CN116549485A - β-多肽或β-多肽聚合物在促进血管形成及抑制器官纤维化中的应用 - Google Patents
β-多肽或β-多肽聚合物在促进血管形成及抑制器官纤维化中的应用 Download PDFInfo
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- CN116549485A CN116549485A CN202210112997.4A CN202210112997A CN116549485A CN 116549485 A CN116549485 A CN 116549485A CN 202210112997 A CN202210112997 A CN 202210112997A CN 116549485 A CN116549485 A CN 116549485A
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Abstract
本发明提供了一种β‑多肽或β‑多肽聚合物在促进血管形成及抑制器官纤维化中的应用。具体地，所述β‑多肽包括n个如式I所示的重复单元组成的肽段，其中，n为1‑5000的正整数，
Description
技术领域
本发明涉及高分子结构及应用领域，具体地涉及一类β-多肽或β-多肽聚合物促进血管形成并抑制器官纤维化的用途。
背景技术
慢性肾脏病导致肾脏毛细血管的破坏及减少，是导致肾间质纤维化的主要原因。随着肾纤维化疾病的发展，慢性缺氧微环境会刺激内皮细胞分泌大量促凋亡分子，导致血管内皮受损，内皮功能紊乱，例如缩血管物质内皮素(ET-1)、血小板衍生生长因子(PDGF)、转化生长因子(TGF)增加，一氧化氮(NO)、前列环素(PGI2)等合成降低，白细胞、血小板黏附，从而引起血栓形成及平滑肌细胞增生，最终使得血管发生堵塞。血管的损伤并且无法修复则导致肾脏缺氧加重，间质纤维结缔组织大量增生，加剧纤维化反应的发生，这一恶性循环使得肾脏纤维化变得愈加严重。与此同时，间质成纤维细胞的增殖与分泌引起的胞外基质过量沉积，也会导致心脏等器官纤维化的发生，进一步使得心功能受损。
因此，为了解决纤维化所导致的器官功能受损问题，本领域亟需开发一种用于抑制纤维化和/或促进血管生成的药物。
发明内容
本发明的目的是提供一种用于抑制纤维化和/或促进血管生成的药物。
本发明第一方面，提供了一种β-多肽、或包含其的聚合物、或它们药学上可接受的盐的用途，其特征在于，用于制备一种药物组合物或用于修饰植入/介入材料；所述药物组合物或植入/介入材料用于：(a)促进血管形成；和/或(b)预防和/或治疗纤维化；
其中，所述β-多肽包括n个如式I所示的重复单元组成的肽段，其中，n为1-5000的正整数，
在另一优选例中，所述β-多肽为具有单一重复单元的均聚物。
在另一优选例中，所述聚合物还包括两个端基，通常选自下组：H、引发剂残基、反应性残基和/或单体残基，如聚合物至少包括一个含有选自下组基团的端基：-SH、-NH2、-COOH、-Br、-Cl、-OH、环氧基、烯基、炔基、-COCl、叠氮基、马来酰亚胺基、邻二硫吡啶基(OPSS)。例如，-C1-C6烷基-SH、-NH-C1-C6烷基-SH、-CO-C1-C6烷基-SH。
在另一优选例中，n为3-100，较佳地5-50，如5、10、15、20、25、35、40、45、60等。
在另一优选例中，所述β-多肽、或包含其的聚合物选自下组：
在另一优选例中，所述介入/植入材料修饰前的基材选自下组：无机非金属生物材料(如生物陶瓷、生物玻璃、石墨烯、骨水泥和医用碳素材料)、生物金属材料(如不锈钢、钴基和钛基合金、形状记忆合金、贵金属如银、铂、钽、铌、锆、钯、铂)、天然高分子材料(如透明质酸、壳聚糖、海藻酸、纤维素、胶原、明胶，如水凝胶形式)、合成高分子材料(聚醚醚酮、聚己内酯、聚乳酸、聚碳酸酯、聚氨酯、聚酯、聚酸酐、聚二甲硅氧烷、聚甲基丙烯酸甲酯、聚磷腈、聚酰胺、聚乙烯、聚丙烯、聚四氟乙烯、聚对苯二酸乙二酯、树脂)，或其组合(如它们的复合材料、组装材料)。
