CN110898223B - 一种基于糖基金属框架材料的肝靶向治疗药物及制备方法 - Google Patents
一种基于糖基金属框架材料的肝靶向治疗药物及制备方法 Download PDFInfo
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Abstract
本发明公开了一种基于糖基金属框架材料的肝靶向治疗药物及制备方法,属于生物医药领域。本发明将金属框架材料PCN‑224载入化疗药物阿霉素,通过酰胺反应在材料表面修饰上靶向分子半乳糖。所得肝靶向治疗药物的生物相容性和细胞毒性已在细胞水平被认真评估。本发明肝靶向治疗药物具有较好的稳定性及酸性pH触发药物释放,能够发挥光动力学治疗和化疗的协同治疗作用;此外,在皮下实体瘤和原位瘤小鼠模型中都进行了体内行为示踪和治疗功效评定,有望在临床应用上发挥巨大作用。
Description
技术领域
本发明涉及一种基于糖基金属框架材料的肝靶向治疗药物及制备方法,属于生物医药领域。
背景技术
原发性肝癌,主要是肝细胞癌(hepatocellular carcinoma,HCC),起病隐匿,早诊困难,进展迅速,治疗棘手,预后凶险。全球恶性肿瘤中HCC发病率居第6位,死亡率居第2位,其中一半以上新发和死亡病例来自中国。2016年全国肿瘤登记中心的高质量基于人群的流行病学调查收集并分析72个登记点的数据(覆盖中国6.5%的人口)显示,中国肝癌新发病例数为46.6万,死亡例数为42.2万,是我国60岁以下男性最常见的、死亡率最高的恶性肿瘤。慢性乙型肝炎、酒精中毒或丙型肝炎感染引起的肝硬化是HCC的主要危险因素,其次是非酒精性脂肪性肝炎。在乙型肝炎病毒(HBV)流行的地区HCC的发病率较高,包括我国、东南亚和撒哈拉以南非洲地区,而慢性丙型肝炎(HCV),酒精性肝硬化和非酒精性脂肪性肝炎是西方人群患HCC的主要原因。基于此,肝癌的治疗越来越受到全世界范围内的关注。手术切除、肝移植或射频消融等根治性治疗仅适用于不到30%的病例。索拉非尼是晚期HCC患者一线治疗药物,但伴随着高频率的不良事件的发生,总生存率未见明显提高。此外,现有药物绝大部分是游离的小分子药物,给药之后遍布全身,无法在病灶部位聚集,由此疗效有限,对患者的毒副作用大。
发明内容
为了解决上述问题,本发明采用纳米级的金属框架材料作为载药载体,修饰上糖分子靶向基团,从而将纳米材料的被动靶向和糖基材料的主动靶向结合在一起,能够很好的在病灶部位聚集,起到靶向治疗效果。本发明克服了目前糖分子作为多羟基醛结构不易修饰到纳米材料表面的问题,将糖分子进行了化学改造,将其端基位连接上氨基连接臂,通过酰胺反应共价连接到金属框架材料外面,从而达到靶向效果。
本发明还实现多种功能集中在一种纳米材料载体中,提出了一种新型治疗系统,将光敏剂和化疗药物整合在一个生物相容性和安全性良好的载体中。首先以卟啉为连接臂的金属框架材料PCN-224作为载体载入抗肿瘤药物阿霉素(将其命名为DOX@PCN-224),从而实现了光动力学治疗和化疗的协同治疗。随后,通过静电吸附在DOX@PCN-224表面修饰上了COOH-PEG-COOH,从而将DOX@PCN-224表面引入了羧基基团。最后通过酰胺反应将半乳糖靶向分子修饰到了材料表面,从而成功组建了靶向协同治疗纳米体系。
本发明的一个目的是提供一种光动力学治疗与化疗联合、酸敏感示踪的靶向治疗肝脏疾病的药物,所述药物的结构为下式(I)所示:
其中,A为选自如下的一个或多个相同或不同的化疗药物:阿霉素(DOX)、索拉非尼、5-氟尿嘧啶(5-FU);
B为具有光敏剂为连接臂的金属框架材料MOFs;
C为连接基,所述连接基为-CO-PEG-CO-;其中PEG的分子量为1000-2000;
D为半乳糖或含有半乳糖胺残基的单糖或寡糖类分子;其可以特异性识别肝癌细胞表面过度表达的去唾液酸糖蛋白受体。
