CN108586551B - IR780-LA/CPT-ss-CPT纳米粒的制备与应用 - Google Patents
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Abstract
本发明公开了一种IR‑780衍生物IR780‑LA的合成及GSH敏感的主动靶向小分子IR780‑LA/CPT‑ss‑CPT纳米粒的制备方法和应用。本发明选取亲水性肝癌细胞靶向分子乳糖酸,与疏水性有机近红外光热分子IR‑780共价结合,合成一种IR‑780衍生物IR‑780‑LA,IR780‑LA分子不仅解决了IR‑780疏水性强,不宜生物应用的缺点,还可以与CPT‑ss‑CPT通过薄膜‑超声法形成联合光热治疗与化疗的小分子自组装纳米粒。这种多功能的纳米药物体系在肿瘤的荧光成像及联合光热治疗和化疗方面有十分广阔的应用前景。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种IR780-LA/CPT-ss-CPT纳米粒的制备与应用。
背景技术
恶性肿瘤严重影响人类生命健康,每年造成数百万人死亡。化疗是目前临床上肿瘤治疗中使用最广泛的方法之一。然而,对肿瘤部位的有限递送效率不仅降低了化疗药物的治疗功效,而且增加了药物的全身毒性。光热治疗是20世纪80年代提出的一种新兴的高选择性和微创性的肿瘤治疗辅助技术,为了进一步提高肿瘤的治疗效果,联合化疗与光热治疗成为研究的热点。但传统化疗药物及光热治疗剂普遍水溶性差,靶向性差,毒副作用大,给患者带来了极大的痛苦。自EPR(Enhanced Permeability and Retention)效应被发现以来,人们意识到纳米药物载体可提高药物的水溶性,并且由于其具有合适的纳米尺寸而能够以较高的比例从肿瘤血管渗透出来,从而使载体中的药物进入到肿瘤组织,提高药物疗效,减少毒副作用。因此为克服传统化疗药物及光热治疗剂的缺点,纳米药物递送系统被广泛研究。其中两亲性小分子前药由于具有结构简单,载药量高,易形成丰富的纳米结构等优点受到了科研工作者的广泛关注。
CPT是一种疏水性抗肿瘤药物,作用于DNA拓扑异构酶I,是一种广谱的抗肿瘤药物,用于治疗胃癌,结肠癌,白血病及非小细胞肺癌等。但它水溶性极低,且具有严重的毒副作用,分子内酯环在生理条件下易开环失活。文献表明,对CPT分子羟基进行修饰,可以有效的抑制CPT分子的开环失活。IR-780是一种疏水性的近红外光热分子,光稳定性强,量子产率高,可用于体内外荧光成像和光热治疗;然而,其在所有药用溶剂中的难溶性限制了其进一步的生物应用。
发明内容
为了解决上述问题,本发明选择了疏水性的化疗药物喜树碱(CPT)以及颇具应用前景的疏水性有机近红外光热分子IR-780作为模型药物分子,构筑氧化还原敏感的主动靶向小分子IR780-LA/CPT-ss-CPT纳米药物运输体系。
为实现上述目的,本发明采用以下技术方案:
本发明目的之一,提供一种IR-780衍生物IR780-LA,由IR-780与乳糖酸连接形成两亲性分子IR780-LA,其结构式如下所示:
本发明目的之二,提供一种IR-780衍生物IR780-LA的制备方法,包括以下步骤:
(1)乳糖酸与乙二胺以酰胺键结合形成LA-NH2;
(2)IR-780与LA-NH2催化反应形成IR-780衍生物IR780-LA。
本发明目的之三,提供一种自组装纳米药物体系IR780-LA/CPT-ss-CPT,由上述IR780-LA与CPT-ss-CPT结合形成;所述CPT-ss-CPT谷胱甘肽的二硫键连接两个喜树碱分子形成。
