CN110016048A - 线粒体靶向ir780碘化物的衍生物及制备方法与应用 - Google Patents
线粒体靶向ir780碘化物的衍生物及制备方法与应用 Download PDFInfo
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Abstract
本公开提供了线粒体靶向IR780碘化物的衍生物及制备方法与应用,IR780碘化物的衍生物的化学结构式为:本公开提供的IR780衍生物能用于制备线粒体靶向制剂,不仅解决了IR780疏水性强,药物体内递送困难的缺点,还可以通过线粒体靶向最大化光疗的治疗效果,增强光疗疗效。
Description
技术领域
本公开涉及医药技术领域,具体涉及线粒体靶向IR780碘化物的衍生物及制备方法与应用。
背景技术
这里的陈述仅提供与本公开有关的背景信息,而不必然构成现有技术。
乳腺癌是发生在乳腺腺上皮组织的恶性肿瘤,严重危及女性的生命健康。目前,临床上对于乳腺癌的治疗方式主要包括手术切除、放疗、化疗等。由于手术方法很难切除所有的癌变细胞,所以复发经常发生。放疗由于依赖癌细胞对射线的敏感性,晚期肿瘤对放疗敏感性差,而广泛应用的化疗由于耐药的出现,治疗效果也不尽如人意。光疗,包括光热疗法和光动力疗法,由于其非侵入性,对正常细胞毒副作用低,近年来是抗肿瘤研究的热点。光热疗法通过染料经外部光源的照射将光能转化为热能来杀死肿瘤细胞,光动力疗法则是利用光敏剂与氧气产生单线态氧来杀死肿瘤。
线粒体是细胞的能量工厂,它在调控细胞凋亡方面发挥着重要的作用。研究表明,线粒体对光动产生的活性氧系和光热产生的过高热特别敏感,将光疗与线粒体靶向相结合被认为是一个提高光疗疗效的策略。并且,研究表明光疗引起的线粒体紊乱可以减少ATP依赖性的p-糖蛋白(P-gp)对化疗药物的外排,从而实现逆转DOX的多药耐药。并且通过将化疗药物DOX靶向线粒体,可以使药物直接作用于线粒体,也是逆转多药耐药的途径之一。因此,通过线粒体靶向把光疗和DOX化疗相结合,可以实现线粒体靶向的光疗-化疗协同增效,进而实现高效的抗肿瘤效果。IR780碘化物(IR780)是一种广泛研究的近红外染料,光热与光动兼具的优良特性使它具备良好的临床应用前景。但是,经过本公开发明人研究发现,由于IR780水溶性差,体内递送是其限制性因素,并且IR780作为光敏剂产生的单线态氧作用时间短、作用距离有限,从而达不到最佳的治疗效果。
发明内容
为了解决现有技术的不足,本公开的目的是提供线粒体靶向IR780碘化物的衍生物及制备方法与应用,旨在制备一种高载药量、多功能的纳米粒载药体系,从而实现光疗联合化疗的临床应用。
为了实现上述目的,本公开的技术方案为:
一方面,一种IR780碘化物的衍生物(T780),其化学结构式如下:
本公开提供的IR780衍生物能用于制备线粒体靶向制剂,不仅解决了IR780疏水性强,药物体内递送困难的缺点,还可以通过线粒体靶向最大化光疗的治疗效果,增强光疗疗效。
另一方面,一种上述IR780碘化物的衍生物(T780)的制备方法,IR780与(3-氨基丙基)三苯基溴化膦(TPP-NH2)通过取代反应得到T780。
第三方面,一种上述IR780碘化物的衍生物在药物载体中的应用。
第四方面,一种纳米制剂,由上述IR780碘化物的衍生物作为药物载体。
可以负载例如多柔比星(阿霉素、DOX)等抗肿瘤药物。当负载DOX时,可以使药物直接作用于线粒体。由于正电荷的纳米粒在体内运输有毒性,采用例如牛血清白蛋白(BSA)对药物载体的正电荷进行遮蔽。
第五方面,一种上述IR780碘化物的衍生物或上述纳米制剂在制备抗肿瘤药物中的应用。
本公开的有益效果为:
