胆酸-聚乙二醇-二硒键阿霉素的合成
化合物e和化合物g溶解在无水二氯甲烷中,同时将1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑添加至反应混合物中。将该混合物在室温搅拌下反应24小时后,收集产物并纯化得到牛磺胆酸-聚乙二醇-二硒键阿霉素即化合物h。
本发明的第二个目的在于提供上述肿瘤靶向的氧化还原响应前药自组装纳米粒的制备方法以及在药物制剂领域的应用。
本发明所述的肿瘤靶向的氧化还原响应前药纳米粒的制备中,其制备方法可以为直接溶解法,乳化溶剂挥发法,透析法,薄膜分散法等。该前药载体可应用于药物制剂中,所述药物制剂可包括片剂、散剂、颗粒剂、胶囊剂、凝胶剂、乳剂,注射剂,冻干粉针剂等。
本发明进一步提供了肿瘤靶向的氧化还原响应前药纳米粒的制备方法,具体制备步骤如下:
采用直接溶解超声辅助法制备纳米粒,称取冻干后的胆酸-聚乙二醇-二硫键紫杉醇即化合物,加注射用水,于冰浴下使用超声细胞破碎仪超声,自组装形成均匀的纳米粒。
本发明的第三个目的在于提供上述肿瘤靶向的氧化还原响应前药自组装纳米粒用于癌症靶向治疗的应用。
本发明的设计原理是本发明巧妙地通过氧化还原敏感键将化疗药物与不同分子量的聚乙二醇结合,然后在其表面修饰胆酸作为靶向配体,使其在靶向肿瘤部位后,在肿瘤细胞内能够快速释放出抗肿瘤活性物质用于癌症的治疗。其中氧化还原敏感键(二硫键、硫醚键、二硒键、硒醚键、硫缩酮键和琥珀酰亚胺-硫醚键等)将疏水性的化疗药物和聚乙二醇连接,成为纳米粒疏水端。聚乙二醇的另一端与胆酸及胆酸类似物结合,成为纳米粒的亲水端,其粒径可以控制在100-200nm以内。化疗药物以聚合物前药形式存在,上述聚合物在水中自组装形成纳米粒。利用胆酸主动靶向癌细胞和纳米粒的被动靶向肿瘤组织的双重特性,聚合物前药在癌部位聚集,在癌细胞中高浓度谷胱甘肽作用下,打开氧化还原敏感连接键,从而释放化疗药物,达到持续给药的效果。
有益效果
1、本发明制备了一种可以高效靶向癌细胞的载体或前药纳米粒,将疏水性化疗药物和胆酸靶头连接到聚乙二醇(PEG)上,这种多重靶向的前药纳米粒在国内属于首创。在器官水平,该纳米可以通过PEG修饰逃避体内单核吞噬系统的捕获来降低清除,以实现长循环的目的。在组织水平,药物可以通过胆酸配体靶向到肿瘤细胞受体,增加药物在病理部位的累积。在细胞水平,该制剂可以通过氧化还原响应的敏感键有效释放化疗药物发挥治疗作用。因此,这种新型的纳米制剂有望成为癌症治疗的候选药物。
2、本发明制备一种新型的多功能肿瘤靶向的氧化还原响应前药载体,载体制备过程简单,易于操作,且所用材料均为可降解材料,具有较好的生物相容性、低免疫源性;肿瘤靶向的氧化还原响应前药载体可装载疏水性化疗药物,可自组装形成纳米粒,制剂的制备方法简便,粒径均一,稳定性好,可作为难溶性药物递送工具;不论是静注还是口服给药,肿瘤靶向的氧化还原响应前药纳米粒明显改善了化疗药物的药代动力学行为,在大鼠体内的暴露水平和半衰期都有很大程度的提高。该前药纳米粒同时具有主动靶向和被动靶向作用,可显著提高肿瘤组织药物摄取量;氧化还原响应释放进一步提高了该纳米制剂的选择性,可实现化疗药物高效低毒的递送。
