CN117535284A - 一种树状dna载药系统及其制备方法和应用 - Google Patents
一种树状dna载药系统及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及DNA纳米载药技术领域,公开了一种树状DNA载药系统及其制备方法和应用;包括Y2、MUC1适配体、VEGF适配体、P‑糖蛋白的反义寡核苷酸;Y2含有9条寡核苷酸链;9条寡核苷酸链中每3条寡核苷酸链中的部分碱基可通过碱基互补配对组装成3种三臂Y型DNA;三臂Y型DNA包括Ya、Yb和Yc;Ya的3个粘性末端相同;Yb有2个粘性末端相同,第3个粘性末端与Ya的粘性末端互补配对组装成Y1;Yc有2个粘性末端相同,第3个粘性末端与Yb的2个相同的粘性末端互补组装成Y2;MUC1适配体、VEGF适配体、P‑糖蛋白的反义寡核苷酸与Yc互补组装成Y‑A‑O。该Y‑A‑O具备高负荷药物输送的能力。
Description
技术领域
本发明涉及DNA纳米载药技术领域,具体涉及一种树状DNA载药系统及其制备方法和应用。
背景技术
二十一世纪以来,在困扰人类的各种疾病中,癌症已然成为威胁生命健康的头号公敌。化学治疗是目前临床上治疗癌症的一种主要方法,即用一种或多种细胞毒性的抗肿瘤药物来治疗癌症。传统的小分子化学药物具有低效性、非特异性和耐药性等难以避免的缺点,因此构建一种可以通过靶向递送抗癌药物选择性累积在肿瘤部位并能持续释放的药物运输系统对癌症治疗具有重要意义。
DNA作为一种天然生物分子,其具有的沃森-克里克碱基配对的固有性质使精确和合理的设计成为可能;此外,基于DNA的载体是由具有良好的生物相容性、低免疫原性、生物降解性和易于从体内消除的内源性材料制成的,因此其与许多其他可能导致细胞毒性、突变或体内积累不可降解的载体相比,具有低毒、高安全性的特点。但在部分DNA纳米载体中,其构型和性质严重影响了功能位点,导致DNA纳米载体不能同时容纳标记剂、药物和靶向配体,从而降低了载体的药物输送能力。
因此有必要开发一种树状DNA载药系统及其制备方法和应用,使其具备高负荷药物输送的能力,用于联合递送化疗药物和反义寡核苷酸,以解决癌症治疗中多药耐药的问题。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出一种树状DNA载药系统及其制备方法和应用,使其具备高负荷药物输送的能力,用于联合递送化疗药物和反义寡核苷酸,以解决癌症治疗中多药耐药的问题。
本发明的第一方面提供一种树状DNA载药系统。
具体的,包括树状DNA主体、MUC1适配体、VEGF适配体(血管内皮生长因子)、P-糖蛋白的反义寡核苷酸(p-gp);所述树状DNA主体含有9条寡核苷酸链;所述9条寡核苷酸链中每3条寡核苷酸链中的部分碱基可通过碱基互补配对组装成3种三臂Y型DNA;所述三臂Y型DNA包括Ya、Yb和Yc;所述Ya的3个粘性末端相同;所述Yb有2个粘性末端相同,第3个粘性末端与Ya的粘性末端互补配对组装成Y1;所述Yc有2个粘性末端相同,第3个粘性末端与Yb的2个相同的粘性末端互补组装成树状DNA主体(Y2);所述MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸的5’端的13个碱基与Yc的2个相同粘性末端互补组装成树状DNA载药系统。
优选的,所述Ya、Yb和Yc的每个臂都由13对碱基对形成的双链和13个碱基形成的单链粘性末端组成。
优选的,所述9条寡核苷酸链均含有1个二硫键。
优选的,所述二硫键均修饰在三臂Y型DNA每个臂的双链和单链粘性末端之间。
优选的,所述MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸的5’端的13个碱基与Yc的2个相同粘性末端互补并自发形成发夹结构。
优选的,所述Ya的3条寡核苷酸链分别为Ya-1、Ya-2、Ya-3;所述Ya-1的寡核苷酸的序列如SEQ ID NO.1所示;所述Ya-2的寡核苷酸的序列如SEQ ID NO.2所示;所述Ya-3的寡核苷酸的序列如SEQ ID NO.3所示;所述Yb的3条寡核苷酸链分别为Yb-1、Yb-2、Yb-3;所述Yb-1的寡核苷酸的序列如SEQ ID NO.4所示;所述Yb-2的寡核苷酸的序列如SEQ ID NO.5所示;所述Yb-3的寡核苷酸的序列如SEQ ID NO.6所示;所述Yc的3条寡核苷酸链分别为Yc-1、Yc-2、Yc-3;所述Yc-1的寡核苷酸的序列如SEQ ID NO.7所示;所述Yc-2的寡核苷酸的序列如SEQ ID NO.8所示;所述Yc-3的寡核苷酸的序列如SEQ ID NO.9所示。
