CN115487310A - 一种靶向药物及其制备方法和应用 - Google Patents
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Abstract
本发明涉及一种靶向药物及其制备方法和应用,涉及药物制备技术领域。本发明的靶向药物,其为单层片状钛迈克烯(Ti3C2),所述单层片状钛迈克烯上修饰有透明质酸(HA),其表达式为Ti3C2‑HA。本发明的靶向药物的制备方法,包括步骤(1)、制备单层片状Ti3C2;步骤(2)、采用透明质酸修饰步骤(1)制备的单层片状Ti3C2,得到靶向药物Ti3C2‑HA。本发明还提供一种靶向药物在制备治疗炎症性肠病的药物上的应用。本发明的药物,能够保证药物在复杂胃肠道环境中稳定性的前提下,有效靶向富集于IBD患者炎性病变部位发挥治疗作用,同时避免全身分布保证安全性。
Description
技术领域
本发明涉及药物制备技术领域,具体涉及一种用于炎症性肠病治疗的靶向药物及其制备方法和应用。
背景技术
炎症性肠病(Inflammatory Bowel Disease,IBD)是一种胃肠道非传染性慢性炎症,主要包括克罗恩病(Crohn’s Disease,CD),溃疡性结肠炎(Ulcerative Colitis,UC),多发于中青年患者中,病程迁延不愈,严重影响患者生活工作质量,给个人、家庭和社会带来极大的负担。
目前IBD无法治愈,临床上常用的传统药物主要有氨基水杨酸类、激素以及小分子生物制剂,但它们靶向性不强、效果不一并且往往伴随着严重的不良反应。因此针对IBD患者开发有效、安全、经济的创新疗法具有重要的临床和社会意义。
IBD的发生机制尚不清楚,主要涉及病变部位大量活性氧成分(ROS)生成、炎症免疫反应失调、肠道屏障功能受损以及菌群失衡。开发有效清除局部ROS,进而调节炎症免疫反应、恢复肠道屏障功能和菌群平衡的药物是治疗IBD的主要研究方向之一。
虽然当前已有50多种纳米药物被批准应用于临床,且临床转化成功率接近传统药物的2倍。并且文献也报道了一些用于治疗IBD的纳米药物基础研究,但是还是存在一些不足,主要有:1.静脉注射存在全身弥散分布、脏器富集滞留和难以靶向抵达病变部位;2.口服类消化道稳定性较差,治疗效果降低。
发明内容
有鉴于此,本发明要解决的技术问题是提供一种用于IBD治疗的靶向药物及其制备方法和应用。本发明的药物,能够保证药物在复杂胃肠道环境中稳定性的前提下,有效靶向富集于IBD患者炎性病变部位发挥治疗作用,同时避免全身分布保证安全性。
为了解决上述技术问题,本发明的技术方案具体如下:
本发明提供一种靶向药物,其为单层片状钛迈克烯(Ti3C2),所述单层片状钛迈克烯上修饰有透明质酸(HA),其表达式为Ti3C2-HA。
在上述技术方案中,优选的是,所述靶向药物的平均和中位粒径分别为149.43nm和300.54nm。
在上述技术方案中,优选的是,所述透明质酸的分子量为20-40万道尔顿。
本发明还提供一种靶向药物的制备方法,包括以下步骤:
步骤(1)、制备单层片状Ti3C2;
步骤(2)、采用透明质酸修饰步骤(1)制备的单层片状Ti3C2,得到靶向药物Ti3C2-HA。
在上述技术方案中,优选的是,所述步骤(1)包括以下步骤:
采用氢氟酸蚀刻Ti3AlC2后超声剥离合成单层片状Ti3C2。
在上述技术方案中,进一步优选的是,所述步骤(1)具体包括以下步骤:
将LiF和HCl混合于聚四氟乙烯容器中,室温搅拌反应30min,缓慢加入适量MAX相Ti3AlC2粉末,在35℃下将混合物搅拌反应24小时,然后用去离子水洗涤、离心和倾析直到pH达到约为6,得到多层片状Ti3C2,将其继续分散在去离子水中,超声剥离48h,然后用去离子水洗涤、离心三次得到单层片状Ti3C2。
在上述技术方案中,优选的是,所述步骤(2)包括以下步骤:
取步骤(1)所制备的单层片状Ti3C2分散在去离子水中,加入透明质酸,超声下聚合,聚合结束后离心分离,然后用去离子水洗涤离心,得到靶向药物Ti3C2-HA。
在上述技术方案中,进一步优选的是,步骤(2)中单层片状Ti3C2与透明质酸的质量比为1:1。
在上述技术方案中,进一步优选的是,步骤(2)中超声下聚合的时间为48小时;去离子水洗涤离心具体为:去离子水洗涤后于13000rpm下离心10min,重复次数为三次。
