CN1052915C - 用于携载基因的蛋白质涂层医用载体及其制作方法 - Google Patents
用于携载基因的蛋白质涂层医用载体及其制作方法 Download PDFInfo
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Abstract
本发明属于用于携载基因的蛋白质载体类医用配制品，它是将加或不加添加剂的经过交联处理的蛋白质粘附于医用底物上而制成。将底物上的蛋白质涂层有效地吸附基因后定位移植入机体的任何部位，可以理想地实现靶向输送局部定位基因。这种涂层可以被机体吸吸改、代谢，对机体没有毒副作用。
Description
本发明涉及一种以蛋白质为载体的医用配制品，具体地说是一种在底物的蛋白质涂层上携载基因的医用配制品。
随着分子生物学的发展，许多疾病的发病机理在基因水平上得以阐明，这使得从基因水平诊断和根治疾病成为可能。在医治肿瘤、糖尿病，心脏病，脑病及爱滋病等方面利用基因转移和调控的治疗方法正在深入研究。例如将抗血栓形成基因(Pro-uk基因)导入心血管内，使之在血管内表达，从而达到抑制血栓形成，防止血管堵塞的目的。然而，怎样将基因向生物体内靶向输送或局部定位，这一关键性的技术问题目前尚未得到解决。美国MichealSimons等人曾用一种聚醚(Pluronic F127)载体，将基因加入这种载体的凝胶中，然后将其送入动物的颈动脉中(Nature，359(3)，67-70，1992.9)。这种方法的缺点在于，该凝胶遇到血流冲击后会很快溶解于血液中，根本无法定位于血管的某一部位，因此无法实现靶向输送基因的目的。另外，以往在医疗器械或医疗装置等底物表面涂上涂层都是用来改善手术的外部环境。其中大多数用来增加底物表面亲水性，使底物遇到含水介质，如体液、血液时表面变得更光滑，从而减小对组织的损伤。已有文献报道的底物表面涂层，都是以人造聚合高分子材料为原料，如USPat.4373009介绍了一种聚乙烯基吡咯烷酮涂层材料，USPat.5091025介绍了一种聚丙烯酸涂层材料。它们都是用来减小底物表面摩擦系数。这些涂层用于携载基因都不理想。首先是因为这些涂层对基因的吸附力很小，其次是这些涂层的生物相容性以及对机体的毒副作用尚不清楚。
本发明的目的是提供一种对基因有强烈吸附作用的涂层医用载体及其制作方法。这种涂层能够牢固地粘附在底物上，可以随底物定位于机体的任何部位，实现靶向输送或局部定位基因的目的。同时这种涂层在体内经过一段时间后会被机体吸收、代谢，对机体没有毒副作用。
本发明的目的是这样实现的：
本发明用于携载基因的蛋白质涂层医用载体是一种分子量大于一万的经过交联处理的，加有或不加一种或多种添加剂的蛋白质涂层。用作这种蛋白质涂层的涂液的原始配方为，蛋白质、添加剂和溶剂，其中蛋白质的浓度为0.1％～40％溶液，添加剂的浓度为0～3.0％。蛋白质来源于动物或人的软、硬组织、可以是明胶、或胶原，或白蛋白，最常用的是明胶。溶剂是水、和/或有机溶剂(如二甲基甲酰胺、二甲基亚砜等)。根据不同的用途、目的或为改进涂层的某种性能可以在蛋白质涂层中加入一种或多种以下的添加剂。增塑剂，如甘油、脂肪酸、醚类、矿物油、硅油等，用以增加涂层的柔性；表面活性剂，如阴离子表面活性剂(十二烷基硫酸钠、十二烷磺酸钠等)、阳离子表面活性剂(烷基季铵盐等)、非离子表面活性剂(吐温类等)，用以改善蛋白质溶液的铺展性能；在应用于与血液接触的制品时可加入抗凝血剂(如肝素钠)、抗血小板沉积剂、抗平滑肌细胞增生剂；协助治疗某种疾病的特定药物(包括生物活性物质药物)；防腐剂(如苯甲酸钠)，用以防止蛋白质变质。
本发明用于携载基因的蛋白质涂层医用载体的制作方法有如下步骤：
1.蛋白质溶液的配制：用水和/或有机溶剂将蛋白质溶解，再根据需要加入一种或多种添加剂，搅拌混匀，配制成蛋白质浓度为0.1％～40％(最好在0.5～30％)，添加剂浓度为0～3.0％的蛋白质溶液。
