CN107375940A - 以粘附因子icam‑1为靶点的纳米药物制备及其应用 - Google Patents
以粘附因子icam‑1为靶点的纳米药物制备及其应用 Download PDFInfo
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Abstract
本发明属于抗肿瘤转移药物的制备领域,具体涉及一种以粘附因子ICAM‑1为靶点的壳聚糖纳米药物及其制备和应用。通过将熊果酸与壳聚糖进行偶联得到CS‑UA偶联物,然后将CS‑UA偶联物与ICAM‑1通过酰胺键形成 ICAM‑1‑CS‑UA偶联物,最后再通过离子交联法形成ICAM‑1‑CS‑UA纳米药物。该纳米药物具有特异性强、毒副反应低,操作简便等优点,为临床上开发具有抗肿瘤和抗转移药物提供了良好的应用前景。
Description
技术领域
本发明属于抗肿瘤转移药物的制备领域,具体涉及一种以粘附因子ICAM-1为靶点的壳聚糖纳米药物及其制备和应用。
背景技术
癌症是严重威胁人类生命健康的疾病之一,肿瘤转移则是癌症患者死亡的最主要原因,不但因为肿瘤转移的过程是复杂和难以控制的,更由于转移灶难以用手术切除和更易形成抗药性。资料表明,临床肿瘤病人中90%的死亡是由肿瘤转移引起的,因此,研发抗肿瘤转移药物对提高癌症患者的存活率至关重要。肿瘤转移过程中牵涉到细胞脱落、浸润、迁移运行、着床、新生血管生成等,只要能够阻止上述一个或多个过程,就能够抑制肿瘤转移。目前发现的抗肿瘤转移药物,如紫杉醇对黑色素瘤高转移株B16-BL6的转移有抑制,但未达到令人满意的结果,找出高效低毒的抗肿瘤转移的药物是当前研究的重点。
纳米技术是近年来迅速发展起来的前沿科技领域,并已在各学科的研究中产生了巨大的影响,尤其在制药领域得到了广泛的应用,而药物纳米化后能增加药物吸收的程度;纳米控释系统可以改善药物性质增加药物的吸收等。利用多功能的纳米材料用于癌症的诊断与治疗也逐渐受到广泛的重视。目前一些多功能的纳米药物载体具有高度靶向、药物控制释放,提高疏水性药物的水溶性和生物利用度,提高药物疗效和降低毒副作用,但是载体本身的生物相容性和细胞毒性却不容忽视,因此就需要开发出一种具有靶向功能的无纳米载体的纳米药物,解决纳米载体带来的诸多安全性问题。
细胞粘附因子-1(intercellular cell adhesion molecule-1,ICAM-1),又叫做CD54,相对分子量70~110kD,是一种单链糖蛋白,属于黏附分子中免疫球蛋白超家族(IGSF)中的成员,是介导黏附反应重要的一个黏附分子。细胞黏附分子参与肿瘤细胞之间、肿瘤细胞与细胞外基质(extracellularmatrix,ECM)、血液细胞或血小板之间的相互作用,被认为在肿瘤的局部浸润和远处转移中起着非常重要的作用。ICAM-1在多种正常细胞及肿瘤中广泛表达,参与细胞生长、分化、细胞黏附、血管发生、肿瘤演进、凋亡、转移等多种生物过程。近年的研究发现,ICAM-1在多种肿瘤表达上调,与肿瘤的侵袭转移及不良预后密切相关,可能在恶性肿瘤侵袭和转移过程中起着极其重要的作用。
壳聚糖(Chitosan,CS)是一种天然直链大分子生物碱性多糖,其化学名称为聚葡萄糖胺(1-4)-2-氨基-B-D葡萄糖。壳聚糖是一种白色或灰白色半透明的片状或粉状固体,不溶于水及有机溶剂,可溶于pH<6.5的稀酸,由于壳聚糖具有组织相容性好、生物活性多样,体内可以有效降解且产物能被人体吸收,分子中存在可供反应的氨基,它可与药物输送体系中的靶向配体连接以达到靶向作用,在弱酸环境pH值5.3中的溶解性好,而在生理条件pH值7.4不溶从而阻止药物在到达靶部位之前过早的释放或被分解和代谢掉以达到pH控释性以及与肿瘤组织的亲和性,已成为抗肿瘤药物新制剂的理想辅料。
熊果酸(Ursolic acid,UA),又名乌索酸,乌苏酸,属α-香树脂醇(α-amyrin)型五环三萜类化合物,以游离或糖苷的形式广泛分布在枇杷叶、冬凌草、夏枯草、山楂、熊果等大自然界的药用植物中。熊果酸也具有来源丰富、价格低廉等优点,因此,熊果酸在生物医药领域中具有良好的研发前景和应用价值,有望成为一种高效低毒的多用途药物。它具有化学预防作用、抗转移、抗肿瘤活性作用、保肝、抗肝炎作用和抗菌、抗病毒作用。但是由于熊果酸的水溶性较差且生物利用度低等限制因素,使得其在国内外将其作为抗癌药物在临床上的开发应用受到限制。
