CN112206307A - 一种可注射的温敏型水凝胶及其制备方法与应用 - Google Patents
一种可注射的温敏型水凝胶及其制备方法与应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域，尤其涉及一种可注射的温敏型水凝胶及其制备方法与应用。本发明的可注射的温敏型水凝胶中包含：N‑异丙基丙烯酰胺、N‑丙烯酰氧基琥珀酰亚胺、聚乙二醇和分支肽；所述分支肽为(GPRPG)4>K2>K或(GPRPG)8>K4>K2>K，其中K为赖氨酸，G为甘氨酸，P为脯氨酸，R为精氨酸。本发明通过构建GPRPG的分支多聚体，增加其活性位点，并选择温敏型凝胶作为药物载体，进一步提高了GPRPG的稳定性和生物活性。本发明的温敏性水凝胶可用于止血、修复骨或软骨，也可以用于促进皮肤愈合和眼科用途，具有广泛的应用前景。
Description
技术领域
本发明涉及生物医药领域，尤其涉及一种可注射的温敏型水凝胶及其制备方法与应用。
背景技术
GPRPG是一种五肽，其为模拟纤维蛋白原的一段序列，纤维蛋白原E结构域内有一个能被凝血酶激活的聚合位点“A”，“A”位点在纤维蛋白肽A从α链上断裂而暴露出GPR序列(Gly-Pro-Arg)，模拟GPR序列的合成短肽能结合纤维蛋白原并抑制其聚合，从而可用于止血和凝血(参见中国专利CN105916524A，以及Laudano AL，Doolittle RF.Syntheticpeptide derivatives that bind to fibrinogen and prevent the polymerization offibrin monomers.Proc Natl Acad Sci USA，1978，75:3085-3089)。此外，中国专利CN110669126A还公开了GPRPG具有促进肝细胞增殖和抑制肝细胞凋亡的用途。但由于GPRPG分子量低，容易降解，导致其稳定性低，在体内作用时间短。
水凝胶是一种能够在水中溶胀同时材料内部保留大量水分而又不会溶解在水中的高分子材料，一般呈电中性或离子性，它由交联的三维网络结构与介质组成多元体系，其力学性能与软组织相似，作为一种软材料，无固定几何形状，内部三维多孔结构，因而不会引发机体强烈的免疫排斥反应并减少免疫因子及免疫细胞的不利影响。使用水凝胶作为药物载体具有如下优点：(1)水凝胶含水量高，有助于凝胶内部与外部环境进行有效的物质交换，维持组织微环境的平衡；(2)生物相容性良好，组织刺激性较低；(3)多孔结构有利于细胞粘附以及细胞长入到支架内部；(4)一般具有生物降解性，可避免组织再生后二次手术取出；(5)可原位凝胶化或通过注射填充任意形状的空腔。
发明内容
本发明的目的在于克服现有技术的不足，提供一种可注射的温敏型水凝胶及其制备方法与应用，通过对GPRPG的结构进行改造，并选择合适的药物载体达到提高其稳定性进而增强其活性的目的。
为实现上述目的，本发明采取的技术方案为：提供一种可注射的温敏型水凝胶，所述温敏型水凝胶中包含：N-异丙基丙烯酰胺、N-丙烯酰氧基琥珀酰亚胺、聚乙二醇和分支肽；所述分支肽为(GPRPG)4>K2>K或(GPRPG)8>K4>K2>K，其中K为赖氨酸，G为甘氨酸，P为脯氨酸，R为精氨酸。
作为本发明所述温敏型水凝胶的优选实施方式，所述(GPRPG)4>K2>K的结构式如下：
所述(GPRPG)8>K4>K2>K的结构式如下：
作为本发明所述温敏型水凝胶的优选实施方式，所述N-异丙基丙烯酰胺、N-丙烯酰氧基琥珀酰亚胺、聚乙二醇的质量比为N-异丙基丙烯酰胺：N-丙烯酰氧基琥珀酰亚胺：聚乙二醇＝70-85：3-10：10-20，优选的，N-异丙基丙烯酰胺：N-丙烯酰氧基琥珀酰亚胺：聚乙二醇＝80：5：15。
本发明提供所述的温敏型水凝胶的制备方法，所述制备方法包括以下步骤：
(1)将N-异丙基丙烯酰胺、聚乙二醇和N-丙烯酰氧基琥珀酰亚胺溶解于二甲基甲酰胺中，反应后冻干得到冻干粉末；
(2)向冻干粉末中加入PBS和所述分支肽，反应即得温敏型水凝胶。
作为本发明所述制备方法的优选实施方式，所述冻干粉末和分支肽的质量比为冻干粉末：分支肽＝90-110：20-40。
本发明提供所述温敏型水凝胶在制备止血药物中的用途。
本发明提供所述温敏型水凝胶在制备骨修复药物中的用途。
本发明提供所述温敏型水凝胶在制备软骨修复药物中的用途。