3、本发明为具有亲水和亲脂的聚合物,故形成纳米粒无需表面活性剂等助剂,在水中经过简单超声即可形成,无需传统纳米粒制备工艺中所需挤出设备、旋转蒸发等设备等,制备方法更加简单,质量更容易控制,其可以制备为冻干粉,完全可以实现临用前超声即为纳米结构,克服了纳米制剂的长时间保存或运输过程中出现聚集、沉淀现象,为实现纳米粒临床应用的提供可能。
附图说明
图1为肿瘤靶向氧化还原响应紫杉醇前药自组装形成纳米粒的粒径(A)和电镜表征图(B);
图2为肿瘤靶向氧化还原响应紫杉醇前药纳米粒的药物释放曲线;
图3为肿瘤靶向氧化还原响应紫杉醇前药纳米粒在肝癌细胞和三阴性乳腺癌细胞中的细胞毒性结果;
图4为肿瘤靶向氧化还原响应紫杉醇前药纳米粒静注(A)和口服给药后的血药浓度-时间曲线(B);
图5为肿瘤靶向氧化还原响应紫杉醇前药纳米粒静注后的抗癌疗效图;
图6为胆酸-聚乙二醇-二硫键紫杉醇的核磁共振氢谱表征;
图7牛磺胆酸-聚乙二醇-二硒键阿霉素的核磁共振氢谱表征;
图8为胆酸-聚乙二醇-二硫键紫杉醇质谱图;
图9为产物d在pH 1.2、6.8、7.4缓冲液中的稳定性曲线;
图10为产物d在人工胃液(SGF),人工肠液(SIF)以及大鼠血浆中的稳定性曲线;
图11为产物d口服吸收机制的体外研究;
图12为产物d口服肠吸收的体内示踪;
图13为产物d纳米制剂的肝靶向机制研究;
具体实施方式
前体药物也称前药、药物前体、前驱药物等,是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。
下面结合实施例对本发明的技术方案做进一步阐述,但本发明的保护范围不局限于此。
实施例1胆酸-聚乙二醇-二硫键紫杉醇的合成
(1)二硫键紫杉醇的合成
将二硫代二丙酸(2当量)溶于1mL二甲基甲酰胺/二氯甲烷混合溶剂中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和4-二甲氨基吡啶活化。1小时后,将紫杉醇(1当量)溶于3mL干燥的二氯甲烷中,并在搅拌下加入到混合溶液中。将该混合物在室温下反应24h。通过薄层色谱分析确认反应完成。反应后,通过蒸发除去溶剂,加入适量的水以使产物沉淀并洗涤3次。粗产物通过硅胶柱色谱法纯化,干燥,残渣用无水乙醚重结晶得到化合物a,并通过薄层色谱法监测,收率86.3%。
(2)胆酸-聚乙二醇胺的合成
使用二氯甲烷作为溶剂,在室温下用N-羟基琥珀酰亚胺和1-羟基苯并三唑活化胆酸(1.5当量)1小时。然后,将N3-PEG-NH2(1当量)溶解在二氯甲烷中,并逐滴添加至反应混合物中。将混合物在室温下搅拌24h。反应后,乙醚沉淀得到化合物b的粗品,用水透析24小时,然后冻干得到化合物b纯品,收率82.1%。化合物b溶于四氢呋喃/水的溶剂中,使用三苯基膦还原化合物b的叠氮基团,透析纯化,冻干得到化合物c,收率82.7%。
(3)胆酸-聚乙二醇-二硫键紫杉醇的合成
化合物a(1当量)溶解在3mL无水二氯甲烷中,并用1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑进行活化。1小时后,在搅拌下将溶解在二氯甲烷中的化合物c(1当量)滴加到该混合物中。将该混合物在室温搅拌下反应24小时。将反应混合物蒸发除去有机溶剂,加入乙醚沉淀,将沉淀过滤,洗涤,干燥,之后用水透析24小时,然后冻干得到化合物d,收率75.3%。化合物d的核磁表征见图6,质谱见图8。
胆酸-聚乙二醇-二硫键紫杉醇的合成路线
实施例2牛黄胆酸-聚乙二醇-二硒键阿霉素的合成