在另一优选例中，所述植入/介入材料为人工血管。
在另一优选例中，所述纤维化为选自下组的组织器官的纤维化：肺脏、心血管系统、肝脏、胰腺、肾脏、脾脏、眼睛、神经系统和骨髓。
本发明第二方面，提供了一种药物组合物，所述药物组合物包括：如权利要求1所述的β-多肽、或包含其的聚合物、或它们药学上可接受的盐，以及药学上可接受的载体。
在另一优选例中，所述药物组合物的剂型选自下组：液体制剂(如溶液、乳液、悬浮液)、固体制剂(如冻干制剂)。
在另一优选例中，所述药物组合物的剂型选自下组：注射液、粉针剂、胶囊剂、片剂、丸剂、散剂、颗粒剂、糖浆、口服液、酊剂、凝胶(如可注射水凝胶)或贴剂。
本发明第三方面，提供了一种植入/介入材料，所述材料包括：基材，且所述基材的至少一部分化学修饰或涂覆有如权利要求1所述的β-多肽、或包含其的聚合物，或它们药学上可接受的盐。
在另一优选例中，所述介入/植入材料修饰前的基材表面的选自下组：无机非金属生物材料(如生物陶瓷、生物玻璃、石墨烯、骨水泥和医用碳素材料)、生物金属材料(如不锈钢、钴基和钛基合金、形状记忆合金、贵金属如银、铂、钽、铌、锆、钯、铂)、天然高分子材料(如透明质酸、壳聚糖、海藻酸、纤维素、胶原、明胶，如水凝胶形式)、合成高分子材料(聚醚醚酮、聚己内酯、聚乳酸、聚碳酸酯、聚氨酯、聚酯、聚酸酐、聚二甲硅氧烷、聚甲基丙烯酸甲酯、聚磷腈、聚酰胺、聚乙烯、聚丙烯、聚四氟乙烯、聚对苯二酸乙二酯、树脂)，或其组合(如它们的复合材料、组装材料)。
在另一优选例中，所述植入/介入材料为人工血管。
在另一优选例中，当所述介入材料为水凝胶时，所述β-多肽或β-多肽聚合物可用于抑制间质成纤维细胞活化和/或抑制肾小管上皮细胞间充质转化和/或抑制肾脏纤维化。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为不同浓度的β-多肽聚合物促进内皮细胞成管的表征。
图2为人工血管的形貌表征。
图3为大鼠颈静脉-颈动脉移植模型的手术照片。
图4为颈静脉移植物的CD31免疫荧光染色。
图5为β-多肽聚合物功能化修饰的水凝胶用于肾脏纤维化模型效果图。
图6为β-多肽聚合物功能化修饰的水凝胶用于抑制肾脏纤维化的效果图。
具体实施方式
本发明人经过广泛而深入的研究，通过大量筛选和测试，意外的发现了本发明的β-多肽能够促进血管生成、抑制器官纤维化，且用所述β-多肽修饰在医用植入/介入材料的表面，可促进植入/介入材料的内皮化，从而使其安全、持久、稳固的留置在患者体内。在此基础上完成了本发明。
术语
除非另有定义，否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“室温”或“常温”是指温度为4-40℃，较佳地，25±5℃。
活性成分
本发明的活性成分为包括n个如式I所示的重复单元组成的β-多肽、或包含其的聚合物、或它们药学上可接受的盐，
其中，n为1-5000的正整数。
在另一优选例中，所述β-多肽为具有单一重复单元的均聚物。
在另一优选例中，所述聚合物还包括两个端基，通常选自下组：H、引发剂残基、反应性残基和/或单体残基，如聚合物至少包括一个含有选自下组基团的端基：-SH、-NH2、-COOH、-Br、-Cl、-OH、环氧基、烯基、炔基、-COCl、叠氮基、马来酰亚胺基、邻二硫吡啶基(OPSS)。例如，-C1-C6烷基-SH、-NH-C1-C6烷基-SH、-CO-C1-C6烷基-SH。
在另一优选例中，n为3-100，较佳地5-50，如10、15、20、25、35、40、45、60等。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。表示其连接的碳原子可以是R构型、S构型或或R构型和S构型的混合物。