本发明提供所述温敏型水凝胶在制备促进皮肤愈合药物中的用途。
本发明还提供所述的温敏型水凝胶在制备眼科药物中的用途。
本发明的有益效果：
本发明通过构建GPRPG的分支多聚体，增加其活性位点，并选择温敏型凝胶作为药物载体，进一步提高了GPRPG的稳定性和生物活性。在体内动物实验中证实本发明的温敏型水凝胶具有止血作用，还在体外细胞和体内动物试验中意外发现本发明温敏型水凝胶具有明显的修复骨或软骨以及促进皮肤愈合的活性，因此本发明的温敏型水凝胶可以作为治疗上述疾病的药物，具有广泛的应用前景。
附图说明
图1：分支肽(GPRPG)4>K2>K的HPLC检测图谱。
图2：L-Gel在不同温度下的形态图；A显示在室温为液体，B显示在体温为白色凝胶。
图3：不同浓度的L-Gel对成骨细胞增殖的影响图。
图4：L-Gel对大鼠颅骨缺损的修复效果图；A为对照组，B为水凝胶组。
图5：对照组和水凝胶组的新骨生成率比较图。
图6：对照组和水凝胶组的ICRS评分图。
图7：对照组和水凝胶组关节软组织的HE染色图；A为对照组，B为水凝胶组。
图8：对照组和水凝胶组皮肤愈合的HE染色图，A为对照组，B为水凝胶组。
具体实施方式
为更清楚地表述本发明的技术方案，下面结合具体实施例进一步说明，但不能用于限制本发明，此仅是本发明的部分实施例。
实施例1分支肽的合成
采用固相合成的方法，合成分支肽(GPRPG)4>K2>K、(GPRPG)8>K4>K2>K分别500mg，纯度＞95％。分支肽(GPRPG)4>K2>K的HPLC检测图谱见图1。
实施例2温敏型水凝胶的制备
将N-异丙基丙烯酰胺(NIPAAm)、聚乙二醇(PEG)和N-丙烯酰氧基琥珀酰亚胺(NAS)按质量比为80：5：15的比例溶解于二甲基甲酰胺(DMF)中，70℃反应24小时，纯净水冲洗3遍后冻干。向冻干得到的白色粉末中加入PBS缓冲液和分支肽(GPRPG)4>K2>K，每100mg冻干粉末加30mg分支肽，室温(25℃)反应2小时，即得温敏型水凝胶，命名为L-Gel。L-Gel在常温下为透明的液体，在体温状态(37℃)下形成白色凝胶，参见图2。
实施例3温敏型水凝胶的制备
本实施例的温敏型水凝胶的制备过程与实施例2相同，不同之处仅在于所采用的分支肽为(GPRPG)8>K4>K2>K。
实施例4水凝胶对止血的作用
利用实施例2制备的水凝胶L-Gel，测定其对新西兰兔的止血作用。
分组：新西兰兔24只，分为阴性对照组、水凝胶组和阳性对照组(凝血酶)，共3组，每组8只动物。
造模：1％戊巴比妥钠，剂量为30mg/kg，经耳缘静脉注射麻醉。术区备皮，碘伏消毒，逐层开腹，暴露肝脏，在距肝脏的左叶下缘切除1cm×1cm×0.3cm的肝脏组织，建立肝脏出血模型。
给药：自由出血5秒后，各组动物分别以无菌纱布浸泡相应药物覆盖在创口上，其中阴性对照组浸泡1.5ml生理盐水，水凝胶组浸泡1.5ml水凝胶L-Gel，阳性对照组浸泡1.5ml凝血酶溶液。
观察：观察出血情况并记录止血时间，纱布吸去渗血并称重，记录出血量。
结果：各组出血量和出血时间参见表1，与阴性对照组相比，水凝胶组的出血时间及出血量均显著降低，具有显著的统计学意义(P＜0.01)，且与阳性对照效果相当，提示水凝胶L-Gel具有止血作用。
表1水凝胶对兔肝脏出血的影响
*，p<0.05vs阴性对照组；**p<0.01vs阴性对照组
实施例5水凝胶对成骨细胞的作用
利用CCK-8法检测实施例2制备的水凝胶L-Gel对人成骨细胞HFOB1.1增殖的影响。
将人成骨细胞HFOB1.1以1×104个/孔的密度接种于96孔板中，置于二氧化碳培养箱中培养贴壁过夜。随后吸出原有的培养基，换上含有不同浓度水凝胶L-Gel的完全培养基，每个浓度设6个平行重复，PBS处理作为阴性对照。96孔板于培养箱中培养24h后用PBS将细胞洗涤一次，并向各孔中加入100μL含有10％CCK-8的新鲜培养基。将96孔板置于培养箱中孵育2h，使用酶标仪测定450nm波长处的吸光度。
测试结果如图3所示，不同浓度水凝胶组，细胞的存活率都很高，显示不同浓度水凝胶L-Gel均未对人成骨细胞HFOB1.1产生细胞毒性，且与阴性对照相比，水凝胶组的吸光度更高，显示水凝胶L-Gel对人成骨细胞HFOB1.1的增殖具有明显的促进作用，能够用于生物体骨的再生和修复。
实施例6水凝胶对骨缺损的修复作用
利用实施例2制备的水凝胶L-Gel，测定其对大鼠颅骨缺损的修复作用。
