CN116602963A - 维替泊芬在制备抑制肺纤维化的药物中的应用 - Google Patents
维替泊芬在制备抑制肺纤维化的药物中的应用 Download PDFInfo
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- CN116602963A CN116602963A CN202310543527.8A CN202310543527A CN116602963A CN 116602963 A CN116602963 A CN 116602963A CN 202310543527 A CN202310543527 A CN 202310543527A CN 116602963 A CN116602963 A CN 116602963A
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- verteporfin
- pulmonary fibrosis
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Life Sciences & Earth Sciences (AREA)
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- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
Abstract
本发明涉及维替泊芬在制备抑制肺纤维化的药物中的应用。本发明所述维替泊芬通过抑制纤维化生成上皮细胞和成纤维细胞使其具有抗肺纤维化的性能，可用于肺纤维化相关疾病治疗或预防的药物制备。
Description
技术领域
本发明涉及药物技术领域，具体涉及维替泊芬在制备抑制肺纤维化的药物中的应用。
背景技术
肺脏是人类重要的生命器官，行使重要的全身供氧功能，也是各种危重疾病时最易受损的器官，常表现为急性呼吸窘迫综合征(acute respiratory distress syndrome，ARDS)。肺在受到损伤后会启动修复响应，部分细胞会产生可控可逆的纤维化以帮助损伤修复，但是如果该过程失控导致过度激活，就会产生不可逆的纤维化。因此，ARDS最常见的转归就是肺纤维化。因此适当抑制纤维化相关细胞亚群的功能，抑制纤维化的过度激活，能有效减轻后期纤维化的负面危害，帮助肺脏保持功能。但目前并没有特异性抑制肺纤维化相关细胞亚群的有效药物。
维替泊芬为已上市成品药，适应症为继发于年龄相关性黄斑变性，病理性近视或可疑眼组织胞浆菌病的，以典型性为主型中心凹下脉络膜新生血管形成的患者。
发明内容
本发明的目的是提供一种维替泊芬在制备抑制肺纤维化的药物中的应用。本发明所述维替泊芬通过抑制纤维化生成上皮细胞和成纤维细胞使其具有抗肺纤维化的性能，可用于肺纤维化相关疾病治疗或预防的药物制备。
本发明的技术方案是：
维替泊芬在制备抑制肺纤维化的药物中的应用。
所述维替泊芬靶向上皮细胞和成纤维细胞。
所述药物为抑制肺纤维化的抑制剂。
所述药物采用静脉注射给药。
所述药物用量为每公斤体重每次1-10毫克。
维替泊芬在制备抑制肺纤维化的药物组合物中的应用。
所述药物组合物包括维替泊芬和药物学上可接受的辅料或载体。
所述药物组合物中维替泊芬的质量百分含量为5～99％。
所述药物组合物中维替泊芬的质量百分含量为50～90％。
申请人通过体外分子实验和活性验证，维替泊芬能够抑制肺纤维化，试验结果表明，维替泊芬能有效抑制肺纤维化上皮细胞和成纤维细胞的功能，进而抑制纤维化的形成；且试验中发现维替泊芬对细胞基本无毒，说明维替泊芬可作为制备抑制肺纤维化的抑制剂。
本发明所述药物组合物的辅料包括盐，所述盐有机酸包括酒石酸、苯磺酸、甲酸、甘油磷酸、乙酸、乙二酸、樟脑酸、丁酸、果胶酯酸、马来酸、环戊烷丙酸、琥珀酸、烟酸、己二酸、藻酸、柠檬酸、天冬氨酸、樟脑磺酸、二葡糖酸、十二烷基硫酸、乙磺酸、葡庚糖酸、2-萘磺酸、庚酸、新戊酸己酸、延胡索酸、2-羟基乙磺酸、3-苯基丙酸、丙酸、乳酸、甲磺酸、扑酸、对-甲苯磺酸和十一烷酸中的一种或多种。所述有机酸采用本领域技术人员熟知的常规市售产品即可。