本发明还提供一种靶向药物在制备治疗炎症性肠病的药物上的应用。
本发明的有益效果是:
本发明提供的靶向药物,口服治疗IBD具备以下优势:
(1)稳定性:在胃肠道环境(强酸和弱碱)中能够保持结构和功能稳定。
(2)安全性:生物相容性好,同时不被肠道吸收不发生全身分布。
(3)靶向性:Ti3C2-HA带负电,可与肠道炎症病灶正电性蛋白结合(正常上皮负电性);同时HA可与炎症病灶大量表达CD44结合。
(4)有效性:Ti3C2-HA具备高效的ROS清除能力和炎症免疫调节能力。
本发明提供的靶向药物的制备方法,采用生物兼容性极佳的钛迈克烯(Ti3C2)作为主要合成原料,通过氢氟酸(HF)蚀刻Ti3AlC2得单层片状Ti3C2,通过透明质酸(HA)对单层片状Ti3C2进行修饰,得到具有如上优势的Ti3C2-HA药物。并且本发明的制备方法,所采用的原料价格低廉易得,合成方法简单,是一种简单、绿色的合成方法。
本发明提供的靶向药物可用于IBD治疗,能够保证药物在复杂胃肠道环境中稳定性的前提下,有效靶向富集于IBD患者炎性病变部位发挥治疗作用,同时避免全身分布保证安全性。
附图说明
下面结合附图和具体实施方式对本发明作进一步详细说明。
图1为Ti3C2和Ti3C2-HA的结构及电位表征图,其中Ti3C2和Ti3C2-HA的TEM图(A),Ti3C2和Ti3C2-HA的电位结果图(B),Ti3C2-HA的粒径分布图(C)。
图2为Ti3C2-HA的安全性考察结果图,其中体外(A),体内(B)。
图3为Ti3C2-HA的稳定性考察结果图,其中(A-C)分别为胃肠道模拟液(GFS)处理前后的TEM,XPS和Zeta电位结果图,(D-F)分别为处理前后Ti3C2-HA对H2O2,O2 ·-,ONOO·-的清除能力检测。
图4为Ti3C2-HA的靶向性考察结果图,其中Ti3C2-HA(A)以及荧光素标记的Ti3C2-HA(B)均富集于IBD肠道病变部位(A,红色圆圈)。
图5为Ti3C2-HA的有效性考察结果图,其中(A)为不同处理组小鼠结肠长度分析图,(B)为不同处理组小鼠疾病活动指数(DAI)分析图,(C-D)分别为不同处理组小鼠炎症因子IL-6和TNFα水平检测图,(E)为不同处理组小鼠肠道菌群β多样性分析图。
具体实施方式
以下实施例所用的试剂均为商品化产品。
实施例
(1)单层片状Ti3C2的制备:
通过将2g LiF粉末和20mL 9M的HCl溶液混合于聚四氟乙烯容器中,室温磁性搅拌30min,缓慢加入2g MAX相Ti3AlC2粉末(M代表早期过渡金属元素,A代表第13或14族元素,X代表碳或氮元素),在35℃下将混合物搅拌反应24小时,然后用去离子水洗涤、离心(13000rpm 10min)和倾析直到pH达到约为6,得到多层片状Ti3C2,将其继续分散在去离子水中,超声剥离48h,然后用去离子水洗涤、离心(13000rpm 10min),重复三次得到单层片状Ti3C2。
(2)透明质酸修饰片状Ti3C2的制备
取(1)中单层片状Ti3C2烘干称重,按单层片状Ti3C2与透明质酸的质量比1:1加入透明质酸(分子量范围20-40万道尔顿),混合于去离子水中,室温下超声48小时,透明质酸聚合于Ti3C2表面后,用去离子水洗涤、离心(13000rpm10min),重复三次得到Ti3C2-HA药物。所得Ti3C2-HA为不规则片状,其平均和中位粒径分别为149.43nm和300.54nm,带负电荷(参见图1)。
(3)体内外实验验证Ti3C2-HA的治疗效果
体外安全性:不同浓度Ti3C2-HA(10、20、40、80、160、320μg/mL)分别与HT29共孵育48小时,MTT检测细胞活性。
体内安全性:分别给于8周雄性小鼠H2O和Ti3C2-HA灌胃(10mg/Kg,隔天一次,共四次,每组4只小鼠),每天监测小鼠体重变化。
对酸稳定性:给于Ti3C2-HA酸处理(pH=1.5)4小时后碱处理(pH=8)1小时,通过TEM和XPS对处理前后Ti3C2-HA进行表征,并对ROS(H2O2,ONOO·-,O2 ·-)清除能力进行检测。
具体检测过程:1.将不同浓度的H2O2(0,0.8,1.6,3.2mM),ONOO·-(0,90,180,360μM)分别与Ti3C2-HA混合后避光反应12小时,紫外分光光度法检测Ti3C2-HA的吸光度变化,反映H2O2,ONOO·-清除效率。2.反应体系(3mL)配制:核黄素(20μM)、甲硫氨酸(0.01M),NBT(0.01M)、PBS(0.01M,pH7.4)和不同浓度(0,25,50,100μg/mL)的Ti3C2-HA。紫外照射反应5min,紫外分光光度法测定560nm波长处吸光度变化情况,反映O2 ·-清除效果。