分组：8周龄雄性SD大鼠20只，随机分为两组，分别为对照组和水凝胶组，每组10只。
造模：两组大鼠给予腹腔注射3.6％的水合氯醛(1ml/100g)进行麻醉。麻醉后剃除大鼠头部周围的毛发，用碘酒对头部及周围进行消毒。纵向剪开头顶大鼠皮肤，分离肌肉组织，暴露出大鼠颅盖骨，用手术刀轻刮颅骨，剥离骨外膜。暴露大鼠颅顶人字缝的骨线，随后用微型电钻在颅骨正中线两侧，各钻一个直径为5mm的骨缺损。
给药：将实施例2制备的水凝胶L-Gel，填充入水凝胶组的颅骨缺损里，对照组则不作任何填充处理，然后缝合软组织、皮肤，再次消毒。术后连续三天肌肉内注射硫酸庆大霉素4万U/d，预防感染。
处死及HE染色结果分析：治疗12周后，处死大鼠，剥离颅骨，保存于福尔马林中，固定48小时后将标本置于10％EDTA中脱钙6周。石蜡包埋，颅骨纵切4μm厚度的连续切片，进行常规HE染色。用图像分析软件Image-Pro-Plus定量分析切片缺损区域新骨生成率，计算公式为：新骨生成率＝新生骨面积/骨缺损区域面积。
结果：治疗12周后，对照组仅少量新生颅骨形成，水凝胶组颅骨缺损部分大部分已被新生颅骨覆盖(参见图4)，水凝胶组的新骨生成率显著高于对照组(P＜0.01)，见图5。
实施例7水凝胶对软骨缺损的修复作用
利用实施例2制备的水凝胶L-Gel，测定其对新西兰兔软骨缺损的修复作用。
造模：新西兰兔16只，3月龄，雌雄各半，以6％戊巴比妥钠(0.7mL/kg)耳缘静脉麻醉。麻醉后，左侧后退膝关节内侧纵向切口，长约3cm，依次切开皮肤、皮下组织和关节囊，保持髌韧带完整性，将髌骨翻向外侧，显露股骨髁。用直径4.2mm钻头在膝关节屈曲90°时髌骨所对应股骨内、外侧髁间关节面中部钻出直径4.2mm、深2mm的关节软骨缺损区。缺损部位用无菌生理盐水冲洗干净。
给药：将膝关节软骨缺损的新西兰兔分成两组，分别为对照组和水凝胶组，每组8只，水凝胶组注射100μl水凝胶L-Gel至缺损部位，对照组不作任何处理，使自然恢复。给药后的动物将髌骨复位后，依次缝合肌肉和皮肤切口。动物术后立即肌肉注射青霉素钠，1次/天，连续3天，以防感染。
处死及观察：治疗后4周，处死动物，取出术测关节，依据国际软骨修复协会(ICRS)评分系统进行大体观察评分。同时，剥离关节软组织，用10％中性福尔马林固定，经脱水、常规石蜡包埋制片及HE染色封片，光镜检查，采用国际软骨修复协会(ICRS)的组织学评分标准进行组织病理评分。
结果：
(1)大体观察：
治疗4周后，水凝胶组缺损区与周围正常软骨分界模糊，呈乳白色，缺损区表面平整光滑，与周围软骨连接好，高度与周围软骨基本一致；与周围正常软骨基本一致，与周围正常软骨不能分离。对照组缺损区由白色组织填充，周边可见部分裸露骨质无组织覆盖，表面粗糙不平，高度低于周围软骨。与对照组相比，水凝胶组的大体观察评分显著提高，且有统计学差异(P＜0.01)，参见图6。
(2)组织病理
治疗4周后，水凝胶组缺损填充区形态与周围正常软骨相似，细胞形态、排列，基质量接近周围正常软骨。对照组纤维组织覆盖缺损仍不完全，未见软骨形成。与对照组相比，水凝胶组的病理评分显著提高，且有统计学差异(P＜0.01)，参见图6和图7。
实施例8水凝胶对皮肤愈合的作用
利用实施例2制备的水凝胶L-Gel，测定其对大鼠皮肤愈合的作用。
分组：8周雄性SD大鼠20只，分为水凝胶组和对照组，每组10只。
造模：SD大鼠俯卧位，剪去背部毛发，脱毛，麻醉，用碘伏及乙醇消毒后，切开皮肤全层，建立1.5cm×2.0cm×0.15cm的全层皮肤损伤模型。
给药：水凝胶组伤口处涂抹水凝胶L-Gel，对照组用医用凡士林敷伤口，敷药后两组均用无菌纱布覆盖伤口。
治疗14天后，处死动物，称大鼠体重，用注水法测量创口的容积，并提取包括伤口的皮肤组织进行病理观察，通过HE染色观察肉芽组织生长情况和再生上皮角质化等变化。
治疗7天后，与对照组相比，水凝胶组伤口容积明显降低(P<0.05)，治疗14天后，与对照组相比，水凝胶组伤口容积降低更加明显(P<0.01)，参见表2。
表2不同时间点对照组和水凝胶组伤口容积(cm3)比较
注：*与对照组相比，P＜0.05，**与对照组相比，P＜0.01。
HE染色结果显示(参见图8)，治疗14天后，对照组皮肤缺损处深度与周围组织仍有差距，且仅少量角质层生成，水凝胶组缺损皮肤处几乎与周围组织齐平，且覆盖一层明显的角质层，提示水凝胶L-Gel具有明显的皮肤愈合作用。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (10)