在本发明的一种实施方式中,所述金属框架材料MOFs选自PCN-224、PCN-222。
在本发明的一种实施方式中,所述药物简写为:化疗药物@Gal–MOFs。
本发明的另一方面是提供一种上述式(I)药物的的制备方法,包括如下步骤:
(1)DOX@-PCN-224的制备
将ZrOCl2·8H2O、TCPP和苯甲酸分散在有机溶剂中,混匀后,加入阿霉素形成混合体系,80-100℃下进行反应,然后固液分离取沉淀,洗涤、干燥,即得DOX@PCN-224;
(2)将步骤(1)得到的DOX@PCN-224和COOH-PEG-COOH分散在水中形成混合液,常温下进行反应,反应结束后固液分离取沉淀,洗涤、干燥即得羧基修饰的DOX@PCN-224;
(3)将步骤(2)所得的羧基修饰的DOX@PCN-224、氨基修饰的半乳糖、缩合剂溶于水中,常温下进行反应;反应结束后固液分离取沉淀,洗涤、干燥即得DOX@Gal-PCN-224。
在本发明的一种实施方式中,所述步骤(1)中阿霉素、ZrOCl2·8H2O、TCPP和苯甲酸的质量比为1:(5-8):(2-4):(50-60)。优选1:6.25:2.08:58.33。
在本发明的一种实施方式中,所述步骤(1)中的有机溶剂为DMF。
在本发明的一种实施方式中,所述步骤(1)中阿霉素在混合体系中的浓度为0.4-0.6mg/mL,优选0.44mg/mL。
在本发明的一种实施方式中,所述步骤(2)中DOX@PCN-224与COOH-PEG-COOH的质量比为(2-2.5):1。优选2:1。
在本发明的一种实施方式中,所述步骤(2)中DOX@PCN-224在混合液中的质量浓度为0.8-1.2mg/mL。优选0.9mg/mL。
在本发明的一种实施方式中,所述步骤(3)中羧基修饰的DOX@PCN-224与氨基修饰的半乳糖的质量比为1:0.5-0.8。优选1:0.67。
在本发明的一种实施方式中,所述步骤(3)中的缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl)和N-羟基琥珀酰亚胺(NHS)。
在本发明的一种实施方式中,所述缩合剂中1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与N-羟基琥珀酰亚胺质量比为1.7:1。
有益效果:
本发明药物集肝肿瘤组织靶向性、示踪性于一体的。本发明药物的生物相容性和细胞毒性已被认真评估,在体外研究了该靶向协同治疗纳米体系的稳定性及酸性pH触发药物释放,在HepG2和Huh7细胞系中都研究药物输送,单线态氧的产生能力,以及光动力学治疗和化疗的协同治疗作用。此外,在皮下实体瘤和原位瘤小鼠模型中都进行了体内行为示踪和治疗功效评定,具有优异的示踪和治疗效果。
附图说明
图1:(A)无机纳米材料DOX@Gal-PCN-224的扫描电镜图;(B)无机纳米材料DOX@Gal-PCN-224的透射电镜图;(C)扫描电镜元素映射C-K,N-K,O-K和Zr-K信号;(D)紫外-可见吸收光谱分析:(a)DOX@PCN-224,(b)COOH-PEG-COOH修饰的DOX@PCN-224和(c)DOX@Gal-PCN-224;(E)无机纳米材料DOX@Gal-PCN-224的水合粒径分布图。
图2:在水、PBS缓冲液(pH 7.4)和含有10%FBS的培养基存在下,DOX@Gal-PCN-224水合粒径的稳定性。
图3:在不同的pH条件下无机纳米材料DOX@Gal-PCN-224的释放曲线。
图4:HepG2,Huh7和HEK293细胞与各种浓度的Gal-PCN-224孵育48小时后的细胞存活率。
图5:无机纳米材料DOX@Gal-PCN-224在有或没有半乳糖(1mM)竞争下孵育HepG2,Huh7和HEK293细胞的激光共聚焦图。