2.蛋白质的交联处理：可以采用化学交联法或高能辐射交联法。化学交联法的步骤是先将需用量的化学交联剂加入配制好的蛋白质溶液中，混匀后再进行涂层，或者是在蛋白质溶液涂于底物表面后，再将需用量的化学交联剂加于涂层上。化学交联剂可以选用醛类(如甲醛、乙醛、戊二醛)、酮类(如丁二酮、己二酮)、异氰酸酯类(如甲苯二异氰酸酯、二苯基甲烷二异氰酸酯、己二异氰酸酯、三苯基甲烷三异氰酸酯、多亚甲基多异氰酸酯)、环氧类化合物(如环氧氯丙烷)中的一种或多种。化学交联剂的用量为每100克蛋白质中加入0.01～10克(最好是0.1～5克)(交联剂按100％浓度计)；高能辐射交联法是用各种放射源产生的高剂量γ-射线照射蛋白质涂层使其产生交联。
3.蛋白质溶液的涂覆：涂覆的方法可以是浸泡(5秒～2小时)、或刷、或涂抹、或喷涂等，只要使蛋白质溶液能均匀地涂于底物表面即可。这里说的底物可以是各种医用制品、医疗器械、或医疗装置、如金属血管内支架、球囊导管、引导导管、高分子血管内支架、人造血管、鞘管、骨钉、人工关节、骨夹板等。底物所用的材质可以是金属(包括不锈钢、钛、钽、锆或记忆合金等)、塑料(包括聚乙烯、聚氯乙烯、聚氨酯、聚对苯二甲酸乙二醇酯、聚对苯二甲酸丁二醇酯、聚酰胺、聚苯乙烯、聚碳酸酯、聚己内酯、聚丙交酯、聚乙交酯、聚二氧杂环己酮、或相应的共聚物)、橡胶、陶瓷、木材、或骨等，也可以是表面已经经过处理的底物，如表面已经涂有涂层的底物，这些已有的涂层可以是聚氨酯涂层、异氰酸酯低聚物涂层、异氰酸酯与二元醇或多元醇加成物涂层、异氰酸酯单体涂层、环氧树脂涂层、或能使底物表面带活性基团(包括异氰酸酯基、胺基、酰胺基、羟基、环氧基、醛基等)的涂层。
4.蛋白质涂层的干燥：将涂覆上交联剂的蛋白质涂层的底物放入烘箱中，或在自然环境中进行干燥，以除去溶剂。干燥的温度为4～100℃，干燥的时间为0.3～100小时。干燥的温度高；需要时间就短。
5.涂层厚度的控制：涂层厚度是通过蛋白质溶液的浓度和涂覆次数(即重复操作2-4步方法)来控制。蛋白质溶液浓度越小、涂层越薄；涂覆次数越多，涂层越厚。一般涂层厚度控制在0.1～100微米范围内，最好是在1～20微米。
本发明与现有技术相比，具有的优点是：本发明的医用底物的涂层是一种可以携载治疗性目的的基因的蛋白质涂层，这是一种全新的涂层。蛋白质涂层之所以能够强烈地吸附基因，首先是因为蛋白质是基因的表达物，蛋白质分子上有大量可与基因形成氢键或其它价键的位点。其次蛋白质涂层是一种水凝胶，它对基因等水溶性物质的强烈吸附是不言而喻的。本发明的蛋白质涂层的原料来自机体组织，有很好的生物相溶性，经过一段时间后自然被机体吸收、代谢、没有毒副作用。因为将携载基因的蛋白质涂于底物表面上，所以基因很容易随底物被定位于机体的治疗部位，达到靶向输送入或局部定位基因的目的。
实施例1.
配制100ml 10％浓度的明胶水溶液，加入浓度为37％的甲醛溶液0.5ml和1.0克甘油、混合均匀。用移液管取此溶液置于不锈钢血管内支架上，用一玻璃棒将溶液铺开，于20℃下，在自然环境中干燥20小时、在底物上形成一层牢固的有很好柔性的涂层。将涂有该涂层的不锈钢血管内支架浸泡于基因原液中1分钟，取出后用球囊导管将其植入狗的股动脉中。七天后对该股动脉进行组化染色(X-gal)分析。结果是实验段股动脉内膜及中膜大量细胞核成深蓝色，这表明基因在该段股动脉高效转染。同时，将没有蛋白质涂层的不锈钢血管内支架进行同样的对照试验。结果是没有发生实验段股动脉的细胞核蓝染。这充分证明蛋白质涂层可以携载基因，并成功地将基因靶向输送。
实施例2-23.
操作方法步骤及携载基因并靶向输送的实验及结果同实施例1，只是采用了不同的底物、不同的蛋白质溶液、不同的交联剂、添加剂、不同的干燥条件和涂覆次数，详细数据见表1。
实施例24.
配制100ml 10％浓度的明胶水溶液，加入1.0克甘油，在电磁搅拌器上搅拌5分钟，将不锈钢片浸泡在上述蛋白质溶液中30秒，取出后在20℃下干燥10小时，然后，将带涂层的不锈钢片浸入10％的甲醛溶液中1分钟，取出后，于20℃下干燥40小时。携载基因和靶向输送的实验及结果同实施例1。
实施例25.