优选的,所述MUC1适配体的核苷酸序列如SEQ ID NO.10所示;所述VEGF适配体的核苷酸序列如SEQ ID NO.11所示;所述P-糖蛋白的反义寡核苷酸的序列如SEQ ID NO.12所示。
本发明的第二方面提供一种树状DNA载药系统的制备方法。
具体的,包括以下步骤:
将9条寡核苷酸链经过90~100℃退火3~10min,分别形成Ya、Yb和Yc;将Ya与Yb室温反应1~5h组装成Y1;再将Y1与Yc室温反应1~5h组装成树状DNA主体(Y2);再将Y2与MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸混合,室温反应2~5h制得树状DNA载药系统。
优选的,所述9条寡核苷酸链经过95℃退火5min。
优选的,将Ya与Yb室温反应2h组装成Y1。
优选的,再将Y1与Yc室温反应2h组装成Y2。
优选的,将Y2与MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸混合,室温反应3h制得树状DNA载药系统。
优选的,所述树状DNA主体与MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸混合的比例为1:3~5:3~5:3~5。
进一步优选的,所述树状DNA主体与MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸混合的比例为1:4:4:4。
本发明的第三方面提供一种树状DNA载药系统在负载抗癌药物中的应用。
相对于现有技术,本发明的有益效果如下:
(1)相比于其他材料的载药系统,使用DNA原料,其双螺旋结构增加了载药系统对细胞内DNA降解酶的稳定性,从而增加了载药系统到达癌细胞的机会;
(2)树状DNA载药系统具有超支化和多孔构象的构型和性质,其所具有的多个功能位点可同时容纳标记剂(荧光团)、药物和靶向配体,这赋予了树状DNA载药系统独有的可以进行高负荷药物输送的能力;
(3)树状DNA载药系统具有稳定的结构,在进入癌细胞之前不容易被分解,从而提高了其药物递送效率;
(4)由于癌细胞的弱酸性环境,当普通的DNA载体负载抗癌药物输送至癌细胞后,普通DNA载体在进入癌细胞一段时间后会被癌细胞外排,无法实现有效给药,对正常细胞与组织毒副作用大。而在内部修饰二硫键的树状DNA载药系统在癌细胞内部会在GSH的作用下迅速解体释放药物,细胞靶向性强。
(5)本发明设计合成的树状DNA载药系统可负载多种不同类型的药物以进行联合治疗。
附图说明
图1为本发明Ya、Yb、Yc和Y2的结构示意图;
图2为本发明Y2与适配体杂交合成示意图;
图3为本发明Doxorubicin与DNA的结合方式示意图;
图4为本发明Netropsin与DNA的结合方式示意图;
图5为本发明1.5%琼脂糖凝胶电泳图;
图6为本发明各世代树状DNA载药系统的原子力显微镜图像;
图7为阿霉素插入不同浓度树状DNA载药系统的荧光强度结果图;
图8为分别在还原型谷胱甘肽和PBS缓冲液孵育的树状DNA载药系统的荧光强度结果图;
图9为基于树状DNA载药系统的细胞毒性检测结果图;
图10为Hela细胞系在树状DNA载药系统与阿霉素混合溶液(Y-A-O-Dox)和阿霉素溶液分别处理2h的激光共聚焦显微镜图像;
图11为DNA与插层剂、沟槽剂结合示意图。
具体实施方式
为了让本领域技术人员更加清楚明白本发明所述技术方案,现列举以下实施例进行说明。需要指出的是,以下实施例对本发明要求的保护范围不构成限制作用。
以下实施例中所用的原料、试剂或装置如无特殊说明,均可从常规商业途径得到,或者可以通过现有已知方法得到。
实施例1
一种树状DNA载药系统。