(1)本公开首次合成新型线粒体靶向的IR780衍生物(T780),并且首次与DOX共组装形成纳米粒作为靶向制剂。该靶向制剂不仅解决了IR780疏水性强,药物体内递送困难的缺点,还可以通过线粒体靶向最大化光疗的治疗效果,增强光疗疗效。
(2)本公开制得的纳米制剂载药量高,且易于运输和保存,为工业的贮存提供了有利条件。
(3)本公开制得的纳米制剂形态均匀,粒径小于200nm,适合静脉注射,可以通过EPR效应蓄积于肿瘤部位。
(4)本公开通过实验表明BSA@T780/DOX NPs制剂对耐DOX的乳腺癌细胞(MCF-7/ADR)显示较强的细胞毒性,表明该制剂可以逆转DOX的多药耐药现象,提高化疗效果。且该制剂生物相容性好,暗毒性低。
(5)本公开体内抗肿瘤实验表明BSA@T780/DOX NPs具有强大的抑瘤效果。
附图说明
构成本公开的一部分的说明书附图用来提供对本公开的进一步理解,本公开的示意性实施例及其说明用于解释本公开,并不构成对本公开的不当限定。
图1为本公开实施例2的T780的核磁图谱;
图2为本公开实施例3的BSA@T780/DOX NPs的紫外图谱;
图3为本公开实施例4的BSA@T780/DOX NPs体外细胞毒性实验表征图;
图4为本公开实施例5的BSA@T780/DOX NPs的体内抗肿瘤效应表征图;左图为瘤体积的变化曲线,右图为肿瘤重量和肿瘤抑制率的表征图,右图中a、b、c、d、e、f条件与左图相同。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本公开提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本公开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公开的示例性实施方式。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、器件、组件和/或它们的组合。
鉴于IR780存在水溶性差、产生的单线态氧作用时间短、作用距离有限的不足,为了解决如上的技术问题,本公开提出了线粒体靶向IR780碘化物的衍生物及制备方法与应用。
本公开的一种典型实施方式,提供了一种IR780碘化物的衍生物(T780),其化学结构式如下:
本公开提供的IR780衍生物能用于制备线粒体靶向制剂,不仅解决了IR780疏水性强,药物体内递送困难的缺点,还可以通过线粒体靶向最大化光疗的治疗效果,增强光疗疗效。
本公开的另一种实施方式,提供了一种上述IR780碘化物的衍生物(T780)的制备方法,IR780与(3-氨基丙基)三苯基溴化膦(TPP-NH2)通过取代反应得到T780。
该实施方式的一种或多种实施例中,取代反应的过程为:IR780与(3-氨基丙基)三苯基溴化膦混合后,加入三乙胺,在惰性气体氛围下,加热反应生成T780。
其制备过程如下:
该实施方式的一种或多种实施例中,步骤为:
将(3-氨基丙基)三苯基溴化膦的溶液滴加至IR780溶液中,加入三乙胺,在惰性气体氛围下,加热至85~90℃,反应3~5h。
为了获得IR780溶液,该系列实施例中,IR780溶液的溶剂为无水N,N-二甲基甲酰胺(DMF)。
为了获得(3-氨基丙基)三苯基溴化膦的溶液,该系列实施例中,(3-氨基丙基)三苯基溴化膦溶液的溶剂为无水N,N-二甲基甲酰胺(DMF)和无水二氯甲烷的混合物。
该系列实施例中,IR780、(3-氨基丙基)三苯基溴化膦与三乙胺的摩尔比为1:1~5:1~5。当IR780、(3-氨基丙基)三苯基溴化膦与三乙胺的摩尔比为1:2:4时,能够保证T780具有更高的收率。