图6:HepG2(B1),Huh7(B2)和HEK293(B3)细胞与DOX@Gal-PCN-224在有或没有半乳糖(1mM)竞争下孵育的流式细胞图。四象限图表示DOX和TCPP的荧光信号。
图7:用DOX@Gal-PCN-224孵育的HepG2,Huh7和HEK293细胞中表征1O2生成的激光共聚焦图。
图8:使用不同处理方式的Huh7细胞活死染色图,比例尺为100μm。
图9:(A)将DOX@Gal-PCN-224-RhB和DOX@PCN-224-RhB经尾静脉注射后,在不同时间点的体内成像图;(B)离体器官在不同时间点的成像图。
图10:(A)在不同治疗组小鼠肿瘤的生长曲线(箭头表示光动力学治疗时间);(B)治疗组中经过21天治疗后剥离的肿瘤组织照片:(a)生理盐水,(b)DOX,(c)DOX+光照,(d)PCN-224,(e)PCN-224+光照,(f)DOX@PCN-224,(g)DOX@PCN-224+光照,(h)DOX@Gal-PCN-224和(i)DOX@Gal-PCN-224+光照。
图11:(A)各实验组肝脏部位T1加权成像图:(a)生理盐水,(b)DOX,(c)DOX+光照,(d)PCN-224,(e)PCN-224+光照,(f)DOX@PCN-224,(g)DOX@PCN-224+光照,(h)DOX@Gal-PCN-224和(i)DOX@Gal-PCN-224+光照(白色虚线圈代表肿瘤部位);(B)各实验组经过21天治疗后,切除的带有肿瘤的肝脏组织照片:(a)生理盐水,(b)DOX,(c)DOX+光照,(d)PCN-224,(e)PCN-224+光照,(f)DOX@PCN-224,(g)DOX@PCN-224+光照,(h)DOX@Gal-PCN-224和(i)DOX@Gal-PCN-224+光照(白色虚线圈代表肿瘤部位),比例尺为5mm。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:药物DOX@Gal-PCN-224的制备
将10mL ZrOCl2·8H2O的DMF溶液(15mg/mL)、20mL,TCPP的DMF溶液(2.5mg/mL)和20m苯甲酸的DMF溶液(70mg/mL)分别加入到圆底烧瓶中,边搅拌边向圆底烧瓶里加入4mL阿霉素水溶液(6mg/mL)。然后在90℃下搅拌5小时,随后离心收集并用DMF和水分别洗三次。最后在真空干燥箱内烘干得到粉末产物DOX@PCN-224。
将上面得到的产物DOX@PCN-224溶于水配置成1mg/mL水溶液,取20mL DOX@PCN-224的水溶液和2mL COOH-PEG-COOH的水溶液(5mg/mL,其中COOH-PEG-COOH的Mw=1K,2mL)加入到圆底烧瓶中,在常温下搅拌4小时,随后离心收集并用水洗三次。最后在真空干燥箱内烘干,得到羧基修饰的DOX@PCN-224。
将羧基修饰的DOX@PCN-224(15mg)、氨基修饰的半乳糖(10mg)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl,17mg)和N-羟基琥珀酰亚胺(NHS,10mg)溶于10mL水中,在常温下搅拌48小时。随后离心收集并用水洗三次,最后在真空干燥箱内烘干得到粉末产物DOX@Gal-PCN-224。其中DOX的载药率为14.2%。(载药率=装载的DOX总量/材料产物总量)
实施例2:药物DOX@Gal-PCN-224的表征
将实例1中制得的DOX@Gal-PCN-224通过扫描电镜(SEM)、透射电镜(TEM)、透射电镜元素分析、扫描电镜元素映射、紫外-可见吸收光谱分析和动态光散射技术来表征粒径的分布。
由图1可以看到,制得的DOX@Gal-PCN-224为分布均匀的球形纳米颗粒,粒径为121nm。