如本文所用，术语“化合物的盐”指本发明的化合物可以以由药学上或生理学可接受的酸或碱衍生的盐形式使用。这些盐包括(但不限于)与如下酸形成的盐：氢氯酸、氢溴酸、硫酸、柠檬酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、琥珀酸、草酸、富马酸、马来酸、草酰乙酸、甲磺酸、乙磺酸、苯磺酸、或羟乙磺酸。其他盐包括：与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐，以及以酯、氨基甲酸酯或其他常规的“前体药物”的形式。
血管形成
如本文所用，血管形成或血管生成是指内皮细胞形成新的血管。促进血管形成可通过建立动脉的小分支、或在血管周围建立侧支循环来改善缺血性疾病。一般情况下，血管形成是在促血管形成因子存在下进行的，意外地，在没有促血管形成因子存在下，本发明的β多肽或聚合物可以促进内皮细胞成管，从而发挥促进血管形成的作用。
纤维化
纤维化是指由于炎症导致器官实质细胞发生坏死，组织内细胞外基质(ECM)异常增多和过度沉积的病理过程。轻者成为纤维化，重者引起组织结构破坏而发生器官硬化。机体器官由实质和间质两部分构成。实质是指器官的主要结构和功能细胞(如肝脏的实质细胞就是肝细胞)，间质由间质细胞和细胞外基质(主要有胶原蛋白、蛋白聚糖、糖胺聚糖、糖蛋白和弹性蛋白)构成，分布在实质细胞之间，主要起机械支撑和连接作用。细胞外基质构成维持细胞生理活动的微环境，是细胞之间的信号传导的桥梁，参与多种生理病理过程，在组织创伤修复和纤维化过程中起重要作用。
常见可以纤维化器官(但并不限于)：肺脏，心血管系统，肝脏，胰腺，肾脏(如肾小球、肾小管、肾血管)，脾脏，眼睛，神经系统，骨髓。
更具体地，肌成纤维细胞是纤维化的主力，通常的伤口愈合，尤其是病理性组织纤维化主要起源于肌成纤维细胞介导的ECM合成和沉积，病变组织中肌成纤维细胞群体的状态反映了纤维化的方向。肌成纤维细胞是指含有肌动蛋白、肌球蛋白和其他肌肉蛋白的成纤维样细胞，α平滑肌肌动蛋白(α-SMA)被认为是肌成纤维细胞的标志物。
意外地，本发明的β多肽或聚合物可以抑制成纤维细胞和内皮细胞等向肌成纤维的转分化，从而降低细胞外基质的形成和积聚，进而有效预防和/或治疗组织器官的纤维化。
介入/植入材料
本发明中，所述肽段或聚合物可通过本领域常用的方法涂覆或共价修饰在基材表面。
通常，共价修饰可包括下述步骤：(i)预活化所述基材的至少一部分表面，形成锚定层；(ii)将具有能够与所述锚定层反应的端基的本发明的聚合物与所述锚定层进行反应，从而将所述链段修饰到材料表面。修饰结束后，还可包括步骤：封闭反应位点和/或洗涤和干燥。
本领域常用的预活化方法包括但并不限于：(a)等离子辐射器活化法；通常包括步骤：将基材置于低温等离子体内，激发活化，从而得到表面含有氧自由基、羟基、羧基、环氧基和/或醛基的预活化表面。将通过上述方法(a)预活化的表面，置于溴仿溶液中，从而得到表面溴化的预活化表面。(b)通过紫外臭氧辐照基材表面，置于3-氨丙基三乙氧基硅烷(APTES)的溶液中，从而得到表面氨基化的预活化表面。(c)将基材置于多巴胺的碱性溶液中，从而得到多巴胺预活化表面。或(d)叠氮修饰，将基材浸入含有叠氮烷酸和EDC的溶液中，从而得到表面叠氮化的预活化表面。可以根据基材的种类选择合适的预活化方法。
相应地，可以根据基材的预活化表面的基团种类选择在本发明的多肽上修饰合适的反应基团或选择具有合适反应基团的聚合物，从而将本发明的多肽通过化学键修改到材料表面。例如，可选自基于巯基-卤原子亲核取代反应、巯基-环氧基团的加成反应、巯基-烯基/炔基或叠氮-炔基的加成反应等。
在另一优选例中，所述介入/植入材料修饰前的基材表面的选自下组：无机非金属生物材料(如生物陶瓷、生物玻璃、石墨烯、骨水泥和医用碳素材料)、生物金属材料(如不锈钢、钴基和钛基合金、形状记忆合金、贵金属如银、铂、钽、铌、锆、钯、铂)、天然高分子材料(如透明质酸、壳聚糖、海藻酸、纤维素、胶原、明胶)、合成高分子材料(聚醚醚酮、聚己内酯、聚乳酸、聚碳酸酯、聚氨酯、聚酯、聚酸酐、聚二甲硅氧烷、聚甲基丙烯酸甲酯、聚磷腈、聚酰胺、聚乙烯、聚丙烯、聚四氟乙烯、聚对苯二酸乙二酯、树脂)，或其组合(如它们的复合材料、组装材料)。
