CN106420664A - 一种具有抗癌活性的阿司匹林偶联物作为药物载体或者分子探针载体的应用 - Google Patents
一种具有抗癌活性的阿司匹林偶联物作为药物载体或者分子探针载体的应用 Download PDFInfo
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- CN106420664A CN106420664A CN201610950086.3A CN201610950086A CN106420664A CN 106420664 A CN106420664 A CN 106420664A CN 201610950086 A CN201610950086 A CN 201610950086A CN 106420664 A CN106420664 A CN 106420664A
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Abstract
一种具有抗癌活性的阿司匹林偶联物作为药物载体或者分子探针载体的应用;所述的阿司匹林偶联物为阿司匹林与含羟基五环三萜类化合物或含有氨基类抗癌药物的偶联物。该应用的实现为阿司匹林偶联物包载药物或者分子探针形成纳米粒。本发明解决了很多药物水溶性问题;该偶联物作为载体具有抗癌活性但细胞毒性不大,包载药物可达到更好的疗效果,包载分子探针可达到实现诊疗一体化。
Description
技术领域
本发明涉及生物医药技术领域,特别涉及一种具有抗癌活性的阿司匹林偶联物作为药物载体或者分子探针载体的应用。
背景技术
自二十世纪以来,癌症已成为困扰人类健康的主要危害之一。无论是发达国家还发展中国家,都存在着较高的癌症发病率。随着科学技术的进步和研究方法的改善(尤其纳米科技的发展),使人们对癌症有一个全新的认识。
阿司匹林(Asp)是一种历史悠久的解热镇痛药,但近年研究发现,阿司匹林不仅可以预防多种癌症,降低癌症的发生率,还对多种癌细胞的生长具有显著地抑制作用,并促进癌细胞发生凋亡。
五环三萜类化合物是一类重要的天然化合物,在抗肿瘤方面的研究颇多,比如:熊果酸(UA)、桦木酸(BA)、等,在癌症治疗中有非常好的前景。含氨基类抗癌药物在临床中的应用逐渐增多,并且都有较好的疗效,比如:阿霉素。本课题组基于前期工作,基于阿司匹林为母体,对其羧基进行结构修饰及改造。
近几年来,纳米材料由于其独特且优异的性质,得到越来越多研究者的关注,尤其是在生物医学领域,有多种脂质体和磷脂形纳米载药体系已经进入了临床应用;其中,利用多功能的纳米材料用于癌症的同时诊断与治疗也逐渐受到广泛的重视,出现了越来越多的文献报道。虽然当前的纳米药物载体在一定程度上提高了疏水性药物的生物利用度,但是载体本身的生物相容性和细胞毒性引起了广泛的关注,此外,大多数载体本身在体内的代谢机制不明确,成为阻碍纳米载药体系进一步应用于临床的棘手问题。与传统的纳米载体相比,无载体纳米粒解决了载体纳米体系复杂,质控困难,作用机制不明确,代谢不清楚等问题。无载体纳米粒优点是避免引入载体对人体带来的毒副作用,同时减轻额外的代谢负担,也解决了载体纳米粒制备过程中批次质量不可控问题。
本专利基于阿司匹林为母体,通过简单的化学偶联,在阿司匹林的羧基引入五环三萜类抗肿瘤药物或氨基类抗肿瘤药物,制得阿司匹林-抗癌药物偶联物;该抗癌药物偶联物可以在水中进一步自组装形成无载体的纳米颗粒,形成稳定的胶束结构,从而发挥其抗肿瘤作用,更重要的是,作为分子成像探针/抗肿瘤药物等的载体,解决了现有纳米载体存在的诸多问题。
发明内容
本发明目的在于提供一种具有抗癌活性的阿司匹林偶联物作为药物载体或者分子探针载体的应用,以解决现有技术中传统载体纳米体系复杂,质控困难,作用机制不明确,代谢不清楚等问题。