本发明目的之四,提供一种所述自组装纳米体系IR780-LA/CPT-ss-CPT的制备方法,将IR780-LA与CPT-ss-CPT分别溶于甲醇后,进行混合,混合均匀后减压旋蒸形成薄膜,然后加入水,在超声条件下形成纳米粒。
本发明目的之五,提供所述自组装纳米药物体系IR780-LA/CPT-ss-CPT在制备用于肿瘤的荧光成像及光热治疗和/或化疗试剂中的应用。
本发明取得了以下有益效果:
(1)本发明首次合成IR-780衍生物IR780-LA,IR780-LA分子解决了IR-780疏水性强,不宜生物应用的缺点;
(2)本发明制备得到的自组装纳米药物体系IR780-LA/CPT-ss-CPT,稳定性良好,易于保存,可用于肿瘤的荧光成像及光热治疗和化疗;并且该自组装纳米药物体系IR780-LA/CPT-ss-CPT可通过简单快速的方法制备获得,易于批量生产。
附图说明
图1IR780-LA的核磁图谱;
图2IR780-LA/CPT-ss-CPT纳米粒的TEM图。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、部件和/或它们的组合。
正如背景技术所述IR-780的难溶性,限制了IR-780的应用。为了解决这个问题,本发明提供了一种IR-780衍生物IR780-LA,由IR-780与乳糖酸连接形成两亲性分子IR780-LA,其结构式如下所示:
本发明目的之二,提供一种IR-780衍生物IR780-LA的制备方法,包括以下步骤:
(1)乳糖酸与乙二胺以酰胺键结合形成LA-NH2;
(2)IR-780与LA-NH2催化反应形成IR-780衍生物IR780-LA。
优选的,所述步骤(2)IR-780与LA-NH2催化反应过程为:LA-NH2,在加入三乙胺条件下,与IR-780反应,生成上述IR-780衍生物IR780-LA。
优选的,所述步骤(2)IR-780与LA-NH2催化反应具体反应步骤为:
S1.将LA-NH2与IR-780溶于无水N,N-二甲基甲酰胺(DMF)中,加入三乙胺,氮气保护、85℃条件下反应4h;
S2.减压旋蒸除去反应溶剂无水DMF,真空干燥,得到粗产物;将粗产物溶于甲醇中,硅胶柱色谱提纯,用二氯甲烷和甲醇梯度洗脱,即得。
优选的,所述步骤S1中所述LA-NH2:三乙胺:IR-780摩尔比为3-5:3-5:1-2。
优选的,所述步骤S1中所述LA-NH2:三乙胺:IR-780摩尔比为2:1:1。
本发明目的之三,提供一种自组装纳米药物体系IR780-LA/CPT-ss-CPT,由上述IR780-LA与CPT-ss-CPT结合形成;所述CPT-ss-CPT谷胱甘肽的二硫键连接两个喜树碱分子形成。
本发明目的之四,提供一种所述自组装纳米体系IR780-LA/CPT-ss-CPT的制备方法,将IR780-LA与CPT-ss-CPT分别溶于甲醇后,进行混合,混合均匀后减压旋蒸形成薄膜,然后加入水,在超声条件下形成纳米粒。
优选的,IR780-LA与CPT-ss-CPT摩尔比为1:1。
本发明目的之五,提供所述自组装纳米药物体系IR780-LA/CPT-ss-CPT在制备用于肿瘤的荧光成像及光热治疗和/或化疗试剂中的应用。
结合具体实例对本发明作进一步的说明,以下实例仅是为了解释本发明,并不对其内容进行限定。如果实例中未注明的实验具体条件,通常按照常规条件,或按照试剂公司所推荐的条件;下述实施例中所用的试剂、耗材等,如无特殊说明,均可从商业途径得到。
实施例1IR780-LA的合成
分析天平精密称取IR-780和LA-NH2,溶于无水N,N-二甲基甲酰胺(DMF)并置于茄形瓶中,搅拌条件下加入三乙胺,氮气保护、85℃条件下反应4h。反应结束后,减压旋蒸除去无水DMF,得到粗产物。将粗产物溶于甲醇中,用少许200-300目的硅胶拌样。硅胶柱色谱提纯,用二氯甲烷和甲醇梯度洗脱(100:1-20:1),得到IR780-LA纯品为蓝色固体,产率为40%。