优选地，所述植入/介入材料可以为(但并不限于)人工血管。
本发明的多肽或聚合物能够促进介入或植入材料周围组织血管化，并抑制伤口、器官等的纤维化，可有效提高介入或植入材料植入的成功率、延长使用寿命并促进其功能的实现，同时减小介入或植入材料带来的副作用(如脱落、排斥、内膜增生等)。
药物组合物、用途
本发明还提供了一种药物组合物，包含上述β-多肽、或包含其的聚合物、或它们药学上可接受的盐作为活性成分。
实验证明，本发明的药物组合物具有显著的(a)促进血管形成；和/或(b)预防和/或治疗纤维化的作用。
本发明的药物组合物包含安全有效量范围内的本发明抑制剂或其药理上可接受的盐及药理上可以接受的赋形剂或载体。
如本文所用，术语“治疗有效剂量”是指药物的任何如下所述的量，当单独使用或与另一种治疗剂组合使用该量的药物时，可促进疾病消退，疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。
本发明药物的“治疗有效剂量”也包括“预防有效剂量”，“预防有效剂量”是药物的任何如下所述的量，当将该量的药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时，可抑制疾病的发生或复发。
通常，药物组合物含有1-2000mg本发明活性成分/剂，更佳地，含有10-500mg本发明活性成分/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、病灶内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明活性成分的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明活性成分可以单独给药，或者与其他药学上可接受的治疗剂联合给药。在某些实施方式中，向患癌对象联合给予本发明的活性成分和其它传统癌治疗物，例如，放疗或手术。放疗是本领域熟知的并且包括X射线治疗，例如伽马放射，和放射药物治疗。
在某些实施方式中，本发明的活性成分在相同或分开的制剂中与作为联合治疗方案的部分的其它试剂同时使用，或与所述其它试剂依次使用。
本发明的活性成分的组合物的治疗有效剂量的一般范围将是：约1-2000mg/天、约10-约1000mg/天、约10-约500mg/天、约10-约250mg/天、约10-约100mg/天，或约10-约50mg/天。治疗有效剂量将以一个或多个剂量给予。然而，应理解，对于任何特定患者的本发明化合物的特定剂量将取决于多种因素，例如，待治疗的患者的年龄、性别、体重、一般健康状况、饮食、个体响应，给予时间、待治疗的疾病的严重性、施用的具体化合物的活性、剂型、应用模式和伴用药物。给定情况的治疗有效量能用常规实验测定，并在临床医生或医师能力和判断范围内。在任何情况中，所述化合物或组合物将基于患者的个体情况以多个剂量给予并以允许递送治疗有效量的方式给予。
本发明的主要优点包括：
本发明提供的多肽或多肽聚合物能够促进血管形成和/或抑制器官纤维化，从而减少或避免由于纤维化导致的功能损伤，能够作为药物对肾脏、心脏、肺、肝脏等器官的纤维化进行治疗。
本发明提供的多肽或多肽聚合物能够修饰人工血管、心脏补片以及水凝胶等植入/介入材料，达到促进血管生成并抑制纤维化的效果，进而提高血管通畅性或促进肾脏功能的修复。
本发明提供的多肽或多肽聚合物具有稳定性高、价格低廉、易于大量制备等方面的显著优势。
下面结合具体实施，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1.β-氨基酸单体的制备
步骤(1)，无保护基团的β-内酰胺单体DM的制备。将5g DM-2化合物溶于70mL甲醇(MeOH)中，加入水合肼(2.3g，46.50mL)，反应过夜，通过TLC分析监测反应物消耗进程。待DM-2反应完全，过滤除去反应体系中的白色固体，随后减压蒸馏除去溶剂，将反应物重新溶解于甲醇中，并加入甲苯共沸蒸馏去除多余的水合肼，重复共沸蒸馏3次，真空干燥两天。