本发明的具体做法为,以阿司匹林和五环三萜类化合物进行偶联制备得到含有酯键的抗癌前药,或以阿司匹林和氨基类抗癌化合物进行偶联制备得到含有酯键的抗癌前药,然后抗癌前药作为载体包载其他的抗癌药物以达到更好的癌症治疗效果,或者包载分子探针,以达到实现诊疗一体化。
一种具有抗癌活性的阿司匹林偶联物作为药物载体或者分子探针载体的应用;所述的阿司匹林偶联物为阿司匹林与含羟基五环三萜类化合物或含有氨基类抗癌药物的偶联物。
该应用的实现为阿司匹林偶联物包载药物或者分子探针形成纳米粒。
具体实现方式为:
1)将阿司匹林偶联物溶于良性溶剂中,为溶液A;溶液浓度范围为20μM-20000μM;良性溶剂为二氯甲烷、氯仿、乙醚、乙酸乙酯、乙酸甲酯、丙酮、正丙醇、甲醇、吡啶、乙酸、二甲基亚砜一种或多种的混合;
2)将溶液A滴入搅拌中的不良溶液中,为悬浊液B;悬浊液最后的浓度范围为2μM-2000μM;不良溶液为磷酸盐缓冲液、水、生理盐水、葡萄糖溶液一种或多种的混合;
3)将含有待包载的药物或分子探针溶液滴入搅拌中的悬浊液B,得悬浊液C;其中阿司匹林偶联物:药物或分子探针和的物质的量的浓度为1:5-10;即载体和待包载的目标物的比例为1:5-10,其目标药物浓度为0.2μM-400μM;
4)将悬浊液C继续搅拌,之后超声处理,之后离心取上清液,即得具抗癌活性的载有药物或者分子探针的阿司匹林偶联物纳米粒。超声时间为20s-1200s;搅拌时间1min-30min;搅拌过程中允许在20-70摄氏度下加热;
所述的偶联物为阿司匹林与含羟基五环三萜类化合物或含有氨基类抗癌药物,含羟基五环三萜类化合物可以为甘草酸、熊果酸、齐墩果酸、白桦酸或雷公藤酮等;所述的氨基类抗肿瘤药物为:阿霉素、氨基蝶呤等。例如如式I所示的齐墩果酸和阿司匹林偶联物(Asp-OA);如式II所示的熊果酸和阿司匹林的偶联物 (Asp-UA);如式III所示的阿霉素和阿司匹林的偶联物 (Asp-DOX);
其制备方法包括但不限于此:先对阿司匹林的羧基进行活化后,与含羟基五环三萜类化合物或含有氨基类抗癌药物中的氨基进行偶联后得到。
具体的制备步骤:
草酰氯活化法
1.将乙酰水杨酸(阿司匹林)溶于干燥的二氯甲烷,加入草酰氯,搅拌10 h,减压蒸除气体和溶剂。
2.重新加入二氯甲烷,溶液通过恒压漏斗向溶有五环三萜类药物或氨基类抗癌药物和DMAP的吡啶:二氯甲烷(1v/1v)混合溶液中滴加,滴加完成后继续搅拌8-10 h。
3.反应完全后,减压蒸除二氯甲烷。
4.向反应瓶中加入水析出产物,抽滤,并用水洗滤饼至中性,真空干燥,柱层析得该偶联物。
以阿司匹林ASP和桦木酸BA为例,偶联物ASP-BA合成路线反应式如下:
a、阿司匹林酰氯化:
b、桦木酸和酰氯化的阿司匹林偶联:
未包载药物的纳米粒即一种具有抗癌活性的阿司匹林偶联物无载体纳米粒,其特征在于制备方法如下:
1)将阿司匹林偶联物溶于良性溶剂中,为溶液A
2)将溶液A滴入搅拌中的不良溶液中,为悬浊液B;
3)将悬浊液B继续搅拌,之后超声处理,之后离心取上清液,即得所述的具抗癌活性的阿司匹林偶联物无载体纳米粒;
其中,所述的良性溶剂为二氯甲烷、氯仿、乙醚、乙酸乙酯、乙酸甲酯、丙酮、正丙醇、甲醇、吡啶、乙酸、二甲基亚砜一种或多种的混合;
所述的不良溶液为为磷酸盐缓冲液、水、生理盐水、葡萄糖溶液一种或多种的混合;
所述的偶联物为阿司匹林与含羟基五环三萜类化合物或含有氨基类抗癌药物,其制备方法为:先对阿司匹林的羧基进行活化后,与含羟基五环三萜类化合物或含有氨基类抗癌药物中的氨基进行偶联后得到。
具有抗癌活性的阿司匹林偶联物无载体纳米粒,其特征在于所述含羟基五环三萜类化合物为甘草酸、熊果酸、齐墩果酸、白桦酸或雷公藤酮;所述的氨基类抗肿瘤药物为:阿霉素、氨基蝶呤。