其中,LA-NH2:三乙胺:IR-780摩尔比为2:1:1
实施例2核磁共振氢谱(1H-NMR)鉴定IR780-LA化学结构
称取IR780-LA约5mg,用氘代二甲亚砜(DMSO-d6)溶解并置于核磁管内,采用400MHz核磁共振氢谱测定其核磁共振氢谱图,以四甲基硅烷为内标物,记录化合物的化学位移值(ppm)。结果如图1所示,核磁结果可以证实,新合成的分子中同时具有IR-780和LA的特征峰。通过1H-NMR谱图可以证实IR780-LA的成功合成。
实施例3IR780-LA/CPT-ss-CPT纳米粒的制备
精密称取2.4mg IR780-LA与2mg CPT-ss-CPT,分别溶于5ml甲醇中,混合均匀,减压旋蒸形成薄膜,然后加入10ml的水,水浴超声3min形成纳米粒。
实施例4IR780-LA/CPT-ss-CPT纳米粒形态观察
用滴管吸取20μL制备好的纳米粒水溶液滴于碳膜铜网上,滤纸吸去多余液体,自然干燥后置于透射电镜下观察IR780-LA/CPT-ss-CPT纳米粒的形态。电镜照片如图2所示,结果表明IR780-LA/CPT-ss-CPT可在水中聚集成直径约(91.0±1.8)nm的纳米粒,形态圆整,粒径分布均匀。
综上所述,本发明首次合成IR-780衍生物IR780-LA,IR780-LA分子解决了IR-780疏水性强,不宜生物应用的缺点。还可以与CPT-ss-CPT形成联合光热治疗与化疗的小分子自组装纳米粒。这种多功能的纳米药物体系可用于肿瘤的荧光成像及光热治疗和化疗。
Claims (7)
2.权利要求1所述自组装纳米体系IR780-LA/CPT-ss-CPT的制备方法,其特征在于,将IR-780衍生物IR780-LA与CPT-ss-CPT分别溶于甲醇后,进行混合,混合均匀后减压旋蒸形成薄膜,然后加入水,在超声条件下形成纳米粒。
3.根据权利要求2所述自组装纳米体系IR780-LA/CPT-ss-CPT的制备方法,其特征在于,所述IR-780衍生物IR780-LA的制备方法包括以下步骤:
(1)乳糖酸与乙二胺以酰胺键结合形成LA-NH2;
(2)IR-780与LA-NH2催化反应形成IR-780衍生物IR780-LA。
4.根据权利要求3所述自组装纳米体系IR780-LA/CPT-ss-CPT的制备方法,其特征在于,所述步骤(2)IR-780与LA-NH2催化反应过程为:LA-NH2,在加入三乙胺条件下,与IR-780反应,生成IR-780衍生物IR780-LA。
5.根据权利要求3所述自组装纳米体系IR780-LA/CPT-ss-CPT的制备方法,其特征在于,所述步骤(2)IR-780与LA-NH2催化反应具体反应步骤为:
S1.将LA-NH2与IR-780溶于无水N,N-二甲基甲酰胺中,加入三乙胺,氮气保护,85℃条件下反应4h;
S2.减压旋蒸除去反应溶剂无水DMF,真空干燥,得到粗产物;将粗产物溶于甲醇中,硅胶柱色谱提纯,用二氯甲烷和甲醇梯度洗脱,即得。
6.根据权利要求5所述自组装纳米体系IR780-LA/CPT-ss-CPT的制备方法,其特征在于,所述步骤S1中LA-NH2:三乙胺:IR-780摩尔比为2:1:1。
7.根据权利要求2所述自组装纳米药物体系IR780-LA/CPT-ss-CPT的制备方法,其特征在于,IR-780衍生物IR780-LA与CPT-ss-CPT摩尔比为1:1。
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