(1)二硒键阿霉素的合成
准确称取二硒代二乙酸(1.5当量)溶于四氢呋喃中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和4-二甲氨基吡啶活化,同时加入少量三乙胺。反应1小时后,在搅拌下滴加阿霉素(DOX,1当量)到混合溶液中。将该混合物在室温下反应24h。通过薄层色谱分析确认反应完成。反应结束后旋蒸除去溶剂,残余物溶于乙酸乙酯中,分别用水和碳酸氢钠洗涤,分离有机相。无水硫酸钠干燥后过柱分离,得到化合物e,产率77.3%。
(2)牛磺胆酸-聚乙二醇胺的合成
准确称取牛磺胆酸钠盐(1当量)溶于四氢呋喃中,然后加入三乙胺(0.1当量)和对硝基氯甲酸苯酯(1.1当量)。室温下搅拌反应8小时后,反应溶液用无水乙醇萃取,合并有机相,在旋转蒸发仪中蒸发有机溶剂,干燥48小时,多次重结晶后得到3位甲酸修饰的牛磺胆酸钠粉末。之后,称取甲酸修饰的牛磺胆酸钠(1当量)和N3-PEG-NH2(1当量)溶于二甲基甲酰胺/二氯甲烷混合溶剂中,同时加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑催化反应。室温下搅拌反应24h后,乙醚沉淀产物,干燥,用水透析24小时,然后冻干得到化合物f纯品,产率88.4%。化合物f溶于四氢呋喃/水的溶剂中,使用三苯基膦还原化合物f的叠氮基团,透析纯化,冻干得到化合物g,收率91.8%。(3)牛磺胆酸-聚乙二醇-二硒键阿霉素的合成
化合物e(1当量)溶解在3mL无水二氯甲烷中,并用1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑进行活化。1小时后,在搅拌下将溶解在二氯甲烷中的化合物g(1当量)滴加到该混合物中。将该混合物在室温搅拌下反应24小时。将反应混合物蒸发除去有机溶剂,加入乙醚沉淀,将沉淀过滤,洗涤,干燥,之后用水透析24小时,然后冻干得到化合物h,收率80.6%。化合物h的核磁表征见图7。
牛磺胆酸-聚乙二醇-二硒键阿霉素的合成路线
实施例3双重靶向前药纳米粒的制备
制备工艺初步考察
1.直接溶解超声辅助法
称取产物d20mg,加水3mL,室温下搅拌溶解20min,于冰浴下探头超声10min,0.45μm滤膜过滤,即得胶束溶液。
2.乳化溶剂挥发法
称取产物d 20mg,溶于乙醇中,逐滴滴加到3mL水中,剧烈搅拌15min,室温敞口搅拌过夜,0.45μm滤膜过滤,即得胶束溶液。
3.透析法
称取产物d20mg,溶于乙醇中,搅拌5min,将溶液转入到透析袋中,重蒸水透析过夜,即得载药胶束溶液。
所得粒径,PDI,zeta电位表征
综合粒径,PDI,zeta各种因素,最终选择使用制备操作相对简便的直接溶解超声辅助法来制备产物d的纳米制剂。
采用直接溶解超声辅助法制备纳米粒,称取冻干后的胆酸-聚乙二醇-二硫键紫杉醇即化合物d 30mg,加注射用水3mL,室温溶解5min,于冰浴下使用超声细胞破碎仪超声10min(超声功率100W,间歇2s),自组装形成均匀的纳米粒。图1中给出了胆酸-聚乙二醇-二硫键紫杉醇自组装形成纳米的粒径分布图和透射电镜图。如图1所示,自组装形成了直径约为56.18±2.06nm的球形纳米,且呈现较窄的单峰分布,多分散系数0.22±0.013。
实施例4前药纳米粒在氧化还原条件下的体外释放