阿司匹林偶联物作为药物载体或者分子探针载体的应用;药物包括但不限于以下:盐酸厄洛替尼、甲苯磺酸索拉非尼、阿柔比星、阿柔比星B、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素、雷公藤内酯醇、米非司酮、紫杉醇、多西紫杉醇、喜树碱、10-羟基喜树碱、秋水仙碱、长春新碱、甲氨蝶呤、他莫西芬、替尼泊苷、顺铂和6-巯基嘌呤、盐酸柔红霉素、盐酸表阿霉素、盐酸佐柔比星、盐酸米托蒽醌和5-氟尿嘧啶;
分子探针包括但不限于以下:钆配合物造影剂、双吡啶硫酮、花氰荧光染料、全氟化碳。
本发明的优点在于:
1、本发明所制备的偶联物作为载体具有一定的抗癌效果但作为载体有没有太大的细胞毒性,合成简单方便;
2、本发明所制备偶联物在水中可以通过溶剂交换法自组装成为纳米粒,做为抗癌药物或荧光物质的载体,有效地解决了一系列抗癌药物水溶性问题;
3、本发明的纳米粒具备pH响应性;
4、可以对无载体纳米粒表面进行修饰,可以使纳米粒具有靶向性等功能;
5、本发明所制备的纳米粒可以解决传统纳米载体在体内代谢不明确,体系复杂等问题,并能为以后新药研发和制备提供新的思路。
附图说明
图1为实施例2中Asp-BA作用24h后对HeLa细胞的增值抑制作用;
图2为实施例3中Asp-UA纳米粒粒径图;
图3.为实施例4中Asp-UA纳米粒的pH响应激光图;
图4.为实施例6中Asp-UA自组装形成的无载体纳米粒作用24 h后对HeLa细胞的增殖抑制作用;
图5.为实施例7中Asp-UA@DOX纳米粒粒径图;
图6.为实施例7中Asp-UA@DOX纳米粒的丁达尔效应图;
图7.为实施例8中Asp-UA@DOX纳米粒的紫外吸收光谱图;
图8.为实施例9中Asp-UA@DOX纳米粒作用24 h后对HeLa细胞的增殖抑制作用;
图9.为实施例11中Asp-UA@El纳米粒作用24 h后对A549细胞的增殖抑制作用;
图10.为实施例13中Asp-UA@ICG纳米粒的荧光光谱图;
图11.为实施例14中Asp-UA@ICG纳米粒小动物成像图。
具体实施方式
为了使本发明所述的内容更加便于理解,下面结合具体实施方式对本发明所述的技术方案做进一步的说明,但是本发明不仅限于此。
实施例1
阿司匹林-桦木酸的合成
室温下,0.5 g 乙酰水杨酸(阿司匹林)溶于20 mL 干燥的二氯甲烷,加入2 mL草酰氯,磁力搅拌10 h,减压蒸除气体和溶剂。重新向反应瓶中加入20 mL 二氯甲烷,通过恒压漏斗向溶有1.27 g 桦木酸和0.1eq DMAP 的20 mL 1v/1v 吡啶:二氯甲烷混合溶液中滴加,滴加完成后继续搅拌8-10 h。反应完全后,减压蒸除二氯甲烷。向反应瓶中加入100 mL 水析出产物,抽滤,用500 mL 水洗滤饼至中性,真空干燥,柱层析得阿司匹林-桦木酸(Asp-BA)。
性状:白色粉末;产率:70.51% ;
分子式:C39H54O6
核磁结果:1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 7.4, 2.0 Hz, 1H), 7.56 –7.49 (m, 1H), 7.35 – 7.27 (m, 1H), 7.14 (dd, J = 7.4, 2.0 Hz, 1H), 4.81 –4.76 (m, 1H), 4.75 – 4.70 (m, 1H), 3.79 (t, J = 6.9 Hz, 1H), 2.39 (s, 3H),2.26 – 2.07 (m, 3H), 1.97 – 1.86 (m, 3H), 1.84 – 1.76 (m, 1H), 1.74 (s, 3H),1.68 – 0.98 (m, 22H), 0.97 (s, 3H), 0.93 (s, 3H), 0.73 (d, J = 10.4 Hz, 6H).