本发明所述辅料包括赋形剂，如，甘露醇、乳糖、蔗糖和果糖中的一种或几种。所述赋形剂采用本领域技术人员熟知的上述赋形剂的常规市售产品即可。
本发明所述维替泊芬结构如下：
附图说明
图1为本发明提供的维替泊芬在不影响肺修复速度的情况下抑制后期纤维化的图片；
图2为本发明提供的维替泊芬能靶向上皮细胞和成纤维细胞并抑制类器官生长的图；
图3为本发明提供的维替泊芬能靶向人源肺切片中的上皮细胞的图片。
具体实施方式
下面结合具体实施例对本发明所述的维替泊芬在制备抑制肺纤维化的药物中的应用做进一步详细的介绍，本发明的技术方案包括但不限于以下实施例。
1、试剂：
博来霉素(Gibco，货号：R25001)；
LPS(Sigmaaldrich，货号：L5418)；
维替泊芬(Sigmaaldrich，货号：SML0534)
DMEM培养基(Thermofisher,货号：10370021)
血清(Thermofisher,货号：10091)
基质胶(Biocoat，货号：354234)
胰蛋白酶(GIBCO,货号：R001100)
2、样品来源：C57BL/6小鼠购买于中国人民解放军陆军特色医学中心动物中心；肺癌临床样本来源于中国人民解放军陆军特色医学中心胸外科。
实施例1利用动物模型筛选抗纤维化药物
将LPS滴加到小鼠鼻腔中，通过鼻饲法诱导肺损伤小鼠(C57小鼠为通利华公司购买)模型，随后给予小鼠不同药物进行药物对修复速度影响的评价。通过鼻饲法单次给予LPS(15mg/kg)后，隔天通过尾静脉注射维替泊芬40微克/只进行治疗，药物每两天给予一次。在诱导后第3天和第9天取出肺组织，观察肺部伤情，评估肺修复速度。
使用博来霉素诱导的小鼠肺纤维化模型进行效果评价。通过气管单次给予博来霉素20微克/只后，隔天通过尾静脉注射维替泊芬40微克/只进行治疗，药物每两天给予一次，共给药5次。在诱导后27天取肺部组织，进行切片染色，评估纤维化程度。
具体分组包括对照组(生理盐水组)、药物处理组(维替泊芬处理组)，对照组和药物处理组各六只小鼠。通过对肺组织切片进行HE和马松染色，判断纤维化的程度。最后得到抗纤维化活性药物维替泊芬(见图1，图1为维替泊芬在不影响肺修复速度的情况下抑制后期纤维化的图片，其中，A：展示了药物维替泊芬对肺脏的修复速度并没有显著影响；B：展示了维替泊芬能够显著抑制后期纤维化的形成；底部图片展示放大后的图片，维替泊芬能够有效的保留肺组织的结构功能)。
实施例2人源肺类器官模型构建
根据研究需要，获取人源肺组织样本(癌旁)，放置于无菌冻存管中，冰上转移至无菌超净台。取出样本放置于含有抗生素的PBS中震荡洗涤5min，眼科弯剪剪碎，加入2ml胰蛋白酶，37℃水浴消化15min，加入含有10％血清的DMEM培养基终止消化，100目过滤筛过滤，1000rpm离心5min。去除上清后，使用培养基重悬细胞，按基质胶与细胞悬液1:1的比例混合接种到培养皿中，放置到二氧化碳培养箱培养，隔天换液观察。培养10天的肺类器官采用加入0.1mg/ml维替泊芬进行处理，7天后收集样品，检测类器官形态，同时收集类器官进行免疫荧光染色。结果显示，相较于对照组，维替泊芬具有显著抑制类器官生长的活性(见图2中的A)。
图2为维替泊芬能靶向上皮细胞和成纤维细胞并抑制类器官生长的图。其中，A：类器官培养后显微镜结果显示，相较于对照组，维替泊芬能够进入类器官内(维替泊芬有不透光性)，并显著抑制类器官生长(类器官大小)；B：显微镜直接观察类器官的免疫荧光结果，维替泊芬与成纤维细胞和二型上皮细胞共定位。
实施例3人源肺组织RNAscope染色