靶向性检测:给于8周的雄性小鼠自由饮用3%DSS溶液一周,建立小鼠IBD模型。给于健康小鼠和模型小鼠Ti3C2-HA(以及荧光素标记的Ti3C2-HA)灌胃24小时后取结肠组织切片进行电镜观察和结肠荧光信号检测,每组3只小鼠。
有效性检测:给于8周的雄性小鼠自由饮用3%DSS溶液一周,建立小鼠IBD模型。分别给于相同剂量(10mg/Kg,隔天一次,共四次,每组6只小鼠)的HA,Ti3C2,Ti3C2-HA,5-ASA,监测小鼠体重变化,症状。第8天处死小鼠,取结肠组织和粪便,进行炎症因子及菌群检测。
检测结果如下:
从药物的安全性角度考虑,钛元素具有良好的生物兼容性,在临床上被广泛用于医疗器材和植入材料;而且透明质酸广泛存在人体细胞间质和关节滑液等,也被临床用于治病治疗,因此Ti3C2-HA理论上是安全的。对其生物兼容性进行考察,通过细胞毒性试验(MTT),发现其对细胞的生长、发育和复制均无不良影响,在320μg/mL的高浓度条件下,细胞的存活不受影响;体内实验表明,在高治疗剂量下(30mg/Kg体重)对小鼠无明显毒副作用(参见图2)。以上实验数据说明,Ti3C2-HA具有非常良好的生物兼容性。
从药物稳定性角度考虑,钛元素对酸碱稳定,因此对胃肠道环境稳定。通过胃肠道模拟液(GFS)处理Ti3C2-HA后,对其结构和功能稳定性进行检测,结果表明处理前后其结构和功能稳定性良好(参见图3)
从药物的靶向性角度考虑,Ti3C2-HA可通过静电相互作用和受体配体结合靶向富集IBD患者肠道炎症病灶。通过对组织切片进行电镜观察,同时对Ti3C2-HA进行荧光素标记,检测肠道组织荧光水平,结果均表明Ti3C2-HA能靶向富集病变部位(参见图4)。
从药物的有效性角度考虑,Ti3C2-HA对IBD小鼠模型具有显著治疗效果,改善症状,恢复肠道屏障功能,降低炎症以及菌群调节等(参见图5)。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种靶向药物,其特征在于,其为单层片状钛迈克烯(Ti3C2),所述单层片状钛迈克烯上修饰有透明质酸(HA),其表达式为Ti3C2-HA。
2.根据权利要求1所述的靶向药物,其特征在于,其平均和中位粒径分别为149.43nm和300.54nm。
3.根据权利要求1所述的靶向药物,其特征在于,所述透明质酸的分子量为20-40万道尔顿。
4.一种权利要求1-3任意一项所述的靶向药物的制备方法,其特征在于,包括以下步骤:
步骤(1)、制备单层片状Ti3C2;
步骤(2)、采用透明质酸修饰步骤(1)制备的单层片状Ti3C2,得到靶向药物Ti3C2-HA。
5.根据权利要求4所述的制备方法,其特征在于,所述步骤(1)包括以下步骤:
采用氢氟酸蚀刻Ti3AlC2后超声剥离合成单层片状Ti3C2。
6.根据权利要求5所述的制备方法,其特征在于,所述步骤(1)具体包括以下步骤:
将LiF和HCl混合于聚四氟乙烯容器中,室温搅拌反应30min,加入MAX相Ti3AlC2粉末,在35℃下将混合物搅拌反应24小时,然后用去离子水洗涤、离心和倾析直到pH达到6,得到多层片状Ti3C2,将其继续分散在去离子水中,超声剥离48h,然后用去离子水洗涤、离心三次得到单层片状Ti3C2。
7.根据权利要求4所述的制备方法,其特征在于,所述步骤(2)包括以下步骤:
取步骤(1)所制备的单层片状Ti3C2分散在去离子水中,加入透明质酸,超声下聚合,聚合结束后离心分离,然后用去离子水洗涤离心,得到靶向药物Ti3C2-HA。
8.根据权利要求7所述的制备方法,其特征在于,步骤(2)中单层片状Ti3C2与透明质酸的质量比为1:1。
9.根据权利要求7所述的制备方法,其特征在于,步骤(2)中超声下聚合的时间为48小时;去离子水洗涤离心具体为:去离子水洗涤后于13000rpm下离心10min,重复次数为三次。
10.一种权利要求1-3任意一项所述的靶向药物在制备治疗炎症性肠病的药物上的应用。
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