材料的稳定性是材料应用在生物医学上的重要前提。由图2可以看到,将无机纳米材料与水、pH 7.4的磷酸盐缓冲液(PBS)和含有10%胎牛血清的培养基孵育7天后,发现粒径没有明显变化,由此可以证明该无机纳米材料稳定性良好。
实施例3:药物DOX@Gal-PCN-224的酸敏感释放
将10mg无机纳米材料DOX@Gal-PCN-224分别置于20mL pH 7.4和5.6的PBS缓冲液中。在37℃下进行搅拌,在固定时间点取上清液测480nm处的吸光度,然后将取的样品返回原释放体系中。根据公式计算DOX的释放百分比,释放百分比(%)=mr/ml,其中mr是释放的DOX量,而ml是装载的DOX总量(1.42mg)。
释放结果如图3所示,无机纳米材料在模仿的生理条件(pH 7.4)下保持稳定,在孵育120小时后略微有15.8%的DOX释放。而在酸性条件下(pH 5.6),DOX的释放速度相对较快(12小时后为25.7%,48小时后为55.4%,120小时后为65.0%)。由此可以说明基于DOX@Gal-MOF的药物递送可用于pH响应释放DOX的肿瘤靶向治疗。
实施例4:药物DOX@Gal-PCN-224细胞毒性的实验
分别将人肝癌细胞HepG2和Huh7细胞,人胚肾细胞HEK293细胞以每孔8×103的密度种植在96孔板上,细胞经过48小时的孵育在孔板中稳定生长后,分别加入实施例1中的无机纳米材料DOX@Gal-PCN-224,浓度分别为0,10,20,40,60,80,100和120μg/mL。材料与细胞共孵育48小时后,将培养基移除,用PBS洗三遍,然后在每个孔中加入100μL未添加酚红的含有0.5mg/mL MTT的培养基,然后每个孔中加入100μL DMSO。已显色的96孔板,用酶标仪检测板中所有孔的吸光度值(λ=490nm)。每种样品重复做6组平行实验。其中,将没有经过材料作用的细胞组定义为100%细胞活性,将只有DMSO溶液而没有细胞的孔定义为空白对照,用以校正各孔中的吸光值。
图4为无机纳米材料DOX@Gal-PCN-224细胞毒性的结果图,结果显示,在实施例1无机纳米材料的浓度从0-120μg/mL浓度范围内,三种细胞的存活率都大于80%,显示该无机纳米材料有较低的毒性和良好的生物相容性。
实施例5:激光共聚焦实验证明药物DOX@Gal-PCN-224能够特异性靶向识别肝癌细胞HepG2和Huh7细胞表面的去唾液酸糖蛋白受体
分别将人肝癌细胞HepG2和Huh7细胞,人胚肾细胞HEK293细胞以每孔8×104的密度种植在激光共聚焦培养皿(35mm)。培养12小时后,半乳糖竞争组加入1mM的半乳糖。继续培养24小时后,移去培养基,用PBS洗三遍。然后加入含有20μg/mL DOX@Gal-PCN-224的培养基孵育3小时。移去培养基,用PBS洗三遍。然后加入4%多聚甲醛在室温下固定15min。随后用4’,6-二脒基-2-苯基吲哚(DAPI)染色细胞核15min。最后用PBS润洗后,置于激光共聚焦下观察。
由图5可以看到,在HepG2和Huh7细胞中可以看到明显的来自无机纳米材料DOX和TCPP的荧光,而COS7和HEK293细胞中几乎观察不到该荧光;并且当在有半乳糖竞争的环境下,HepG2和Huh7细胞内也观测不到DOX和TCPP的荧光。该实验证明DOX@Gal-PCN-224无机纳米材料能够通过半乳糖-去唾液酸糖蛋白受体识别并进入HepG2和Huh7细胞中。
实施例6:流式细胞仪检测证明药物DOX@Gal-PCN-224能够特异性靶向识别肝癌细胞HepG2和Huh7细胞表面的去唾液酸糖蛋白受体