本申请基于抗肿瘤活性的熊果酸(UA),以细胞间粘附因子-1抗体为靶标与具有pH响应的壳聚糖(CS)通过酰胺键进行偶联形成细胞间粘附因子抗体-壳聚糖-熊果酸(ICAM-1-CS-UA) 偶联物,并进一步制备成具有抗肿瘤活性及抗转移的纳米药物。两种方法制备的基于细胞粘附因子为靶点的壳聚糖纳米药物具有特异性强、毒副反应低,操作简便等优点,为临床上开发具有抗肿瘤和抗转移药物提供了良好的应用前景。
发明内容
本发明的目的在于针对现有技术的不足,提供一种以粘附因子ICAM-1为靶点的壳聚糖纳米药物及其制备和应用。通过以pH响应的壳聚糖为载体与具有抗肿瘤活性、抗转移活性的熊果酸和介导肿瘤细胞迁移的细胞间粘附因子-1(ICAM-1) 抗体通过酰胺键进行偶联形成偶联物;其中以CS为载体可保护ICAM-1抗体,降低了ICAM-1-CS-UA纳米药物在血液循环中被降解的概率,使其能顺利到达肿瘤部位发挥抗转移的作用。
为实现上述发明目的,本发明采用如下技术方案:
一种以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法:将熊果酸与壳聚糖进行偶联得到壳聚糖-熊果酸偶联物(CS-UA),以CS-UA为基础再与ICAM-1通过酰胺键形成ICAM-1-CS-UA偶联物,该偶联物进一步通过离子交联法或自组装法形成纳米药物(ICAM-1-CS-UANPs)达到更好的治疗肿瘤的效果。
根据CS分子量的不同,ICAM-1、CS和UA的摩尔比范围为1~2000:1:1~2000。
一种以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法,包括以下步骤:
1)精确称取熊果酸:溶于良性溶剂中,再依次加入EDC (物质的量为熊果酸的1-2.5倍) 和NHS (物质的量为熊果酸的1-3倍)于室温下搅拌一定的时间,得到活化的UA溶液;其中良性溶剂为甲醇、乙醇、吡啶、乙酸、二甲基亚砜一种或多种的混合;
2)称取壳聚糖:溶于一定体积1wt%的乙酸溶液中,得到壳聚糖溶液;将活化的UA溶液缓慢加入不断搅拌的壳聚糖溶液中,于室温反应一定的时间后得混合溶液,经纯化冷冻干燥后即得到熊果酸及壳聚糖的偶联物(CS-UA);其中CS的分子量范围为3KD~300KD,CS和UA的摩尔比为1:19~2000,该偶联物中CS的氨基数与熊果酸中羧基分子数比为1~2000:1;
3)称取羧基化的ICAM-1抗体溶于水中,依次加入一定量的EDC和NHS于室温搅拌一段时间后,得到活化的ICAM-1溶液,将1wt%的CS-UA偶联物乙酸溶液缓慢加入活化的ICAM-1溶液中,于室温下搅拌反应一段时间,纯化冷冻干燥后即得到ICAM-1-CS-UA偶联物;
4)采用离子交联法制备出相应的ICAM-1-CS-UA 纳米药物。
步骤1)中所述的良性溶剂为甲醇、乙醇、吡啶、乙酸和二甲基亚砜中的一种或多种的混合。
步骤1)中EDC的摩尔量为熊果酸的1-2.5倍,NHS的摩尔量为熊果酸的1-3倍。
按照如上方法制得的以粘附因子ICAM-1为靶点的壳聚糖纳米药物,粒径为145-220nm。
一种如上所述的以粘附因子ICAM-1为靶点的壳聚糖纳米药物在制备抗肿瘤和抗肿瘤转移药物中的应用。
本发明的优点在于:
1)本发明的熊果酸、ICAM-1与壳聚糖偶联形成的纳米药物是一种安全、高效、稳定、毒副作用低的抗肿瘤药物,显著抑制肿瘤细胞的生长,对肿瘤转移具有较好的治疗效果;
2)本发明使用的ICAM-1可以与肿瘤细胞中高度表达细胞间粘附因子-1竞争受体,从而抑制肿瘤细胞等与内皮细胞间的黏附作用,实现抗肿瘤转移的目的,具有高效性、高稳定性和放大效应等诸多优点;
3)本发明利用共价键结合熊果酸,有效地解决了抗癌药物熊果酸的水溶性和生物利用度的问题。
附图说明
图1为实施例2中CS-UA NPs的粒径分布图及电势图;
图2为实施例1中ICAM-1-CS-UA NPs的粒径分布图及电势图;
图3为实施例3中CS/UA NPs的粒径分布图及电势图;
图4为实施例4中ICAM-1/CS/UA NPs的粒径分布图及电势图;