为了获得更纯净的T780,该实施方式的一种或多种实施例中,将反应后的物料去除溶剂后获得粗产品,采用甲醇将粗产品溶解后进行硅胶柱色谱提纯,提纯过程采用二氯甲烷和甲醇梯度洗脱。
本公开的第三种实施方式,提供了一种上述IR780碘化物的衍生物在药物载体中的应用。
本公开的第四种实施方式,提供了一种纳米制剂,由上述IR780碘化物的衍生物作为药物载体。
该实施方式的一种或多种实施例中,负载的药物为DOX。
该系列实施例中,其制备方法为:将T780溶液与DOX溶液混合后,加入至水中,自发形成纳米聚集体,即为T780/DOX NPs纳米制剂。由于DOX以盐酸盐的形式(DOX·HCl)存在,为了获得DOX溶液,将DOX·HCl加入至溶剂中,并加入三乙胺获得DOX溶液。三乙胺能够去除DOX·HCl中的HCl,从而实现T780与DOX的聚集、负载。
该系列实施例中,T780与DOX的摩尔比为1:0.25~4。T780与DOX的摩尔比为1:1时,效果更好。
由于正电荷的纳米粒在体内运输有毒性,为了消除毒性,该系列实施例中,所述纳米制剂包括牛血清白蛋白。能够对T780中的正电荷进行遮蔽。
该系列实施例中,T780与牛血清白蛋白的质量比为1:1~5。当T780与牛血清白蛋白的质量比为1:2时,效果更好。
该实施方式的一种或多种实施例中,纳米制剂为静脉制剂。
本公开的第五种实施方式,提供了一种上述IR780碘化物的衍生物或上述纳米制剂在制备抗肿瘤药物中的应用。
本公开所述的抗肿瘤的方式包括化学药物治疗、光动力治疗和/或光热治疗。
本公开所述的抗肿瘤药物包括但不限于烷化剂、生物碱类、抗菌抗肿瘤磺酰胺类药物、铂类药物、抗代谢类或其他的抗癌药物;可以联合的光疗药物包括但不限于吲哚菁绿、新吲哚菁绿、二氢卟吩e6,IR780碘化物等。
为了使得本领域技术人员能够更加清楚地了解本公开的技术方案,以下将结合具体的实施例详细说明本公开的技术方案。
实施例1:T780靶向分子合成。
分析天平精密称取一定量的IR780,溶于无水N,N-二甲基甲酰胺(DMF)和无水二氯甲烷的混合溶剂中,并置于双颈瓶中。称取一定量的TPP-NH2(参考文献C.J.Zhang,J.G.Wang,J.B.Zhang,Y.M.Lee,G.X.Feng,T.K.Lim,H.M.Shen,Q.S.Lin,B.Liu,Mechanism-guided design and synthesis of a mitochondria-targeting artemisinin analoguewith enhanced anticancer activity,Angew.Chem.Int.Ed.2016,55,13770.合成),溶于DMF中,加入正在搅拌的上述IR780的溶液中,并加入三乙胺,氮气保护、85℃条件下反应4小时。其中IR780:TPP-NH2:TEA的物质的量比1:2:4。反应结束后,减压旋蒸除去无水DMF和二氯甲烷,真空干燥过夜,得到粗产物。将粗产物溶于甲醇中,少许柱层层析硅胶拌样,硅胶柱色谱提纯,二氯甲烷和甲醇梯度洗脱,洗脱程序为100:1→90:1→80:1→70:1→60:1→50:1→40:1→30:1→20:1→10:1,当比例变为10:1时,产物被洗脱出来,得到T780纯品为蓝色固体,产率为39%。
实施例2:核磁共振氢谱(1H-NMR)鉴定T780化学结构。
称取T780约5mg,氘代二甲亚砜(DMSO-d6)溶解并置于核磁管内,采用400MHz核磁共振氢谱仪测定其核磁共振氢谱,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,新合成的分子中出现了原料分子IR780和TPP-NH2的峰,证实T780的成功合成。