分别将HepG2,Huh7和HEK293细胞以每孔2×105个的密度种植于24孔板。培养12小时后,半乳糖竞争组加入1mM的半乳糖。继续培养24小时,细胞密度达到了90%。将培养基移除,并用PBS洗三次后,将上述三种细胞用含有20μg/mL DOX@Gal-PCN-224的培养基孵育3小时。然后用胰酶将细胞消化下来,以1000rpm的转速离心3分钟,倒掉上清液,将聚集的细胞用PBS重悬,吹散。这一离心过程重复三遍,以除去残留的培养基和无机纳米材料,减少对荧光检测的干扰。最后,将细胞用PBS分散,置于流式管中,用流式细胞仪检测各组细胞的荧光强度。
如图6所示,HEK293细胞在不同环境下,DOX@Gal-PCN-224无机纳米材料进入细胞的速度基本没有差别,与未经过DOX@Gal-PCN-224处理的对照组基本无差别。这是由于HEK293细胞表面只有低表达的去唾液酸蛋白受体,因此无机纳米材料无法通过表面半乳糖-去唾液酸糖蛋白受体靶向介导的内吞作用快速进入细胞内。然而HepG2和Huh7细胞在不同环境下,DOX@Gal-PCN-224无机纳米材料进入细胞的速度明显不同。对于表面去唾液酸糖蛋白受体被提前饱和的情况下,DOX@Gal-PCN-224无机纳米材料无法通过表面键连的半乳糖识别HepG2和Huh7细胞,只能通过非靶向的内吞作用进入到肿瘤细胞中,因此DOX和TCPP的荧光强度很低;而对于表面受体过度表达的细胞,DOX@Gal-PCN-224无机纳米材料能够通过表面键连的半乳糖快速的与肿瘤细胞表面去唾液酸糖蛋白受体结合,然后通过受体介导的内吞作用进入到肿瘤细胞中。
实施例7:药物DOX@Gal-PCN-224产1O2的能力
2’,7’-二氯荧光黄双乙酸盐(DCFH-DA)用于评估在活细胞中DOX@Gal-PCN-224产生1O2的能力。将HepG2,Huh7和HEK293细胞与DOX@Gal-PCN-224(20μg/mL)孵育3小时。除去培养基后,将细胞用PBS洗涤3次。然后将含有DCFH-DA(10μM)的培养基孵育细胞,用660nm LED灯照射10分钟。在37℃下再孵育15分钟后,将细胞用PBS洗涤3次,并使用共聚焦显微镜在488nm处激发捕获DCFH-DA染色的荧光图像。无光照组除不进行光照外,其余与上面保持一致。
由图7可以看到,HepG2和Huh7细胞经过光照后,能够产生1O2,从而显示出了DCF绿色荧光。而没经过光照的HepG2和Huh7细胞,只能看到微弱的绿色荧光,说明没有光照的触发,几乎没有1O2产生。HEK393细胞不管是否有光照都看不到明显的绿色荧光,这是因为在3小时内只有极少数的无机纳米材料进入了该细胞内,从而没有足够的光敏剂用来产生1O2。
实施例8:药物DOX@Gal-PCN-224的体外治疗效果
通过活死染色法和相应的MTT实验来检测无机纳米材料DOX@Gal-PCN-224的体外治疗效果。
将人肝癌细胞Huh7以每孔8×104的密度种植在激光共聚焦培养皿(35mm)。培养24小时后,将上述细胞用分别含有10μg/mL DOX、60μg/mL PCN-224、70μg/mL DOX@PCN-224(载药率14.2,DOX含量约为10μg/mL)或70μg/mL DOX@Gal-PCN-224(载药率14.2,DOX含量约为10μg/mL)的培养基孵育24小时。然后光照组用660nm的光源照射10min,继续孵育24小时后,进行Calcein-AM/PI活死共染。最后置于激光共聚焦下观察。相同的处理后通过MTT实验进一步定量每组实验的治疗效果。
活死染色激光共聚焦图如图8所示,绿色荧光指示的是活细胞,红色荧光指示的是死细胞。加入PBS的对照组,不管是否光照,都只观察到了绿色荧光,说明几乎没有细胞凋亡。加入DOX的化疗组,不管是否光照,都只能观察到零星的红色荧光,说明单独的化疗只能引起Huh7细胞的少量凋亡。加入PCN-224的光动力治疗组,没有施加光照时,几乎观察不到红色荧光;施加光照后,我们看到了一定量的红色荧光,说明有部分细胞由于光动力学治疗而导致了凋亡。加入DOX@PCN-224的化疗和光动力学治疗协同治疗组,没有施加光照时,也有部分细胞凋亡,这是因为化疗而导致的细胞凋亡;施加光照后,我们可以看到大量的细胞凋亡,说明化疗和光动力学治疗协同治疗加剧了细胞的凋亡。加入DOX@Gal-PCN-224的靶向化疗和光动力学治疗协同治疗组,没有施加光照时,也有大量的细胞凋亡,这体现了其靶向化疗的效果;施加光照后,几乎看不到绿色荧光,说明由于靶向协同治疗几乎导致了所有细胞凋亡,由此显示出了我们靶向协同治疗的优势。