图5为CS-UA NPs、ICAM-1-CS-UA NPs、CS/UA NPs和ICAM-1/CS/UA NPs 的细胞毒性实验图;
图6为ICAM-1-CS-UA NPs对细胞的迁移能力的影响;
图7为ICAM-1-CS-UA NPs对细胞的侵袭能力的影响;
图8为ICAM-1-CS-UA NPs对细胞的粘附能力的影响。
具体实施方式
根据下述实施例,可以更好地理解本发明,下面结合具体实施方式对本发明所述的技术方案作进一步的说明,但是本发明不仅限于此。
实施例1
ICAM-1-CS-UA NPs的制备方法,包括以下步骤:
1)制备熊果酸溶液
准确称取60mg熊果酸 (UA),加入40 mL DMSO 溶解,再依次加入63.2mg EDC和50.3mgNHS于室温下搅拌2 h,得到活化的UA溶液;
2)熊果酸壳聚糖偶联物的制备
精确称取40mg壳聚糖,其分子量为30KD,溶解于10 mL 1wt%的乙酸溶液中,得壳聚糖溶液;将活化的UA溶液缓慢加入不断搅拌的壳聚糖溶液中,经纯化冷冻干燥后即得到熊果酸及壳聚糖的偶联物(CS-UA);具体纯化的方法如下:于室温下反应16 h后将上述混合液置于截留分子量为1000的透析袋中,放在含40%甲醇pH为7.4的PBS缓冲液中连续透析3天,之后再用截留分子量为30KD的透析袋中,于1%乙酸水溶液中透析3天,冷冻干燥即得熊果酸壳聚糖偶联物(CS-UA),该偶联物中UA与CS的接枝率达到50%;
采用傅里叶红外光谱仪测定CS-UA纯品红外吸收光谱,样品充分干燥,与溴化钾混合均匀压片,在4000cm-1~ 400 cm-1范围内扫描;结果如下:
UA图谱发现有明显的-COOH基团特征峰VO-H 3000cm-1,VC=O 1705cm-1;CS图谱中有明显的-OH峰3315cm-1吸收,δNH1550 cm-1;CS-UA偶联物红外图谱中发现有特征峰1679cm-1和1565cm-1出现,判断为-CO-NH基团中VC=O和δNH的吸收;当UA中-COOH基团与CS中的-NH2基团反应成酰胺,由于-CO-NH存在共轭效应使VC=O的吸收向低频方向移动,诱导效应的存在使δNH移向高波数,CS-UA的红外图谱证明了UA和CS成功偶联;
3)量取羧基化修饰的抗ICAM-1的抗体(anti-ICAM-1-COOH) 100μL,加入5mlDMSO中再依次加入6mg EDC和4mg 的NHS,在室温下反应1h得到活化的抗ICAM-1抗体;将1wt%的CS-UA偶联物乙酸溶液缓慢加入活化的ICAM-1溶液中,于室温下搅拌反应一段时间,将上述溶液置于截留分子量为1000的透析袋中,之后透析袋放在含40%甲醇pH为7.4的PBS缓冲液中连续透析3天,透析得到的产物再置于截留分子量为100KD的透析袋在超纯水中连续透析3天,冷冻干燥后即得到ICAM-1-CS-UA偶联物;其中ICAM-1、CS和UA的摩尔比为90:1: 90;ICAM-1、UA和CS的接枝率分别为35.7%和42.6%;
采用傅里叶红外光谱仪测定ICAM-1-CS-UA纯品红外吸收光谱。样品充分干燥,与溴化钾混合均匀压片,在4000cm-1~ 400 cm-1范围内扫描。
结果如下:
在CS-UA中有特征峰δNH1550 cm-1出现,在ICAM-1-CS-UA的红外图谱中有特征峰1570cm-1出现,由于CS-UA中的-NH2,与ICAM-1中-COOH基团反应成酰胺,诱导效应使-NH2移向高波数方向,因此ICAM-1-CS-UA偶联物红外图谱中出现了δNH1570cm-1特征峰,证明了抗ICAM-1抗体与CS-UA成功偶联。
4)称取步骤3)制备得到的ICAM-1-CS-UA偶联物溶于0.1mol/L乙酸中,将浓度为0.84mg/mL的TPP水溶液0.4mL逐滴加入到ICAM-1-CS-UA乙酸溶液中,在室温下磁力搅拌4h,即得到经离子交联法制备的ICAM-1-CS-UA纳米 (ICAM-1-CS-UA NPs)。
实施例2
将CS-UA偶联物溶于0.1mol/L的乙酸溶液中,得到浓度为1mg/mL的CS-UA溶液,调节CS-UA溶液的pH=5.0,在室温下磁力搅拌,将浓度为1mg/mL 的三聚磷酸钠 (TPP) 溶液缓慢逐滴加入到CS-UA溶液中 (V:V=5:1) 中,直至出现白色乳光,在滴加过程中不断的搅拌,反应进行2h,得到经离子交联法制备的CS-UA纳米粒 (CS-UA NPs)。