实施例3:BSA@T780/DOX NPs的制备。
精密称取T780约5mg,溶于150μLDMSO中;精密称取2.8mgDOX·HCl溶于150μLDMSO,加入10μL TEA后,与T780的DMSO溶液混合,滴加入搅拌的5mL水中,纳米聚集体自发形成,将混悬液离心,弃去上清,用水重新分散,超声,得到纳米粒溶液。称取2倍于T780质量的BSA,溶于适量水中,加入上述制得的纳米粒溶液,即可得到最终制剂。紫外结果如图2所示,显示制备的BSA@T780/DOX NPs中同时出现T780和DOX的特征峰,证实制剂的成功制备。
实施例4:BSA@T780/DOX NPs制剂体外细胞毒性实验。
1.细胞的培养
选取耐DOX的人源乳腺癌MCF-7/ADR细胞作为研究对象。取冻存细胞,用培养基于37℃、5%CO2条件下培养,待细胞生长至高密度时传代,按比例转移至培养瓶中继续培养并进行细胞计数。
2.细胞毒性实验
收集对数生长期的MCF-7/ADR细胞,用培养基将细胞稀释为约3.5×104个/mL。用培养基将待测目标化合物IR780,DOX·HCl,T780,T780与DOX·HCl混合液和BSA@T780/DOXNPs制剂各稀释至10μM、5μM、2μM、1μM、0.5μM。细胞以7×103个/孔(200μL)的浓度加入96孔板中,过夜贴壁后,弃去培养基,加入不同浓度的目标化合物溶液200μL,设3个复孔,设不加药物的孔为阴性对照组,不加细胞的组为空白组,37℃分别培养4h。然后弃去上层含药培养基,换成新鲜培养基,IR780组用808nm光源照射,T780、T780与DOX·HCl混合液和BSA@T780/DOX NPs制剂组均用660nm激光器照射(功率均为1W/cm2,照射时间为2min)。为考察IR780和T780本身的暗毒性,同时设立暗毒性孔,除不经激光照射外,所有处理均一致。继续孵育20h,各孔加入10μL的MTT溶液(5mg/mL),继续孵育4h,然后弃去孔内液体,每孔加200μL的DMSO溶解,用酶标仪测定490nm处吸光度,按以下公式计算抑制率:
其中,A阴性表示未经药物处理的细胞的孔的吸光度,A样品表示各种样品处理过的细胞的孔的吸光度,A空白表示没有接种细胞且没有药物处理的孔的吸光度。
不同样品在不同浓度下对MCF-7/ADR细胞抑制率实验结果如图3。由图3可以看出,与IR780相比,线粒体靶向的T780的细胞抑制率显著增加,对比BSA@T780/DOX NPs与T780和DOX·HCl的混合物的抑制率,由于前者不仅可以通过光疗损伤线粒体切断P-gp的能力供应达到逆转耐药的作用,还可以将DOX靶向至线粒体发挥作用来逆转耐药,而后者只有切断能量供应一条途径,所以BSA@T780/DOX NPs的细胞抑制作用优于混合物。IR780和T780对该细胞的暗毒性小于20%,表明毒性较小。通过细胞抑制率实验,可以得出结论:该线粒体靶向的BSA@T780/DOX NPs可以同时增强光疗和化疗的疗效来最大化肿瘤的治疗效果。
实施例5:BSA@T780/DOX NPs制剂体内抗肿瘤实验。
Balb/c小鼠腋下荷瘤(每只100万个4T1细胞),等瘤长至100mm3左右,随机分成6组,每组6只,分别静脉注射生理盐水(NS)、DOX·HCl、IR780、T780、T780与DOX·HCl混合溶液和BSA@T780/DOX NPs,第二天激光照射(1W/cm2)5min,IR780组用808nm的激发光照射,T780、T780与DOX·HCl混合溶液和BSA@T780/DOX NPs用660nm的激发光照射。在治疗过程中记录瘤体积的变化。6次治疗过后,处死老鼠,取出肿瘤,称重并计算抑瘤率。