高分辨质谱分子量:618.8575
实施例2
Asp-BA纳米粒子的制备方法
精确称取Asp-BA粉末0.00618g,溶于1 ml的甲醇中,超声溶解,配置成10 mM的溶液;取20 µL甲醇溶液,逐滴加入到装有180 µL的EP管中(注:滴加过程中进行涡旋,20 µL滴加时间为20s),然。后超声1min,以12000rpm离心5min,上清即为Asp-BA纳米粒。
本实施例制备的Asp-BA纳米粒水溶液的粒径的平均尺寸在170纳米左右,粒径图如图1所示。
因为目前大多数批准的抗癌纳米医学颗粒的尺寸范围为100-200纳米,并且在一定范围内,较小尺寸的抗癌纳米医学颗粒,在体内显示出更强的抗癌性能。
实施例3
抗癌活性实验通过细胞毒性来实现,采用标准MTT 比色法测定了Asp-BA纳米粒和Asp,BA溶液以及组合物对HeLa细胞的增殖抑制活性。具体步骤为:(1)取处于对数生长期状态良好的HeLa细胞,经胰蛋白酶消化后,计数并调整细胞密度为0.8×105 个/mL,配成细胞悬液。于每孔100 µL接种到96孔板中,周围用PBS封板,置于37 ℃, 5% CO2培养箱中培养24h。
(2)去除旧的培养基,每孔加入100 µL不同浓度梯度的含样品的培养基,另设空白对照组,每组设置5个复孔,于培养箱中继续孵育24h。
(3)移除培养基,于每孔中加入100 µL MTT溶液(无血清、无酚红的RMPI1640培养基:MTT母液=9:1,V:V),继续孵育4 h。
(4)取出96孔板终止培养,用移液枪轻轻吸去96孔板中的上清液,每孔加入DMSO溶液 100 µL,振荡摇匀10 min,使蓝紫色结晶全部溶解,用酶标仪于570 nm波长处测定每孔的OD值,使用GraphPad Prism 5处理实验结果。结果如图2所示。
图2结果表明,在浓度范围为20 μM-100 μM之间,BA和其组合物对HeLa具有显著性的细胞增值抑制作用,且药物杀伤具有明显的药物剂量依赖性,但两者的作用没有显著性差异,而偶联物Asp-BA纳米粒在5 μM已经对HeLa细胞具有明显的细胞增殖抑制作用,因此偶联物纳米粒相对于其他药物具有明显的细胞增殖抑制作用。
实施例4
将实施例2所制备的纳米粒水溶液取200ul两份于比色皿中,然后分别加入pH为7.0和pH为5.0的PBS溶液800ul,然后用激光笔照射,观察现象,结果如图3所示。
如图3所示,结果表明Asp-BA纳米粒水溶液在中性pH=7.0溶液中保持其纳米结构,在酸性条件pH=5.0时,胶体结构破坏,产生絮状沉淀。众多研究表明,肿瘤微环境呈弱酸性,这对于药物进入肿瘤微环境后,pH响应后,药物大量释放。
实施例5
精确称取Asp-BA粉末0.00618 g,溶于1mL的乙醇中,超声溶解,配置成10 mM的溶液;取20 μL上述溶液,逐滴加入到装有176 μL葡萄糖水溶液(10 mg/mL)的EP管中(注:滴加过程中进行涡旋,20 μL滴加时间为20s),之后滴加10mM的盐酸厄洛替尼(简写El)乙醇溶液4 μL,然后超声1min,以12000rpm离心5min,上清即为Asp-BA@El纳米粒葡糖糖水溶液。
本实施例制备的Asp-BA纳米粒水溶液的粒径的平均尺寸在100-170纳米。
实施例6
阿司匹林和熊果酸偶联物纳米粒的生物学效应
根据本课题组专利ZL201510466210.4,制备Asp-UA,按照实施例3的方法制备Asp-UA纳米粒,其抗癌活性实验通过细胞毒性来实现,采用标准MTT 比色法测定了无载体的Asp-UA纳米粒和Asp-UA溶液对HeLa细胞的增殖抑制活性。具体步骤为参照实施例2,结果如图4所示。