步骤(2)，侧链Cbz保护的β-内酰胺单体DM的制备。氯甲酸苄酯(Cbz-Cl，3.63g)用甲醇溶解待用，将上一步得到的产物与三乙胺(TEA)溶于200mL甲醇(MeOH)中，在冰浴中滴加Cbz-Cl反应1h，之后恢复室温并搅拌过夜。TLC分析监测反应结束后，减压蒸馏去除溶剂，加入DCM溶解粗产物，再分别用去离子水、5％柠檬酸水溶液和饱和食盐水进行萃洗，并无水硫酸镁干燥，减压蒸馏除去溶剂后得到粗产物。通过硅胶柱层析法分离纯化得到最终产物，为无色粘稠状液体，产率50％。
步骤(3)，侧链Cbz保护的β-内酰胺单体开环。将上一步产物用20mL的5N HCl与3mL甲醇溶解，待反应过夜后点板进行监测。减压蒸馏去除盐酸与甲醇，用DCM洗涤水相三次后冻干。
步骤(4)，Fmoc保护的β-氨基酸单体的制备。将上一步产物与1.4g Na2CO3溶于40mL H2O和20ml MeCN的混合溶液中，使用20mL MeCN溶解Fmoc-Cl后在0℃滴加到上述溶液中，常温反应过夜。减压蒸馏去除MeCN，使用2M HCl将PH调至PH＝5。随后分别用DCM和饱和食盐水萃取收集有机相，通过硅胶柱层析法分离纯化得到最终产物750mg。
实施例2.β-多肽的制备
称取rink amide MBHA树脂140mg(取代度0.53mmol/g)于10ml反应管中,使用3ml超干二氯甲烷(DCM)浸泡过夜使其充分溶胀。用三倍树脂球体积的N,N-二甲基甲酰胺(DMF)洗涤树脂球后抽干，重复三次后加入一定量的20％哌啶的DMF溶液，将溶液与树脂球共同转移至微波反应管中，80℃微波加热，反应4分钟后取出树脂球，用三倍树脂球体积的DMF洗涤三次，随后取少量树脂球用kaiser检测试剂进行检测(100℃反应1min 20s)树脂球发生颜色变化，表明脱保护成功。称取2.5倍当量比的DM氨基酸单体与1-羟基苯并三唑(HOBT)，O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)于离心管中，加入DMF将其溶解，随后加入与树脂球5倍当量比的N,N-二异丙基乙胺(DIEA)常温震荡2min，将溶液转移至微波反应管中，70℃微波加热反应40分钟，取少量树脂用kaiser检测试剂进行检测(100℃反应2min)，树脂球颜色不发生变化，表明氨基酸接枝成功，重复该脱保护与接枝过程三次，待第三个氨基酸接枝成功并脱保护完全后，使用DMF与DCM交替洗涤三次，以DCM结尾，接下来用DCM与MeOH交替洗涤三次,以MeOH结尾，使树脂球充分收缩后真空干燥过夜。
配置3倍树脂球体积的切割液(氢溴酸:三氟乙酸＝1:1)浸没树脂球,将侧链保护基团(cbz)脱去并使多肽从树脂球上切割下来，用45mL冰乙醚沉降离心三次后进行真空干燥。最后，使用高效液相色谱(HPLC)分离纯化后冻干，得到一定纯度的DM多肽。
实施例3.使用β-内酰胺单体DM制备β-氨基酸均聚物
步骤(1)氨基保护的DM均聚物的合成。在N2保护的手套箱中分别称取β-内酰胺单体DM和(2,5-二氧杂吡咯烷-1-基)2-三苯甲基硫基乙酸酯放入干燥的反应瓶中，分别使用超干四氢呋喃(THF)溶解后共混，加磁子进行搅拌，加入六甲基二硅基胺基锂盐(Li-HMDS)溶液，搅拌反应4小时。TLC监测单体反应完全后将反应瓶从手套箱内取出，滴加1滴甲醇(MeOH)淬灭反应。将所得溶液转移至50mL离心管，加入冰石油醚(45mL)，析出白色絮状沉淀；白色沉淀经离心收集，并通过真空泵进行干燥，得到氨基保护状态的DM均聚物。
步骤(2)，氨基脱保护后的DM均聚物的合成。用含体积比为5％的三乙基硅烷的三氟乙酸(TFA)处理聚合物，分别脱去侧链胺和末端硫醇上的Boc以及三苯甲基保护基。将得到的粘性液体吹干溶解于甲醇(0.2mL)中，加入冰乙醚沉淀后离心，重复三次后真空干燥除去剩余溶剂，随后使用超纯水溶解后冻干，得到白色粉末状产物，即为脱保护后的DM均聚物(产率80％，由GPC表征得知DP＝30)。