包括树状DNA主体、MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸;树状DNA主体含有9条寡核苷酸链;9条寡核苷酸链中每3条寡核苷酸链中的部分碱基可通过碱基互补配对组装成3种三臂Y型DNA(如图1中的a所示);三臂Y型DNA包括Ya、Yb和Yc;Ya的3个粘性末端相同;Yb有2个粘性末端相同,第3个粘性末端与Ya的粘性末端互补配对组装成Y1;Yc有2个粘性末端相同,第3个粘性末端与Yb的2个相同的粘性末端互补组装成树状DNA主体Y2(如图1中的b所示)。MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸的5’端的13个碱基与Yc的2个相同粘性末端互补并自发形成发夹结构(如图2所示),再组装成树状DNA载药系统,简称为Y-A-O。
MUC1和VEGF适配体被选择作为功能化组件以增加树枝状大分子的靶向性。MUC1适配体能选择性地与异常糖基化的粘蛋白-1结合,粘蛋白-1是一种跨膜糖蛋白,在许多肿瘤细胞膜上过表达,包括乳腺癌、卵巢癌、肺癌和结肠癌等;血管内皮生长因子(VEGF)适配体能选择性地与VEGF蛋白结合,VEGF通过激活所有内皮细胞中的VEGF受体酪氨酸激酶来刺激血管生成和淋巴管生成。血管内皮生长因子对血管的发育是不可或缺的,肿瘤的异常快速生长和分裂促进了血管内皮生长因子的过度表达,从而诱导肿瘤淋巴管的生成,促进肿瘤的转移。因此,VEGF是控制肿瘤生长的一个有吸引力的靶点。P-糖蛋白(P-glycoprotein,P-gp)是一种能将药物泵出细胞外的外排药物转运蛋白,当癌细胞细胞膜上的P-糖蛋白过表达时则会导致严重的耐药性,严重影响治疗效果,因此选用反义寡核苷酸(ASO)p-gp作为基因药物,以下调相应蛋白的表达从而提高肿瘤治疗的效果。
具体的各寡核苷酸序列及修饰如表1所示。
表1各寡核苷酸序列及修饰
注:碱基中间的[-s-s-]代表二硫键修饰。
该树状DNA载药系统的制备方法为:
将9条寡核苷酸链经过95℃退火3~10min,分别形成Ya、Yb和Yc;将Ya与Yb室温反应2h组装成Y1;再将Y1与Yc室温反应2h组装成树状DNA主体;再将树状DNA主体与MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸按1:4:4:4混合,室温反应3h制得树状DNA载药系统。
抗癌药物的负载:
1.阿霉素(Doxorubicin)的负载。
(1)称取盐酸阿霉素11.6mg,加入5mL去离子水,充分震荡溶解,得到4mM橙红色澄清盐酸阿霉素溶液,密封后4℃保存备用;
(2)经过对负载不同质量抗癌药物的树状DNA载药系统进行对肿瘤细胞的毒性试验,确定以树状DNA载药系统与抗癌药物的浓度比为1:2000进行后续实验;
(3)按照上述浓度比,将95μL 90nM的树状DNA载药系统(Y-A-O)与5μL 4mM的抗癌药物阿霉素充分混合,室温下温和摇晃6h使阿霉素充分嵌入DNA双螺旋结构内,DNA与阿霉素的具体结合方式如图3所示。
2.Netropsin的负载。
同阿霉素(Doxorubicin)的负载,将Netropsin负载至树状DNA载药系统上,DNA与Netropsin的具体结合方式如图4所示。
3.树状DNA载药系统合成结果的表征。
3.1琼脂糖凝胶表征结果:
图5-1为1.5%琼脂糖凝胶电泳图,电压100V,时间20min。通道1和6为2μM的Ya;通道2为2μM的Yb;通道3为2μM的Yc;通道4为2μM的MUC1适配体;通道5为2μM的VEGF适配体;通道7为0.5μM的Y1;通道8为0.2μM的Y2;通道9为0.14μM的Y2-ASO;通道10为90.9nM的Y-A-O。
根据琼脂糖凝胶电泳图5-1的(a)所示:通道1-5均有明显且唯一条带,并且通道1-3中DNA的电泳速度明显小于通道4-5,说明Ya、Yb和Yc经过退火成功合成,并且无其他产物。从图5-1的(b)可以看出,适配体功能化(VEGF,MUC1)和P-糖蛋白的反义寡核苷酸(p-gp)修饰的树状DNA载药系统(Y-A-O)在琼脂糖凝胶上运行最慢(通道10),其次是P-糖蛋白的反义寡核苷酸P-gp的DNA树状分子(通道9),三树状DNA主体(Y2)次之(通道8),两层的DNA树状分子(Y1)运行较快(通道7),单独的Y型DNA在凝胶上运行最快(通道6),说明树状DNA分子的尺寸随着层和功能元件(适配体及反义寡核苷酸)的增加而增加,证实了树状DNA载药系统的合成。