实验结果如图4所示,无载体的Asp-UA纳米粒作用于HeLa细胞24 h之后, UA给药组、Asp-UA给药组、Asp-UA纳米粒给药组和Asp给药组对HeLa细胞具有不同程度的增殖抑制作用,并呈浓度依赖性依赖性。Asp-UA给药组在>50μM的条件下能有效的抑制HeLa细胞的增殖,此时细胞的存活率大约在60%左右;与Asp-UA给药组相比无载体的Asp-UA纳米粒能够明显的降低抗癌前药Asp-UA的毒副作用;UA给药组能够更加有效的抑制HeLa细胞的增殖,效果最好;Asp给药组几乎没有毒副作用。
实施例 7
Asp-UA@DOX纳米粒子的制备方法
取10mM的Asp-UA二氯甲烷溶液20 μL,在室温下将其逐滴加入176 μL的水中(注:整个制备过程进行涡旋,20 μL滴加时间为20s),然后加入浓度为10mM的抗肿瘤药DOX水溶液4 μL,室温搅拌两个小时振荡,之后超声1min即得包载抗肿瘤药盐酸阿霉素(缩写DOX)的Asp-UA@DOX纳米粒水溶液。
本实施例制备的Asp-UA@DOX纳米粒水溶液的粒径的平均尺寸在150纳米左右,粒径图如图5所示,粒径小于单一的药物纳米,更利于药物的吸收和利用,发挥更好的抗癌效果。
将空白水溶液、Asp-UA@DOX纳米粒、Asp-UA纳米粒稀释5倍于比色皿中激光照射,产生丁达尔效应,如图6所示。结果表明,本实验做出为胶体溶液。
实施例8
将实施例5和实施例6所制备的Asp-UA纳米粒水溶液和Asp-UA@DOX纳米粒水溶液稀释10倍以及相同浓度的Asp-UA的甲醇溶液和DOX水溶液进行紫外检测,结果如图7所示。
如图7所示,DOX被包载后,发生位移变化,结果证实DOX被成功包载在Asp-UA纳米空腔内。
实施例 9
Asp-UA@DOX的抗癌活性
Asp-UA@DOX抗癌活性实验通过细胞毒性来实现,采用标准MTT 比色法测定了无载体的Asp-UA纳米粒和包载DOX的无载体的Asp-UA纳米粒对HeLa细胞的增殖抑制活性,具体步骤参见实施例3。结果如图8所示。
实验结果如图8所示,无载体的Asp-UA@DOX纳米粒作用于HeLa细胞24 h之后,Asp-UA给药组、DOX给药组、Asp-UA和DOX联合给药组、无载体的Asp-UA纳米粒及包载抗肿瘤药盐酸阿霉素的无载体的Asp-UA@DOX纳米粒给药组对HeLa细胞具有不同程度的增殖抑制作用,并呈浓度依赖性依赖性。Asp-UA给药组在>50μM的条件下能有效的抑制HeLa细胞的增殖,此时细胞的存活率大约在60%左右;与Asp-UA给药组相比无载体的Asp-UA纳米粒能够明显的降低抗癌前药Asp-UA的毒副作用;包载抗肿瘤药盐酸阿霉素的无载体的Asp-UA@DOX纳米粒给药组相比于Asp-UA给药组、DOX给药组、Asp-UA和DOX联合给药组能够更加有效的抑制HeLa细胞的增殖,效果最好。
实施例10
Asp-UA@El纳米粒子的制备方法
取10mM的Asp-UA乙醇溶液20 μL,在室温下将其逐滴加入178ul的生理盐水中(注:整个制备过程进行涡旋,20 μL滴加时间为20s),然后加入浓度为10mM的盐酸厄洛替尼(简写El)乙醇溶液2 μL,室温搅拌两个小时,之后超声1min即得包载抗肿瘤药盐酸厄洛替尼的Asp-UA@El纳米粒生理盐水溶液。
实施例11
Asp-UA@El的抗癌活性
Asp-UA@El抗癌活性实验通过细胞毒性来实现,采用标准MTT 比色法测定了无载体的Asp-UA纳米粒和包载El的无载体的Asp-UA纳米粒对A549细胞的增殖抑制活性,操作步骤同实施例3,实验结果如图9所示。