MTT结果如表1所示,各实验组细胞存活率与活死染色结果保持一致,进一步验证了无机纳米材料DOX@Gal-PCN-224的体外治疗效果。其中,金属骨架材料本身基本没有抑制效果,但是负载DOX后,能够协同DOX,促进其抑制效果的提升。
表1不同药物治疗体系的体外治疗效果
实施例9:药物DOX@Gal-PCN-224的体内分布效果
为了达到更好的荧光成像效果,首先将罗丹明B(RhB)修饰到了无机纳米材料上,将其记为DOX@PCN-224-RhB和DOX@Gal-PCN-224-RhB。
对于皮下实体瘤小鼠模型的建立,取4周龄平均体重为14-17g的雄性BALB/c裸鼠,在右臀处接种0.1mL 6×106个细胞/mL PBS的细胞数。四周后待肿瘤尺寸超过200mm3(体积=0.52×肿瘤长度×肿瘤宽度2)时,将小鼠分为2组,每组5只小鼠。分别尾静脉注射DOX@PCN-224-RhB(0.1mL 0.4mg/mL)和DOX@Gal-PCN-224-RhB(0.1mL 0.4mg/mL)。通过小动物成像仪(Bruker In Vivo Xtreme II)在设定的时间点(3,6,12,24,48小时)检测RhB的荧光信号。然后处死小鼠,剥离出心、肝、脾、肺和肾,检测各个器官的RhB荧光信号。
体内成像结果如图9所示,将注射DOX@Gal-PCN-224-RhB的实验组命名为靶向组,将注射DOX@PCN-224-RhB的实验组命名为非靶向组。由图9A可以观察到,相比于非靶向组,靶向组在肿瘤部位的浓聚效果更好。当尾静脉注射3小时和6小时后,我们可以观察到靶向组和非靶向组的无机纳米材料都已经遍布小鼠全身。靶向组尾静脉注射12小时和24小时后,在肿瘤部位观察到了更明显的荧光,说明由于靶向作用,更多的无机纳米材料进入到了肿瘤部位。当尾静脉注射48小时后,观察到整个体内的荧光减弱,表明无机纳米材料在体内循环过程中被逐渐代谢。图9B是各个时间点剥离出来的器官成像图,同样也反映了这一趋势。由此我们得出靶向无机纳米材料更易聚集在肿瘤部位,并且在肿瘤部位滞留时间更久。
实施例10:药物DOX@Gal-PCN-224在皮下实体瘤小鼠模型中抑制肿瘤的生长
待小鼠皮下瘤尺寸超过50mm3时,将小鼠随机分为9组,每组5只小鼠:(1)saline,(2)free DOX saline(2mg/kg),(3)free DOX+660nm laser(2mg/kg),(4)PCN-224(12mg/kg),(5)PCN-224+660nm laser(12mg/kg),(6)DOX@PCN-224(14mg/kg),(7)DOX@PCN-224+660nm laser(14mg/kg),(8)DOX@Gal-PCN-224(14mg/kg),and(9)DOX@Gal-PCN-224+660nmlaser(14mg/kg)。第一次尾静脉注射的前一天,我们将其设定为“第0天”。在规定的时间点(第1,4,7,10,13,16,19天)对上述各实验组小鼠进行尾静脉注射。对于光照组,在第2、8和14天对其肿瘤部位用660nm的光源(20mW/cm2)照射10分钟。在规定的时间点(第3,6,9,12,15,18,21天)对上述各实验组的肿瘤体积和小鼠体重进行测量。