肿瘤细胞中的谷胱甘肽浓度明显高于循环系统和正常细胞中的谷胱甘肽浓度,形成还原性微环境。为了研究化合物d的控释特性,采用透析法进行体外释放的考察,以pH5.0、含10mM的谷胱甘肽条件模拟肿瘤细胞内环境,以pH 7.4、含10μM谷胱甘肽条件模拟生理环境。体外释放满足漏槽条件,取0.5mL胆酸-聚乙二醇-二硫键紫杉醇纳米溶液置于截留分子量为3500Da的透析袋中,之后将透析袋浸没于预温的50mLPBS缓冲液中(pH 7.4,含0.5%(w/w)的吐温80)。整个体系在100rpm振速和37±0.5℃的条件下进行体外释放实验。按预设的时间间隔取出1mL释放介质,并补充1mL新鲜的同种介质溶液,测定释放液中紫杉醇含量。计算紫杉醇的累积释放百分比,并绘制体外释放曲线。如图2所示,当谷胱甘肽浓度为10mM时,化合物d释放了92%的紫杉醇,而低谷胱甘肽浓度时,化合物d只释放了11%的紫杉醇。这些结果表明,化合物d前药纳米粒在肿瘤细胞高还原条件下可转化为活性的紫杉醇,对紫杉醇的化疗疗效产生积极影响。化合物d前药纳米粒在pH为5.0,谷胱甘肽浓度为10mM的条件下释放更快,这说明该纳米在肿瘤特异性的氧化还原微环境中可智能响应释放有效负载,因此在到达肿瘤组织后可短时间内大量释放紫杉醇,发挥治疗作用。
实施例5前药纳米粒细胞毒性研究
按照每孔5×103个细胞的密度接种HepG 2或MDA-MB 231细胞于96孔板上,200μL/孔。将培养板转入恒温CO2培养箱中,在37℃,5%CO2及饱和湿度条件下培养24h。显微镜下观察细胞完全贴壁且细胞形态良好则可进行试验。弃去细胞悬液,实验组每孔加入不同浓度的药液200μL,每种药设一系列浓度梯度(n=6)。空白组和对照组加入不含药的培养液200μL。置于孵箱中培养48h后,弃去含药培养液,PBS清洗2次后,每孔加入200μL含0.5mg/mL MTT的培养液。于孵箱培养4h后,弃去MTT培养液,每孔加入150μL的DMSO,于酶标仪上振动3min,490nm波长测定各孔吸光度A。如图3所示,和化合物d的纳米制剂处理的肝HepG 2细胞和三阴性乳腺癌细胞MDA-MB 231在孵育48h后均表现出剂量依赖性的细胞毒性,且随浓度的增加逐渐增强。与紫杉醇的市售制剂相比,同等浓度下,化合物d自组装形成的纳米制剂对两种癌细胞均具有更强的细胞毒性作用,可以有效杀死肿瘤细胞。增强的细胞抗癌活性可能是胆酸配体介导的主动靶向和纳米制剂改善的内吞共同作用的结果。
实施例6前药纳米粒口服及静注的药代动力学研究
取SD大鼠20只,给予大鼠标准饮食和水以使其适应一周。在施用制剂之前将动物禁食12小时,并且在给药后10小时重新引入食物。实验前,将大鼠按体重随机分成4组,每组5只。并分别以20mg/kg紫杉醇剂量口服和产物d。以10mg/kg的剂量向大鼠静脉内注射和产物d。于给药前30min和给药后0.033,0.083,0.167,0.5,0.75,1,2,4,8,12,24,48h眼底静脉丛取血约200μL至肝素化离心管中,8000rpm离心5min,分离出血浆,-70℃超低温冰箱保存待测。紫杉醇制剂静脉注射(10mg/kg紫杉醇)和口服(相当于20mg/kg紫杉醇)后血浆浓度曲线如图4A和图4B所示。口服和静注给药后,产物d的纳米制剂在各时间点的血药浓度均高于非房室药代动力学分析表明,静注后,和产物d的曲线下面积(AUC0-t)分别为6.35μg/mL*h和187.43μg/mL*h,与组相比,静注后,产物d纳米制剂的AUC升高约29倍。