其中,wNS是生理盐水组老鼠的平均瘤重,w样品是其他各组老鼠的平均瘤重。
从图4可以看出,由于线粒体靶向增强的光疗,T780组老鼠瘤体积生长较IR780组缓慢,并且由于制剂的EPR效应,肿瘤部位药物蓄积多,所以BSA@T780/DOX NPs制剂抑瘤效果明显优于T780和DOX·HCl混合物,抑瘤率高达90%。表明该线粒体靶向的光疗化疗极大地提高了抗乳腺癌效果。
本公开首次合成线粒体靶向的IR780衍生物(T780),并且首次与化疗药物DOX共组装形成纳米粒,并以牛血清白蛋白作为蛋白外层。这个线粒体靶向的纳米组装结构不仅解决了疏水性IR780的体内递送问题,还逆转了DOX的多药耐药,同时增强光疗和化疗的效果。
以上所述仅为本公开的优选实施例而已,并不用于限制本公开,对于本领域的技术人员来说,本公开可以有各种更改和变化。凡在本公开的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本公开的保护范围之内。
Claims (10)
1.一种IR780碘化物的衍生物,其特征是,化学结构式如下:
2.一种权利要求1所述的IR780碘化物的衍生物的制备方法,其特征是,IR780与(3-氨基丙基)三苯基溴化膦通过取代反应得到T780。
3.如权利要求2所述的制备方法,其特征是,取代反应的过程为:IR780与(3-氨基丙基)三苯基溴化膦混合后,加入三乙胺,在惰性气体氛围下,加热反应生成T780;
优选的,步骤为:
将(3-氨基丙基)三苯基溴化膦的溶液滴加至IR780溶液中,加入三乙胺,在惰性气体氛围下,加热至85~90℃,反应3~5h;
进一步优选的,IR780溶液的溶剂为无水N,N-二甲基甲酰胺;
进一步优选的,(3-氨基丙基)三苯基溴化膦溶液的溶剂为无水N,N-二甲基甲酰胺和无水二氯甲烷的混合物;
进一步优选的,IR780、(3-氨基丙基)三苯基溴化膦与三乙胺的摩尔比为1:1~5:1~5,优选的,IR780、(3-氨基丙基)三苯基溴化膦与三乙胺的摩尔比为1:2:4。
4.如权利要求2所述的制备方法,其特征是,将反应后的物料去除溶剂后获得粗产品,采用甲醇将粗产品溶解后进行硅胶柱色谱提纯,提纯过程采用二氯甲烷和甲醇梯度洗脱。
5.一种权利要求1所述的IR780碘化物的衍生物在药物载体中的应用。
6.一种纳米制剂,其特征是,由权利要求1所述的IR780碘化物的衍生物作为药物载体。
7.如权利要求6所述的纳米制剂,其特征是,负载的药物为DOX。
8.如权利要求7所述的纳米制剂,其特征是,其制备方法为:将T780溶液与DOX溶液混合后,加入至水中,自发形成纳米聚集体,即为T780/DOX NPs纳米制剂;
或,T780与DOX的摩尔比为1:0.25~4;优选的,T780与DOX的摩尔比为1:1;
或,所述纳米制剂包括牛血清白蛋白;
优选的,T780与牛血清白蛋白的质量比为1:1~5;进一步优选的,T780与牛血清白蛋白的质量比为1:2。
9.如权利要求6所述的纳米制剂,其特征是,纳米制剂为静脉制剂。
10.一种权利要求1所述的IR780碘化物的衍生物或上述纳米制剂在制备抗肿瘤药物中的应用;
优选的,抗肿瘤的方式包括化学药物治疗、光动力治疗和/或光热治疗;
优选的,所述的抗肿瘤药物还包括但不限于烷化剂、生物碱类、抗菌抗肿瘤磺酰胺类药物、铂类药物、抗代谢类抗癌药物;
优选的,抗肿瘤药物还包括光疗药物,所述光疗药物包括但不限于吲哚菁绿、新吲哚菁绿、二氢卟吩e6、IR780碘化物。
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