实施例4.β-多肽或β-多肽聚合物功能化修饰人工血管的制备
(1)取数均分子量为80000Da的聚己内酯(PCL)2.25g和叠氮化可降解聚合物材料(PCL2000-N3)0.25g，加入10mL有机溶剂(氯仿和甲醇体积比为5:1)中，室温搅拌12h，获得电纺丝溶液；
(2)将上述电纺丝溶液装入注射器中，为注射器加上21-G不锈钢针头，并将高压直流电源与注射器针头相连。调整注射器位置，使其针头对准圆柱接收器的中央，并将针头与接收器之间的距离调整为15cm。设置流速为8mL/h，电压为13kV。以直径为1.2mm的不锈钢圆柱为接收棒，接收棒的转速为400rpm，接收棒的移动速度为5mm/s；调整纺丝环境的温度和相对湿度，使其分别在23℃和50。静电纺丝30min后，将所得管状材料从接收棒上取下，在温度为22℃、压力为-0.075MPa的条件下真空干燥，使溶剂彻底挥发，得到厚度为400μm的叠氮化修饰的PCL人工血管。
(3)配制2.17mg/mL的炔基化修饰β-多肽(实施例2制备)或β-多肽聚合物(实施例3制备)溶液。按照摩尔比为1：0.1:1(β-多肽：CuSO4：抗坏血酸钠)的比例的在β-多肽或β-多肽聚合物溶液中加入CuSO4和抗坏血酸钠，以配制β-多肽或β-多肽聚合物反应液。
(4)截取1cm的叠氮化修饰的人工血管，将其置于500μL离心管中，并在离心管中充满上述的β-多肽或β-多肽聚合物反应液。封口膜密闭离心管，于室温孵育24小时。经过Click反应，共价结合上炔基化修饰的β-多肽或β-多肽聚合物，用去离子水清洗人工血管3次，室温下干燥功能化修饰的人工血管。
实施例5.β-多肽或β-多肽聚合物功能化修饰的水凝胶的制备
(1)对300kD的透明质酸(HA)进行改性处理，分别制备氨基改性的HA(HA-ADH)和醛基改性的HA(HA-ALD)，并于室温保存；
(2)用PBS配制浓度为1％(w/v)的HA-ADH和1％(w/v)的HA-ALD，室温过夜放置使其充分溶解；
(3)取β-多肽或β-多肽聚合物母液适量，加入1％HA-ADH溶液中，使β-多肽聚合物(实施例3制备，式Ib)终浓度为100ng/mL；
(4)将混有β-多肽或β-多肽聚合物的1％HA-ADH溶液和1％HA-ALD溶液分别置于U型注射器之中，使用时通过U型注射器将两种溶液同时推出，二者混合成胶。
实施例6.β-多肽或β-多肽聚合物调控内皮细胞成管
(1)将Matrigel胶于4℃过夜融化。同时将1mL、200μL、10μL三种规格的枪头、48孔板于-20℃过夜预冷。
(2)次日在48孔板的每孔中加入150μL Matrigel液。并将培养板平稳置于4℃冰箱，静置24h，使胶液自动铺平，并消除胶中气泡。
(3)待胶液完全铺展后，将48孔板置于37℃培养箱中2h，使Matrigel成胶。
(4)制备100个细胞/μL的HUVEC细胞悬液。最后在每个Matrigel孔中加入300μL的细胞悬液。
(5)加入不同浓度的β-多肽聚合物(实施例3制备，式Ib)诱导，并开始计时，于12h时观察HUVEC细胞成管情况，并拍照记录，每个凝胶表面取5个视野。
内皮细胞成管情况如图1所示，结果表明β-多肽聚合物可促进HUVEC相互连接形成血管网络。
实施例7.β-多肽或β-多肽聚合物功能化修饰人工血管体内移植的方法
采用大鼠颈动脉移植模型体内评价β-多肽或β-多肽聚合物功能化修饰人工血管的通畅性。分别截取长度为0.7cm的实施例4制备的β-多肽或β-多肽聚合物功能化修饰人工血管以及未修饰的人工血管，利用大鼠颈总动脉移植模型，用10-0尼龙缝合线通过端端吻合术将人工血管植入自体大鼠的颈动脉中，具体如下：
(1)SD(Sprague-DawLey)大鼠，体重280～300g，经腹腔注射水合氯醛(10％，350mg/kg)诱导麻醉，固定大鼠的四肢于手术板上，颈部备皮；