与此同时,和产物d纳米制剂在体内的平均停留时间分别为3.91h和9.25h明显提升的循环时间可能是纳米制剂的形成,避免了紫杉醇在体内的过早降解。口服后,和产物d的AUC0-t分别为1086.96±293.66ng/mL*h、10506.84±1556.11ng/mL*h。与组相比,产物d纳米制剂的AUC升高约10倍,同时,产物d纳米制剂的血药浓度峰值(Cmax)635.47±28.01ng/mL,比高5.3倍(118.68±13.91ng/mL)。值得注意的是,与相比(7.65±0.876h),产物d纳米制剂在体内的平均停留时间显著延长至14.06±1.61h。这些药代动力学结果表明,口服和静注产物d的纳米制剂均能增加全身暴露、延长循环时间,因此,可以延长药物暴露于癌细胞的时间,有利于药效的提升。
实施例7前药纳米粒静注后的抗癌疗效研究
选取健康的5-6周龄,体重在18-22g ICR小鼠,将荧光素酶标记的肝癌细胞Hepa1-6-Luc细胞悬液接种于小鼠的肝脏表面,肿瘤生长3周后,将荷瘤小鼠随机分为3组(n=6),分别静注给予生理盐水,和产物d的纳米制剂,给药剂量为10mg/kg紫杉醇。每3天给药1次,共给药5次。实验结束后,采用IVISTMSpectrum In vivo Imaging获取生物发光图像,观察肿瘤抑制情况。如图5所示,动物体内化学发光的情况与肿瘤大小相关联。与生理盐水组相比,和产物d的纳米制剂均能够很好的抑制肿瘤生长。与紫杉醇的市售制剂相比,同等剂量下,化合物d自组装形成的纳米制剂抑制肝癌的效果更为明显。
实施例8稳定性研究
使用pH 7.4(模拟血液环境),6.8(模拟近端小肠)和1.2(模拟胃液)的磷酸盐缓冲溶液(PBS)评估产物d的化学稳定性。同时使用含胃蛋白酶的人工模拟胃液(SGF)和含有胰酶的人工模拟肠液(SIF)和血浆测试了前药的酶稳定性。为了研究稳定性,将1mL产物d与20mL介质混合,并在37℃下孵育。在预定时间,收集100μL样品,通过HPLC对产物d进行定量分析,得到产物d随时间变化的稳定性曲线。
如图9所示,在pH 1.2、6.8、7.4缓冲液中孵育24h后,产物d转化为PTX的量均低于20%,表明产物d能够抵抗胃内的酸性环境。此外,在SGF中孵育2h后,产物d的残留量高于90%,在SIF中孵育12h后,产物d剩余量仍高于77%(图10)。考虑到药物在胃肠道中的保留时间,产物d在胃肠道中具有足够的稳定性来避免过早的降解,因而可以降低口服化疗对胃肠道的额外毒性。产物d在大鼠血浆中的半衰期约为18.7h,该结果表明,大多数产物d前药能在血液循环中保持结构完整性。
实施例9跨Caco-2细胞单层的渗透性实验及吸收机制研究
将Caco-2细胞以1.0×105细胞/孔的密度接种在(0.4μm孔径,面积1.12cm2)小室上,并培养21天,直到获得恒定的跨膜电阻(TEER>500Ω·cm2)。培养21天后,首先用Hanks平衡盐溶液(HBSS)于37℃平衡细胞单层膜。为研究它们在Caco-2细胞单层上的转运效率,将400μL和产物d(相当于50μg/mL PTX)分别添加至顶侧(AP侧),基底侧(BL)加入1mL空白HBSS作为接收室。在30、60、120min从接收室中取出样品100μL,并补充100μL新鲜HBSS。为研究产物d的肠运输机制,使用牛磺胆酸钠(ST)作为顶端钠依赖性胆盐转运体(ASBT)抑制剂来竞争性抑制前药纳米粒的转运。ST预先添加到AP一侧孵育30min,然后加入产物d的纳米制剂孵育一定时间,不含ASBT抑制剂的组别作为对照。收集样品,HPLC测定样品中PTX和产物d的含量。