1.一种可注射的温敏型水凝胶，其特征在于，所述温敏型水凝胶中包含：N-异丙基丙烯酰胺、N-丙烯酰氧基琥珀酰亚胺、聚乙二醇和分支肽；所述分支肽为(GPRPG)4>K2>K或(GPRPG)8>K4>K2>K，其中K为赖氨酸，G为甘氨酸，P为脯氨酸，R为精氨酸。
2.根据权利1所述的温敏型水凝胶，其特征在于，所述(GPRPG)4>K2>K的结构式如下：
所述(GPRPG)8>K4>K2>K的结构式如下：
3.如权利要求1所述的温敏型水凝胶，其特征在于，所述N-异丙基丙烯酰胺、N-丙烯酰氧基琥珀酰亚胺、聚乙二醇的质量比为N-异丙基丙烯酰胺：N-丙烯酰氧基琥珀酰亚胺：聚乙二醇＝70-85：3-10：10-20。
4.权利要求1-3任一所述的温敏型水凝胶的制备方法，其特征在于，所述制备方法包括以下步骤：
(1)将N-异丙基丙烯酰胺、聚乙二醇和N-丙烯酰氧基琥珀酰亚胺溶解于二甲基甲酰胺中，反应后冻干得到冻干粉末；
(2)向冻干粉末中加入PBS和所述分支肽，反应即得温敏型水凝胶。
5.根据权利要求4所述的制备方法，其特征在于，所述冻干粉末和分支肽的质量比为冻干粉末：分支肽＝90-110：20-40。
6.权利要求1-3任一所述温敏型水凝胶在制备止血药物中的用途。
7.权利要求1-3任一所述温敏型水凝胶在制备骨修复药物中的用途。
8.权利要求1-3任一所述温敏型水凝胶在制备软骨修复药物中的用途。
9.权利要求1-3任一所述温敏型水凝胶在制备促进皮肤愈合药物中的用途。
10.权利要求1-3任一所述温敏型水凝胶在制备眼科药物中的用途。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4014655A1 (de) * | 1990-05-08 | 1991-11-14 | Behringwerke Ag | Peptidamide, verfahren zu deren herstellung und diese enthaltende mittel als fibrin/thrombin-gerinnungsinhibitoren |
| US20140031293A1 (en) * | 2011-02-01 | 2014-01-30 | Haemostatix Limited | Therapeutic agents with improved fibrinogen binding |
| US20150071985A1 (en) * | 2012-02-01 | 2015-03-12 | Haemostatix Limited | Haemostatic wound dressing |
| CN105916524A (zh) * | 2014-01-08 | 2016-08-31 | 哈莫斯塔蒂斯有限公司 | 包含纤维蛋白原结合肽的肽类树状聚合物 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4014655A1 (de) * | 1990-05-08 | 1991-11-14 | Behringwerke Ag | Peptidamide, verfahren zu deren herstellung und diese enthaltende mittel als fibrin/thrombin-gerinnungsinhibitoren |
| US20140031293A1 (en) * | 2011-02-01 | 2014-01-30 | Haemostatix Limited | Therapeutic agents with improved fibrinogen binding |
| US20150071985A1 (en) * | 2012-02-01 | 2015-03-12 | Haemostatix Limited | Haemostatic wound dressing |
| CN105916524A (zh) * | 2014-01-08 | 2016-08-31 | 哈莫斯塔蒂斯有限公司 | 包含纤维蛋白原结合肽的肽类树状聚合物 |
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