实验结果如图9所示,无载体的Asp-UA@El纳米粒作用于A549细胞24 h之后,Asp-UA给药组、El给药组、Asp-UA和El
联合给药组、无载体的Asp-UA纳米粒及包载抗肿瘤药盐酸厄洛替尼的无载体的Asp-UA@El纳米粒给药组对A549细胞具有不同程度的增殖抑制作用,并呈浓度依赖性依赖性。Asp-UA给药组在>25 μM的条件下能有效的抑制A549细胞的增殖,此时细胞的存活率大约在60%左右;与Asp-UA给药组相比无载体的Asp-UA纳米粒能够明显的降低抗癌前药Asp-UA的毒副作用;包载抗肿瘤药盐酸厄洛替尼的无载体的Asp-UA@El纳米粒给药组相比于Asp-UA给药组、El给药组、Asp-UA和El联合给药组能够更加有效的抑制A549细胞的增殖,效果最好。
实施例12
Asp-UA@Sora纳米粒子的制备方法
取10mM的Asp-UA甲醇溶液20 μL,在室温下将其逐滴加入177 μL的水中(注:整个制备过程进行涡旋,20 μL滴加时间为20s),然后加入浓度为10 mM的甲苯磺酸索拉非尼(简称Sora)甲醇溶液3 μL,室温搅拌两个小时,之后超声1min即得包载抗肿瘤药甲苯磺酸索拉非尼的Asp-UA@Sora纳米粒水溶液。其制备的纳米粒粒径在100-150 nm。
实施例13
Asp-UA@ICG纳米粒的制备方法
取10mM的Asp-UA甲醇溶液20 μL,在室温下将其逐滴加入160 μL的水中(注:整个制备过程进行涡旋,20 μL滴加时间为20s),然后加入浓度为3mg/ml的ICG甲醇溶液20 μL,室温搅拌两个小时振荡,之后超声1 min即得包载吲哚菁绿(缩写ICG)的Asp-UA@ICG纳米粒水溶液。
取其溶液200μL和同等浓度的ICG溶液200 μL于EP管中,进行荧光检测。实验结果如图10所示。
实验结果表明,Asp-UA@ICG溶液和ICG溶液,荧光位移不同,说明Asp-UA无载体纳米粒可以作为载体成功包载ICG。
实施例14
小动物成像
Bev/Asp-UA@ICG纳米粒的制备方法
取10mM的Asp-UA甲醇溶液100 μL,在室温下将其逐滴加入800 μL的水中(注:整个制备过程进行涡旋,20 μL滴加时间为20s),然后加入浓度为3 mg/mL的ICG甲醇溶液50 μL,室温搅拌两个小时振荡,除去甲醇,之后滴加10 mg/mL贝伐单抗(BEV)50 μL,超声1min即得靶向包载吲哚菁绿(缩写ICG)的BEV/Asp-UA@ICG纳米粒水溶液。
将上述制备的纳米粒,取通过尾静脉注射200 μL于肿瘤裸鼠体内,然后对其进行拍照。结果如图11所示:
如图11所示,包载ICG的纳米粒成功进入体内,成功靶向肿瘤组织并成像。该实验结果表明,无需借助纳米材料载体,借助无载体纳米粒Asp-UA,即可完成荧光材料ICG的运输,即可完成诊疗一体化。
实施例15
Asp-UA@ZnPc纳米粒的制备方法
取10 mM的Asp-UA甲醇溶液20 μL,在室温下将其逐滴加入160 μL的锌酞菁水溶液(浓度为3 mg/mL,简称ZnPc)中(注:整个制备过程进行涡旋,20 μL滴加时间为20 s),室温搅拌两个小时,之后超声1min即得包载光敏剂ZnPc的Asp-UA@ZnPc纳米粒水溶液。
实施例16
Asp-OA@DOX纳米粒的制备
取10mM的阿司匹林和齐墩果酸偶联物Asp-OA甲醇溶液20 μL,在室温下将其逐滴加入176 μL的水中(注:整个制备过程进行涡旋,20 μL滴加时间为20s),然后加入浓度为10 mM的抗肿瘤药DOX水溶液4 μL,室温搅拌两个小时振荡,之后超声1 min即得包载抗肿瘤药盐酸阿霉素(缩写DOX)的Asp-OA@DOX纳米粒水溶液。其纳米粒粒径大小为100-150 nm。