(2)颈部涂抹碘伏消毒以后，用眼科剪在大鼠颈部沿中线剪开长约2cm的口子；用持针器和止血钳惰性分离两边的唾液腺，并将右侧唾液腺向外翻出，敷上湿纱布保湿；
(3)3-0的黑线将皮下肌肉向外拉出，使视野开阔；分离右侧颈总动脉，勿伤及与其并行的迷走神经和颈静脉；
(4)尾静脉注射100U的肝素，用止血夹分别夹住颈总动脉近心端和远心端，从中间剪开并用肝素冲洗端口的血液；
(5)用10-0尼龙缝合线通过端端吻合术将人工血管植入大鼠的右侧颈总动脉中，每端8针；待两端缝好后，缓慢摘除动脉夹，恢复血流；
(6)用硫酸庆大霉素冲洗颈部手术部位，之后3-0手术缝合线缝皮，碘伏消毒，并标记大鼠；
由于颈动脉移植模型通畅率较低，容易引发急性血栓。术后2和4周观察，利用多普勒超声检测β-多肽(实施例2制备)或β-多肽聚合物(实施例3制备)功能化修饰人工血管以及未修饰的人工血管的植入后血管的通畅情况，并计算血管的通畅率。
采用静电纺丝技术制备的PCL人工血管的形貌如图2所示，纤维均匀分布，且纤维直径约为8μm。
实施例8.β-多肽或β-多肽聚合物功能化修饰的水凝胶治疗自体血管搭桥后血管再狭窄的方法
大鼠静脉移植模型采用如下方法建立：
(1)选取300g SD大鼠，并通过腹腔注射巴比妥酸(50mg/kg)，待麻醉后，取出其颈静脉作为静脉移植物。利用含有100U/ml肝素的生理盐水清洗获取的颈静脉，随后将其置入保存液中。
(2)动脉夹夹闭颈动脉两端，从颈动脉中部剪断血管。从保存液中取出静脉移植物，并利用8-0缝合线将移植物反向与动脉缝合，进而将静脉移植物移植于大鼠颈动脉。
(3)在移植后的静脉移植物外侧均匀涂上实施例6所述β-多肽聚合物(实施例3制备，式Ib)功能化修饰的水凝胶。
大鼠颈静脉-颈动脉移植模型如图3所示，将大鼠的颈静脉移植于大鼠的对侧颈动脉，利用β-多肽聚合物功能化修饰水凝胶调控静脉移植物的体内行为。
实施例9.β-多肽或β-多肽聚合物对于移植静脉血管重构的调控
(1)静脉移植4周和8周后，将大鼠麻醉，尾静脉注射肝素进行全身肝素化，腹部和颈部备皮，打开皮肤肌肉层，再用生理盐水心脏灌注。然后取出颈部静脉移植物；
(2)在冷冻切片后进行组织学分析。通过H&E等组织学染色考察血管的重构，通过TUNEL染色考察血管内皮细胞和平滑肌细胞的凋亡情况，并通过PCNA免疫荧光染色考察血管细胞的增殖活力。
(3)利用CD31和CD144免疫荧光染色考察受损血管内皮的覆盖率。通过α-SMA、calponin以及MHC等收缩相关蛋白免疫荧光染色，考察血管功能型平滑肌的再生。
大鼠的颈静脉移物的内皮再生情况如图4所示，通过CD31染色结果表明β-多肽聚合物可有效促进静脉移植物内皮的再生。
实施例10.β-多肽或β-多肽聚合物功能化修饰的水凝胶治疗肾脏纤维化的方法
小鼠单侧输尿管梗阻模型采用如下方法建立：
(1)将10周龄小鼠适应饲养3天，模型建立前一天禁食，自由饮水。
(2)按照0.2mL/20g的剂量对小鼠腹腔注射4％水合氯醛，使小鼠麻醉。
(3)待小鼠稳定后，将其固定于手术台上，局部剃毛，用碘伏局部消毒，取腹中线右侧为手术切口，依次拨开皮肤、肌肉及腹壁。
(4)暴露右侧肾脏及肾蒂，小心游离右侧输尿管，用7-0手术缝合线结扎输尿管，假手术组仅游离右侧输尿管，不结扎。
(5)治疗组对肾被膜进行水凝胶注射。利用U型注射器被膜下注射水凝胶，注射总体积为30μL。注射时应避免破坏肾脏被膜，注射完成后用棉签轻轻按压注射器刺入点，待水凝胶成胶移除棉签。
(6)恢复脏器位置，缝合肌肉、皮肤，并用碘伏对伤口消毒。
肾脏纤维化的治疗结果如图5所示，将β-多肽聚合物功能化修饰水凝胶移植于肾包膜下，切片结果表明β-多肽聚合物可维持肾脏的结构，并抑制管型(管型是肾脏损伤评价中常用的指标)的形成以及肾小管管腔的膨大。
HE染色统计结果表明，与梗阻组相比，β-多肽聚合物治疗组显著抑制了肾小管的膨大，膨大面积降低了61.6％(p＜0.01)并且管型的形成降低了56.6％(p＜0.001)，每组样本量n＝6。
实施例11.β-多肽或β-多肽聚合物功能化修饰的水凝胶抑制肾脏纤维化