3.2AFM表征结果:
图6中的(a)、(b)、(c)、(d)分别为Ya、Y1、Y2及Y-A-O的形貌图像,可以看出各世代树状DNA载药系统均呈现规则、分散的球型。使用NanoScope Analysis对其进行了粒子分析(Particle Analysis),结果显示Ya的平均粒径约为14.398nm,Y1的平均粒径约为25.153nm,Y2的平均粒径约为41.671nm,Y-A-O的平均粒径约为53.246nm。随着树状DNA载药系统的层数增多,纳米颗粒的粒径也随之增大,这进一步证实了树状DNA载药系统的成功合成。
4.树状DNA载药系统载药能力的测定。
为了评价树状DNA载药系统的载药能力,对负载抗癌药物阿霉素的DNA大分子Y-A-O进行了荧光光谱分析。如图7所示,固定阿霉素的摩尔量,在469nm激发光源下负载阿霉素的树状DNA载药系统的荧光强度随树状DNA载药系统Y-A-O浓度的增大而逐渐减小,说明Doxorubicin成功嵌入树状DNA载药系统的双螺旋结构内,进而导致了Doxorubicin的荧光淬灭。并且从该浓度下荧光强度的明显变化可以得出,树状DNA载药系统Y-A-O对Doxorubicin的荧光有明显的淬灭作用,这说明Y-A-O具有很高的药物负载能力。
5.树状DNA载药系统的药物释放能力。
为了检测树状DNA载药系统Y-A-O进入细胞后的药物释放能力,测量了负载阿霉素的树状DNA载药系统在不同浓度GSH孵育前后的树状DNA载药系统Y-A-O样品在469nm激发光源下的荧光强度。如图8所示,作为对照组的没有与树状DNA载药系统混合的阿霉素荧光强度最高,未经GSH孵育的Y-A-O-Doxorubicin的荧光强度明显低于在GSH孵育后的Y-A-O-Doxorubicin的荧光强度,且孵育时GSH的浓度越高,测量时荧光强度越高,这说明本发明设计的DNA载药系统可以快速响应肿瘤细胞内的GSH,并将所负载的药物进行靶向释放,且GSH浓度越高,药物释放速率越快。
6.树状DNA载药系统及前药的体外抗癌活性。
使用抗癌药物阿霉素及纺锤菌素作为对照,选用Hela细胞系为模型,评价了树状DNA载药系统的体外抗癌活性。CCK-8的实验结果如图9所示,图中,下横坐标代表抗癌药物的相对浓度,上横坐标代表Y-A-O载体的相对浓度,纵坐标代表细胞相对活力。
由图9中的(a)可以看出,原药阿霉素、负载反义寡核苷酸g-pg的树状DNA载药系统Y-A-O以及负载阿霉素的树状DNA载药系统Y-A-O-Doxorubicin均有一定的细胞毒性,且树状DNA载药系统Y-A-O-Doxorubicin在细胞水平的杀伤效果明显强于阿霉素原药及载体Y-A-O;同样的,由图9中的(b)可以看出,原药纺锤菌素、Y-A-O和树状DNA载药系统Y-A-O-Netropsin也都有一定的细胞毒性,且Y-A-O-Netropsin在细胞水平的杀伤效果明显强于纺锤菌素原药及树状DNA载药系统Y-A-O,这说明此树状DNA载药系统不但可以携载生物制剂药物进入肿瘤细胞并发挥药效,并且可以同时负载化学药物和生物制剂并提高其进入肿瘤细胞的能力从而更高效地杀死肿瘤细胞。
此外,从图9中的(c)可以看出,树状DNA载药系统可以同时负载包括多种化学药物和生物制剂等抗癌药物并输送至肿瘤细胞,提高对肿瘤细胞的杀伤能力。
最后,横向对比不同抗癌药物的细胞毒性实验结果,可以发现在树状DNA载药系统的作用下,两种药物同时输送至靶细胞的细胞毒性不完全是这两种抗癌药物单独作用于靶细胞对其细胞毒性的加和。这说明此树状DNA载药系统还有较大潜力应用于相关抗癌药物的筛选以及评价不同药物的共同作用对于杀死肿瘤细胞的影响,进而筛选出最佳药物治疗方案以提高治疗效率。
7.树状DNA载药系统及前药的体外细胞内化能力。
利用激光共聚焦显微镜观察了在同样扫描条件下Hela细胞在Y-A-O-Doxorubicin和阿霉素溶液分别处理2h后对Doxorubicin的摄取情况。如图10所示,可以看出在负载阿霉素的载药体系的作用下,Hela细胞内的红色荧光强度明显强于对照组,即在树状DNA载药系统Y-A-O的作用下抗癌药物阿霉素更高效快速的进入了肿瘤细胞内,这与预期及细胞毒性检测结果均相符合,说明此类树状DNA载药系统可以显著提高肿瘤细胞对抗癌药物阿霉素的摄取效率,从而使抗癌药物更快的发挥药效以杀死肿瘤细胞。