Caco-2细胞单层用作评估CPP肠通透性的模型。如图11所示,对于吸收性转运(AP→BL),产物d转运量比提高了约4倍,这可能有助于紫杉醇整体口服生物利用度的提高。当ASBT抑制剂ST与Caco-2细胞共培养时,在紫杉醇制剂组中没有观察到明显的转运量变化。然而,ST预先孵育后,导致产物d制剂组的吸收转运显著降低(p<0.01),ASBT抑制剂可竞争性抑制产物d制剂的转运,表明由ASBT介导的主动转运是产物d制剂口服吸收增加的一个原因。
实施例10产物d纳米制剂的肠吸收研究
使用香豆素6(C6)标记的产物d研究其肠运输。简而言之,将游离的C6,C6标记的C6标记的产物d分别以1mg/kg(相当于香豆素6)的剂量口服给予大鼠。4h后,处死大鼠并分离选择的回肠段。将组织切片与4%多聚甲醛在室温下孵育30min,然后用冷PBS洗涤3次。然后,将样品切片并用DAPI染色20min。最后,通过倒置荧光显微镜(日本Nikon Ts2R)观察盖玻片,可视化产物d纳米制剂在回肠中的吸收情况。口服游离C6,C6-产物d4h后,所有测试制剂在回肠中的生物分布如图12所示。蓝色荧光为细胞核,绿色荧光称为药物标记。口服C6-产物d后回肠中观察到亮绿色荧光,而游离C6则显示微弱的荧光,C6-产物d发出的荧光强度明显强于游离C6发出的荧光强度。从而得出结论,ASBT配体修饰有助于提高药物在肠道中的积累和吸收。
实施例11产物d纳米制剂的肝靶向机制研究
Claims (8)
3.如权利要求1所述的载体或权利要求2所述的前药,其特征在于:所述的氧化还原敏感键为二硫键、硫醚键、二硒键、硒醚键、硫缩酮键或琥珀酰亚胺-硫醚键。
4.如权利要求3所述的前药,其特征在于:所述的化疗药物为紫杉醇、顺铂、阿霉素、多西紫杉醇、熊果酸。
5.如权利要求1所述的载体或权利要求2所述的前药,其特征在于:所述的胆酸为牛黄胆酸、胆酸、甘氨胆酸、去氧胆酸、猪去氧胆酸、熊去氧胆酸、鹅去氧胆酸或石胆酸。
6.一种如权利要求2-5任意一项所述的前药的纳米制备方法,其特征在于:所述的前药在水中自组装形成纳米颗粒。
7.如权利要求2-5任意一项所述的前药制成冻干粉、无菌分装产品、水针注射剂、片剂、散剂、颗粒剂、胶囊剂、凝胶剂或乳剂。
8.如权利要求2-5任意所述的前药在制备治疗肝癌、胆管癌、肠癌、乳腺癌、肺癌药物中的应用。
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CN116199799A (zh) * | 2022-12-08 | 2023-06-02 | 安徽工业大学 | 光交联gsh/ros响应靶向的壳聚糖基药物载体及制备方法和应用 |
CN116199799B (zh) * | 2022-12-08 | 2024-06-04 | 安徽工业大学 | 光交联gsh/ros响应靶向的壳聚糖基药物载体及制备方法和应用 |
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