实施例3
精确称取UA 6 mg溶于1mL甲醇中,CS 4 mg溶于2mL 1% 的乙酸-水溶液中,取100μL甲醇溶液逐滴滴加到CS乙酸-水溶液中,磁力搅拌30min,离心取上清即得自组装的CS/UA 纳米药物(CS/UA NPs) ,其中CS与UA的摩尔比为1:90。
实施例4
精确称取UA 6 mg溶于1mL甲醇中,CS 4 mg溶于2mL 1% 的乙酸-水溶液中,含抗ICAM-1抗体溶液50μL加入到CS乙酸-水溶液中,取UA甲醇溶液100μL 逐滴加入到上述混合溶液中,磁力搅拌30min,离心取上清,即得ICAM-1/CS/UA 纳米药物(ICAM-1/CS/UA),ICAM-1:CS:UA的摩尔比为90:1: 90。
性能检测:
1、用动态光散射测定CS-UA NPs、ICAM-1-CS-UA NPs、CS/UA NPs和ICAM-1/CS/UA NPs的粒径和电势,结果如图1、2、3、4所示。
2、制备的CS-UA NPs、ICAM-1-CS-UA NPs、CS/UA NPs和ICAM-1/CS/UA NPs抗癌活性,通过细胞毒性来实现,采用标准MTT法测定对肿瘤细胞HeLa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100µl接种到96孔板中,周围用NaCl封板,置于37℃,5% CO2培养箱中培养24 h;
(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490nm波长处测定每孔的OD值,使用GraphPad Prism 5处理实验结果如图5所示,其结果表明本研究所制备的ICAM-1/CS/UA NPs和ICAM-1/CS/UA抗癌药物能增强对细胞的毒性。
3、CS-UA NPs、ICAM-1-CS-UA NPs、CS/UA NPs和ICAM-1/CS/UA NPs药物抗肿瘤细胞迁移活性,通过细胞划痕来测定对HeLa细胞的迁移抑制作用,具体步骤为:
(1) 取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8×105个/mL,配成细胞悬液;于每孔150 µl接种到12孔板中,周围用NaCl封板,置于37 ℃,5% CO2培养箱中培养24 h;
(2) 24h后用枪头比着直尺,尽量垂至于孔板,枪头要垂直,每个孔划3天平行的直线;
(3) PBS洗细胞3次,去处划下的细胞,加入无血清培养基;
(4) 按照相应的药物浓度加入药物UA、CS-UA NPs、ICAM-1/CS/UA NPs、CS/UA NPs和ICAM-1/CS/UA NPs;
(5) 放入37℃ 5% CO2培养箱,培养。24h取样,拍照。
结果如图6所示,在相同浓度下,ICAM-1/CS/UA NPs、ICAM-1/CS/UA NPs和空白组对比有一定的抗肿瘤细胞迁移效果。
4、为了验证CS-UA NPs、ICAM-1-CS-UA NPs、CS/UA NPs和ICAM-1/CS/UA NPs的抗侵袭能力,利用Traswell实验验证CS-UA NPs、ICAM-1-CS-UA NPs、CS/UA NPs和ICAM-1/CS/UA NPs对HeLa的抗侵袭能力,具体步骤如下:
Transwell 法测定肿瘤细胞的侵袭能力,用1 mg/mL 的 Matrigel 稀释液包被Transwell 小室底部膜的上室面,4 ℃风干。弃去小室中残余液体,每孔加入50 μL 的 1%BSA 无血清培养液,于37 ℃放置1h。
取指数生长期的肿瘤细胞,消化离心,弃去上清液后用含0.1% BSA 的无血
清培养基重悬。调整细胞密度至1×106 /mL,吸取200 μL 加入Transwell 上室,下室加入500 μL 含有20% FBS 及含有药物的培养基。37 ℃培养24 小时后,取出Transwell 小室用PBS 洗2 遍,用棉签擦去基质胶和上室内的细胞,用95%预冷的甲醇溶液中固定20min,后用0.1 %的结晶紫染色15 min,弃去染色液,用PBS 清洗2 遍。室温晾干后于正置显微镜进行观察和拍照。随机选取8 个不同的视野细胞拍照并计数,实验重复3 次。