(1)建模10天后，按照0.2mL/20g的剂量腹腔注射4％水合氯醛将待取材小鼠麻醉。
(2)将小鼠固定于手术台，先用生理盐水缓慢灌注，待心脏流出血液为无色时，换注射器用4％多聚甲醛(PFA)灌注，待小鼠全身僵硬，灌注完成。
(3)剖开小鼠腹腔，取出肾脏，沿肾脏的纵面，将肾脏切分为两部分，两部分分别用于制备石蜡切片和冰冻切片。石蜡切片的样品浸泡于4％PFA中，4℃过夜。冰冻切片的样品于4％PFA浸泡2h后，用30％蔗糖溶液进行脱水处理，4℃过夜。
(4)取材后通过免疫荧光染色评价功能化修饰水凝胶对于肾脏纤维化的调控作用，并通过肌酐和尿氮检测评价肾脏功能的修复。
肌成纤维细胞是肾脏纤维化进程中胞外基质的主要来源，通过图6所示结果可以看出，β-多肽聚合物可抑制α-SMA+的肌成纤维细胞的形成，表现出抑制肾脏纤维化的功能。
免疫组化统计结果表明，与梗阻组相比，β-多肽聚合物治疗组显著抑制了α-SMA+肌成纤维细胞的形成，α-SMA+所占面积相对于梗阻组降低了37.5％(p＜0.001)，每组样本量n＝6。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种β-多肽、或包含其的聚合物、或它们药学上可接受的盐的用途，其特征在于，用于制备一种药物组合物或用于修饰植入/介入材料；所述药物组合物或植入/介入材料用于：(a)促进血管形成；和/或(b)预防和/或治疗纤维化；
其中，所述β-多肽包括n个如式I所示的重复单元组成的肽段，其中，n为1-5000的正整数，
2.如权利要求1所述的用途，其特征在于，n为3-100，较佳地5-50，如5、10、15、20、25、35、40、45、60等。
3.如权利要求1所述的用途，其特征在于所述β-多肽、或包含其的聚合物选自下组：
4.如权利要求1所述的用途，其特征在于，所述介入/植入材料修饰前的基材选自下组：无机非金属生物材料(如生物陶瓷、生物玻璃、石墨烯、骨水泥和医用碳素材料)、生物金属材料(如不锈钢、钴基和钛基合金、形状记忆合金、贵金属如银、铂、钽、铌、锆、钯、铂)、天然高分子材料(如透明质酸、壳聚糖、海藻酸、纤维素、胶原、明胶，如水凝胶形式)、合成高分子材料(聚醚醚酮、聚己内酯、聚乳酸、聚碳酸酯、聚氨酯、聚酯、聚酸酐、聚二甲硅氧烷、聚甲基丙烯酸甲酯、聚磷腈、聚酰胺、聚乙烯、聚丙烯、聚四氟乙烯、聚对苯二酸乙二酯、树脂)，或其组合(如它们的复合材料、组装材料)。
5.如权利要求1所述的用途，其特征在于，所述植入/介入材料选自下组：人工血管。
6.如权利要求1所述的用途，其特征在于，所述纤维化为选自下组的组织器官的纤维化：肺脏、心血管系统、肝脏、胰腺、肾脏、脾脏、眼睛、神经系统和骨髓。
7.一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1所述的β-多肽、或包含其的聚合物、或它们药学上可接受的盐，以及药学上可接受的载体。
8.一种植入/介入材料，其特征在于，所述材料包括：基材，且所述基材的至少一部分化学修饰或涂覆有如权利要求1所述的β-多肽、或包含其的聚合物，或它们药学上可接受的盐。
9.如权利要求8所述的植入/介入材料，其特征在于，所述介入/植入材料修饰前的基材表面的选自下组：无机非金属生物材料(如生物陶瓷、生物玻璃、石墨烯、骨水泥和医用碳素材料)、生物金属材料(如不锈钢、钴基和钛基合金、形状记忆合金、贵金属如银、铂、钽、铌、锆、钯、铂)、天然高分子材料(如透明质酸、壳聚糖、海藻酸、纤维素、胶原、明胶，如水凝胶形式)、合成高分子材料(聚醚醚酮、聚己内酯、聚乳酸、聚碳酸酯、聚氨酯、聚酯、聚酸酐、聚二甲硅氧烷、聚甲基丙烯酸甲酯、聚磷腈、聚酰胺、聚乙烯、聚丙烯、聚四氟乙烯、聚对苯二酸乙二酯、树脂)，或其组合(如它们的复合材料、组装材料)。
10.如权利要求8所述的植入/介入材料，其特征在于，所述植入/介入材料为人工血管。
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