实施例17
Asp-DOX纳米粒的制备
取10 mM的阿司匹林和阿霉素偶联物Asp-DOX甲醇溶液20 μL,在室温下将其逐滴加入180 μL的磷酸盐缓冲液中(pH=7.0)(注:整个制备过程进行涡旋,20 μL滴加时间为20s),室温搅拌两个小时振荡,之后超声1min即得Asp-DOX纳米粒磷酸盐溶液。其纳米粒粒径大小为100-150nm。
Claims (7)
1.一种具有抗癌活性的阿司匹林偶联物作为药物载体或者分子探针载体的应用;所述的阿司匹林偶联物为阿司匹林与含羟基五环三萜类化合物或含有氨基类抗癌药物的偶联物。
2.如权利要求1所述的应用,其特征在于, 阿司匹林偶联物包载药物或者分子探针形成纳米粒。
3.如权利要求1所述的应用,其具体应用方式为:
1)将阿司匹林偶联物溶于良性溶剂中,为溶液A
2)将溶液A滴入搅拌中的不良溶液中,为悬浊液B;
3)将含有待包载的药物或分子探针溶液滴入搅拌中的悬浊液B,得悬浊液C
4)将悬浊液C继续搅拌,之后超声处理,之后离心取上清液,即得具抗癌活性的载有药物或者分子探针的阿司匹林偶联物纳米粒。
其中,所述的良性溶剂为二氯甲烷、氯仿、乙醚、乙酸乙酯、乙酸甲酯、丙酮、正丙醇、甲醇、吡啶、乙酸、二甲基亚砜一种或多种的混合;
所述的不良溶液为为磷酸盐缓冲液、水、生理盐水、葡萄糖溶液一种或多种的混合;
所述的偶联物为阿司匹林与含羟基五环三萜类化合物或含有氨基类抗癌药物,其制备方法为:先对阿司匹林的羧基进行活化后,与含羟基五环三萜类化合物或含有氨基类抗癌药物中的氨基进行偶联后得到。
4.如权利要求1所述的应用,其特征在于所述含羟基五环三萜类化合物为甘草酸、熊果酸、齐墩果酸、白桦酸或雷公藤酮;所述的氨基类抗肿瘤药物为:阿霉素、氨基蝶呤。
5.一种具有抗癌活性的阿司匹林偶联物无载体纳米粒,其特征在于制备方法如下:
1)将阿司匹林偶联物溶于良性溶剂中,为溶液A
2)将溶液A滴入搅拌中的不良溶液中,为悬浊液B;
3)将悬浊液继续搅拌,之后超声处理,之后离心取上清液,即得所述的具抗癌活性的阿司匹林偶联物无载体纳米粒;
其中,所述的良性溶剂为二氯甲烷、氯仿、乙醚、乙酸乙酯、乙酸甲酯、丙酮、正丙醇、甲醇、吡啶、乙酸、二甲基亚砜一种或多种的混合;
所述的不良溶液为为磷酸盐缓冲液、水、生理盐水、葡萄糖溶液一种或多种的混合;
所述的偶联物为阿司匹林与含羟基五环三萜类化合物或含有氨基类抗癌药物,其制备方法为:先对阿司匹林的羧基进行活化后,与含羟基五环三萜类化合物或含有氨基类抗癌药物中的氨基进行偶联后得到。
6.如权利要求5所述的具有抗癌活性的阿司匹林偶联物无载体纳米粒,其特征在于所述含羟基五环三萜类化合物为甘草酸、熊果酸、齐墩果酸、白桦酸或雷公藤酮;所述的氨基类抗肿瘤药物为:阿霉素、氨基蝶呤。
7.如权利要求1所述的应用,其特征在于药物为盐酸厄洛替尼、甲苯磺酸索拉非尼、阿柔比星、阿柔比星B、伊达比星、吡柔比星、紫杉醇、多西他赛、福美坦、埃博霉素、雷公藤内酯醇、米非司酮、紫杉醇、多西紫杉醇、喜树碱、10-羟基喜树碱、秋水仙碱、长春新碱、甲氨蝶呤、他莫西芬、替尼泊苷、顺铂和6-巯基嘌呤、盐酸柔红霉素、盐酸表阿霉素、盐酸佐柔比星、盐酸米托蒽醌和5-氟尿嘧啶;分子探针为钆配合物造影剂 、双吡啶硫酮、花氰荧光染料、全氟化碳。
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