如图10所示,DOX@Gal-PCN-224+660nm laser,DOX@Gal-PCN-224和DOX@PCN-224+660nm laser都有很好的抑制肿瘤生长效果。根据最后一个实验天得到的各组肿瘤体积数据计算出肿瘤抑制效率(肿瘤抑制效率=(1-实验组肿瘤体积平均值/生理盐水对照组肿瘤体积平均值)×100%),其中DOX@Gal-PCN-224+660nm laser组抑制效率最高为97.8%。可以得出结论,DOX@Gal-PCN-224+660nm laser能够最大化抑制肿瘤生长。
表2不同药物治疗体系的肿瘤抑制结果
实施例11:药物DOX@Gal-PCN-224在原位瘤小鼠模型中抑制肿瘤的生长
对于原位瘤小鼠模型的建立,将剥离出来的皮下肿瘤组织切割成2mm×3mm×3mm尺寸的小组织块,将小组织块置于接种针中,接种于小鼠肝脏的肝包膜内。待原位瘤模型建立2周后,将原位荷瘤小鼠随机分为9组,每组5只小鼠。分组类别和给药时间与皮下瘤实验保持一致,小鼠体重测量时间也与皮下瘤实验保持一致。第11天时,利用光纤将660nm光源引入到原位肿瘤表面,照射10min。第20天时,对所有实验小鼠的肝脏部位进行T1-加权磁共振成像(Aspect Imaging,Israel)。
如图11所示,通过T1-加权磁共振成像图和原位肿瘤图可以看到,DOX@Gal-PCN-224+660nm laser组几乎看不到肿瘤区域,是所有实验组中最小的,说明DOX@Gal-PCN-224+660nm laser组肿瘤抑制效率最高,与皮下瘤模型抑瘤效果保持一致。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (7)
1.一种靶向治疗肝脏疾病的药物,其特征在于,所述药物的制备方法包括如下步骤:
(1)化疗药物@-PCN-224的制备:
将ZrOCl2·8H2O、TCPP和苯甲酸分散在有机溶剂中,混匀后,加入化疗药物形成混合体系,80-100℃下进行反应,然后固液分离取沉淀,洗涤、干燥,即得化疗药物@PCN-224;所述化疗药物选自如下的一个或多个:阿霉素、索拉非尼、5-氟尿嘧啶;
(2)将步骤(1)得到的化疗药物@PCN-224和COOH-PEG-COOH分散在水中形成混合液,常温下进行反应,反应结束后固液分离取沉淀,洗涤、干燥即得羧基修饰的化疗药物@PCN-224;
(3)将步骤(2)所得的羧基修饰的化疗药物@PCN-224、氨基修饰的半乳糖、缩合剂溶于水中,常温下进行反应;反应结束后固液分离取沉淀,洗涤、干燥即得化疗药物@Gal-PCN-224;
所述步骤(1)中化疗药物、ZrOCl2·8H2O、TCPP和苯甲酸的质量比为1:(5-8):(2-4):(50-60)。
2.根据权利要求1所述的药物,其特征在于,所述步骤(1)中化疗药物在混合体系中的浓度为0.4-0.6 mg/mL。
3.根据权利要求1所述的药物,其特征在于,所述步骤(2)中化疗药物@PCN-224与COOH-PEG-COOH的质量比为(2-2.5):1。
4.根据权利要求1所述的药物,其特征在于,所述步骤(2)中化疗药物@PCN-224在混合液中的质量浓度为0.8-1.2 mg/mL。
5.根据权利要求1所述的药物,其特征在于,所述步骤(3)中羧基修饰的化疗药物@PCN-224与氨基修饰的半乳糖的质量比为1:0.5-0.8。
6.根据权利要求1-5任一所述的药物,其特征在于,所述步骤(3)中的缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺。
7.根据权利要求6所述的药物,其特征在于,所述缩合剂中1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与N-羟基琥珀酰亚胺质量比为1.7:1。
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