获取人源肺组织样本(癌旁)制备冰冻切片。购买待测基因(PDGFR,SPC,T1α基因的探针购买于acdbio公司)的探针。针对RNAscope多通道荧光的检测，实验步骤方法如下：首先，向烧杯中倒入靶标修复液(购买于acdbio公司)，用锡箔纸覆盖烧杯，将烧杯放在热板上。将加热板调至高档，加热10-15分钟至靶标修复试剂达到缓慢沸腾状态(98-102℃)后，将热板调至低档，以维持缓慢沸腾状态。使用前煮沸不超过30分钟。用镊子将粘有样品的载玻片非常缓慢地浸没在靶标修复试剂中，5分钟。将热载玻片从靶标修复试剂中转移至盛有蒸馏水的染色皿中。上下移动载玻片，清洗载玻片3次/5分钟。随后将载玻片转移至100％乙醇，孵育3分钟，室温下完全干燥载玻片。将载玻片置于载玻片夹上，滴加约5滴RNAscope蛋白酶III试剂(购买于acdbio公司)，以完全覆盖切片，放入杂交炉，40摄氏度，30分钟。从杂交炉取出湿盒并取出载玻片夹，立即将载玻片夹放入盛有蒸馏水的清洗槽中。不时地晃动清洗槽，清洗载玻片3-5次。去除载玻片夹中的载玻片上多余的液体，滴加4-6滴探针混合物，完全覆盖样本，放入湿盒，盖上盖，放入杂交炉。在40℃下孵育2小时。取出载玻片夹，立即将其放入盛有新鲜清洗缓冲液的清洗槽中。不时地晃动清洗槽，在室温下清洗载玻片2分钟/2次。去除载玻片上多余的液体，滴加4-6滴RNAscope多通道二代荧光AMP(购买于acdbio公司)，完全覆盖样本。将载玻片夹放入湿盒，盖上盖，放入杂交炉。在40℃下孵育30分钟。后续根据通道数的需求重复AMP的孵育步骤。根据Perkin Elmer公司的TSA荧光染料说明书，配置荧光染料储备液。滴加150-200μL稀释的荧光染料完全覆盖样本。将载玻片夹放入湿盒，盖上盖，放入杂交炉。在40℃下孵育30分钟。用新鲜RNAscope清洗缓冲液洗涤载玻片，在室温下洗涤2分钟,重复此步骤1次。去除载玻片上多余的液体，滴加4-6滴多通道二代荧光HRP阻断剂(购买于acdbio公司)，完全覆盖样本。将载玻片夹放入湿盒，盖上盖，放入杂交炉。在40℃下孵育15分钟。取出载玻片夹，立即将其放入盛有新鲜清洗缓冲液的清洗槽中。不时地晃动清洗槽，在室温下清洗载玻片2分钟,重复此步骤1次。最后，可使用荧光显微镜进行观察拍照。RNAscope多通道荧光检测结果能观察到单细胞上原位RNA基因的表达，染色结果为散点或成簇的荧光点。该技术能实现器官单细胞水平上同时定量多个RNA的表达，以在获得单细胞中拷贝RNA表达数据的同时提供完整的组织形态学信息。
结果显示维替泊芬能够靶向部分细胞亚群，且不靶向YAP蛋白，参见图3，图3为维替泊芬能靶向人源肺切片中的上皮细胞的图片，其中，A：展示了药物维替泊芬靶向部分二型上皮细胞；B：展示了维替泊芬与YAP蛋白并不重叠，说明维替泊芬在肺组织中并没有靶向YAP蛋白。
本发明基于旧药新用策略，利用动物模型方法筛选机械信号通路相关药物化合物对肺损伤修复以及后期纤维化的影响。能够阻止肺纤维化的形成，并在一定程度上逆转肺纤维化的形成。相比于从零开始的新药研发，旧药新用基于已有药物的重新开发能够节省大量前期研发投入和新药研发时间。结合体外分子实验和活性验证等方法，大大增加了结果的可靠性。本发明提供了全新的通过直接抑制肺脏中部分细胞亚群从而抑制肺损伤后纤维化发生的治疗和预防药物——维替泊芬。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.维替泊芬在制备抑制肺纤维化的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述维替泊芬靶向上皮细胞和成纤维细胞。
3.根据权利要求1所述的应用，其特征在于：所述药物为抑制肺纤维化的抑制剂。
4.根据权利要求1所述的应用，其特征在于：所述药物采用静脉注射给药。
5.根据权利要求1所述的应用，其特征在于：所述药物用量为每公斤体重每次1-10毫克。
6.维替泊芬在制备抑制肺纤维化的药物组合物中的应用。
7.根据权利要求6所述的应用，其特征在于：所述药物组合物包括维替泊芬和药物学上可接受的辅料或载体。
8.根据权利要求7所述的应用，其特征在于：所述药物组合物中维替泊芬的质量百分含量为5～99％。
9.根据权利要求8所述的应用，其特征在于：所述药物组合物中维替泊芬的质量百分含量为50～90％。
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| CN117482239B (zh) * | 2023-12-29 | 2024-04-16 | 北京大学口腔医学院 | Yap通路干预剂在制备抑制牙根吸收的药物中的应用 |
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