结果如图7所示,ICAM-1/CS/UA NPs、ICAM-1/CS/UA NPs对HeLa细胞具有显著的抗侵袭能力。
5、为了验证ICAM-1-CS-UA NPs的抗粘附能力,利用细胞粘附实验验证ICAM-1/CS/UA NPs、ICAM-1/CS/UA NPs对HeLa的抗粘附能力,具体步骤如下:
细胞粘附实验:将处于对数期的HeLa细胞消化后接种于24孔板,待上述24孔板的内皮细胞长满孔板时,用PBS清洗两三次,然后加入含有内皮刺激因子IL-1β,浓度为1 ng/L的培养基,在37 ℃, 5% CO2的条件下孵育4 h,以此激活内皮细胞。
4h 后取出孔板,用PBS 清洗两三次后,取对数生长期肿瘤细胞,荧光标记后制成4×105 / mL-1 单细胞悬液,并加入含药物的RPM-1640 培养液,每孔500 μL。37 ℃、5% CO2孵育2h 后,PBS 轻洗3 遍,控干后加入无血清培养液500 μL。然后在荧光显微镜下进行拍照,计算粘附率。
结果如图8所示,ICAM-1-CS-UA NPs、ICAM-1/CS/UA NPs对HeLa细胞具有显著的抗粘附能力。
表1 为壳聚糖不同分子量所得纳米药物的粒径、电势和PDI分布
以上所述仅为本发明的较佳实施例,凡依本发明申请专利范围所做的均等变化与修饰,皆应属本发明的涵盖范围。
Claims (8)
1.一种以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法,其特征在于:将熊果酸与壳聚糖进行偶联得到CS-UA偶联物,然后将 CS-UA 偶联物与 ICAM-1通过酰胺键形成ICAM-1-CS-UA偶联物,最后再通过离子交联法或自组装法形成ICAM-1-CS-UA纳米药物。
2.根据权利要求1所述的以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法,其特征在于:ICAM-1、CS和UA的摩尔比为19~2000:1:19~2000。
3.根据权利要求1所述的以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法,其特征在于:包括以下步骤:
1)将熊果酸溶于良性溶剂中,再依次加入EDC和NHS,于室温下搅拌一定的时间,得到活化的UA溶液;
2)将壳聚糖溶解于1wt%乙酸溶液中,得到壳聚糖溶液;将活化的UA溶液缓慢加入不断搅拌的壳聚糖溶液中,于室温反应一定的时间后得混合溶液,混合溶液经纯化冷冻干燥后得到CS-UA偶联物;
3)将羧基化的ICAM-1溶于水中,依次加入一定量的EDC和NHS于室温搅拌一段时间后,得到活化的ICAM-1溶液,将1wt% CS-UA偶联物乙酸溶液缓慢加入至活化的ICAM-1溶液中,于室温下搅拌反应一段时间,纯化冷冻干燥后即得到ICAM-1-CS-UA偶联物;
4)通过离子交联法或自组装法形成ICAM-1-CS-UA纳米药物。
4.根据权利要求3所述的以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法,其特征在于:步骤1)中所述的良性溶剂为甲醇、乙醇、吡啶、乙酸和二甲基亚砜中的一种或多种的混合。
5.根据权利要求3所述的以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法,其特征在于:步骤1)中EDC的摩尔量为熊果酸的1-2.5倍,NHS的摩尔量为熊果酸的1-3倍。
6.根据权利要求3所述的以粘附因子ICAM-1为靶点的壳聚糖纳米药物的制备方法,其特征在于:步骤2)所制得的CS-UA偶联物中,CS的-NH2与UA的-COOH分子个数比为1~2000:1。
7.一种如权利要求1-6任一项所述的制备方法制得的以粘附因子ICAM-1为靶点的壳聚糖纳米药物,其特征在于:粒径为145-220nm。
8.一种如权利要求7所述的以粘附因子ICAM-1为靶点的壳聚糖纳米药物在制备抗肿瘤和抗肿瘤转移药物中的应用。
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