8.树状DNA载药系统可负载多种不同类型的药物以进行联合治疗。
(1)含有共轭体系的小分子药物可镶嵌于DNA碱基平面之间:如图11中的(a)所示药物分子可通过与碱基之间的共轭作用稳定与DNA双链区域结合。该类药物如阿霉素、更生霉素、柔红霉素等。
(2)含有正电荷的小分子药物可附着于DNA双链的小沟槽内:沟槽剂是一类与双链DNA小沟槽结合的小分子,例如聚酰胺、Netropsin和Distamycin等。如图11中的(b)所示,这些分子具有月牙形,与小沟槽中DNA的曲率相匹配,并且可以通过氢键以及范德瓦尔斯力与小沟槽相互作用,也可以序列特定的方式与靶DNA主干通过静电作用相互吸附。
以上详细描述了本发明的较佳具体实施例。应当理解,本领域的普通技术人员无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此,凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验所作的任何修改、等同替换、改进等得到的技术方案,皆应在由权利要求书所确定的保护范围内。
Claims (10)
1.一种树状DNA载药系统,其特征在于,包括树状DNA主体、MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸;所述树状DNA主体含有9条寡核苷酸链;所述9条寡核苷酸链中每3条寡核苷酸链中的部分碱基可通过碱基互补配对组装成3种三臂Y型DNA;所述三臂Y型DNA包括Ya、Yb和Yc;所述Ya的3个粘性末端相同;所述Yb有2个粘性末端相同,第3个粘性末端与Ya的粘性末端互补配对组装成Y1;所述Yc有2个粘性末端相同,第3个粘性末端与Yb的2个相同的粘性末端互补组装成树状DNA主体;所述MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸的5’端的13个碱基与Yc的2个相同粘性末端互补组装成树状DNA载药系统。
2.根据权利要求1所述的树状DNA载药系统,其特征在于,所述Ya、Yb和Yc的每个臂都由13对碱基对形成的双链和13个碱基形成的单链粘性末端组成。
3.根据权利要求1所述的树状DNA载药系统,其特征在于,所述9条寡核苷酸链均含有1个二硫键。
4.根据权利要求3所述的树状DNA载药系统,其特征在于,所述二硫键均修饰在三臂Y型DNA每个臂的双链和单链粘性末端之间。
5.根据权利要求1所述的树状DNA载药系统,其特征在于,所述MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸的5’端的13个碱基与Yc的2个相同粘性末端互补并自发形成发夹结构。
6.根据权利要求1所述的树状DNA载药系统,其特征在于,所述Ya的3条寡核苷酸链的序列如SEQ ID NO.1~3所示;所述Yb的3条寡核苷酸链的序列如SEQ ID NO.4~6所示;所述Yc的3条寡核苷酸链的序列如SEQ ID NO.7~9所示。
7.根据权利要求1所述的树状DNA载药系统,其特征在于,所述MUC1适配体的核苷酸序列如SEQ ID NO.10所示;所述VEGF适配体的核苷酸序列如SEQ ID NO.11所示;所述P-糖蛋白的反义寡核苷酸的序列如SEQ ID NO.12所示。
8.权利要求1至7中任一项所述树状DNA载药系统的制备方法,其特征在于,包括以下步骤:
将9条寡核苷酸链经过90~100℃退火3~10min,分别形成Ya、Yb和Yc;将Ya与Yb室温反应1~5h组装成Y1;再将Y1与Yc室温反应1~5h组装成树状DNA主体;再将树状DNA主体与MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸混合,室温反应2~5h制得树状DNA载药系统。
9.根据权利要求8所述的制备方法,其特征在于,所述树状DNA主体与MUC1适配体、VEGF适配体、P-糖蛋白的反义寡核苷酸混合的比例为1:3~5:3~5:3~5。
10.权利要求1至7中任一项所述的树状DNA载药系统在负载抗癌药物中的应用。
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