配制100ml 10％浓度的明胶水溶液，加入1.0克甘油和15毫克十二烷基硫酸钠，在电磁搅拌器上搅拌5分钟、将聚对苯二甲酸乙二醇酯膜片浸入该溶液中1分钟，然后用剂量为3.0 Mrad的γ-射线照射，使明胶交联，取出在20℃下干燥10小时。携载基因和靶向输送的实验及结果同实施例1。
表1.
| 实施例 | 底物名称 | 蛋白质溶液 | 交联剂 | 添加剂 | 干燥条件 | 涂覆次数(方法) | ||||
| 名称 | 浓度(％) | 名称 | 浓度(％) | 名称 | 浓度(％) | 温度℃ | 小时 | |||
| 2 | 不锈钢板 | 明胶+水 | 5 | 甲醛 | 0.30 | -- | -- | 20 | 24 | 1(涂) |
| 3 | 不锈钢板 | 明胶+DMS* | 2 | TDI* | 0.40 | -- | -- | I.60II.20 | 1.548 | 2(浸) |
| 4 | 不锈钢板 | 明胶+水+DMS | 6 | 甲醛 | 0.30 | 甘油 | 1.0 | I.60II.20 | 148 | 2(浸) |
| 5 | 不锈钢板 | 明胶+水 | 10 | 甲醛 | 0.30 | 肝素钠 | 0.1 | 20 | 24 | 1(涂) |
| 6 | 不锈钢板 | 明胶+水 | 10 | 甲醛 | 0.30 | S* | 0.015 | 20 | 24 | 1(涂) |
| 7 | 聚对苯二甲酸乙二醇酯膜 | 明胶+水 | 10 | 甲醛 | 0.30 | 甘油S | 1.00.015 | 20 | 40 | 1(涂) |
| 8 | 尼仑-6膜 | 明胶+水 | 10 | 甲醛 | 0.30 | 甘油S | 1.00.015 | 20 | 40 | 1(涂) |
| 9 | 球囊导管(USCI公司) | 明胶+水 | 5 | 甲醛 | 0.30 | 甘油S | 0.70.015 | 20 | 40 | 1(浸) |
| 10 | 球囊导管(Cordis公司) | 明胶+水 | 5 | 甲醛 | 0.30 | 甘油S | 0.70.015 | 20 | 40 | 1(浸) |
| 11 | 球囊导管(Cordis公司) | 明胶+水 | 5 | 甲醛 | 0.30 | 甘油 | 1.0 | I.20II.20 | 0.220 | 2(浸) |
| 12 | 带有异氰酸酯基过渡涂层的不锈钢条 | 明胶+水 | 10 | 甲醛 | 0.30 | 甘油 | 1.0 | 20 | 48 | 1(喷) |
续表1
* DNS-二甲基亚砜
| 13 | 带有异氰酸酯基过渡涂层的PET膜 | 明胶+水 | 10 | 甲醛 | 0.30 | 甘油S | 1.00.015 | 20 | 48 | 1(喷) |
| 14 | 不锈钢人工关节 | 明胶+水 | 5 | 戊二醛 | 0.15 | 甘油吐温-80 | 0.70.1 | 20 | 24 | 1(浸) |
| 15 | 聚氨酯片 | 明胶+水 | 5 | 丁二酮 | 0.50 | 甘油S | 0.70.020 | 20 | 24 | 1(涂) |
| 16 | 陶瓷片 | 明胶+水 | 4 | 甲醛/戊二醛(1∶1 | 0.50 | 甘油N* | 1.00.012 | 20 | 24 | 1(涂) |
| 17 | 不锈钢板 | 牛血清白蛋白+水 | 5 | 甲醛 | 0.12 | 甘油S | 0.60.014 | 20 | 24 | 1(涂) |
| 18 | 钽血管内支架 | 明胶+水 | 5 | 甲醛 | 0.15 | 甘油S | 0.40.014 | 20 | 40 | 1(浸) |
| 20 | 钛血管内支架 | 明胶+水 | 5 | 甲醛 | 0.15 | 甘油S | 0.40.014 | 20 | 40 | 1(浸) |
| 21 | 记忆合金血管内支架 | 明胶+水 | 5 | 甲醛 | 0.15 | 甘油S | 0.40.014 | 20 | 40 | 1(浸) |
| 22 | 不锈钢血管内支架 | 明胶+水 | 10 | 甲醛 | 0.5 | 甘油 | 1.0 | I.30II.20 | 0.540 | 2(浸) |
| 23 | 不锈钢血管内支架 | 胶原+水 | 1 | 甲醛 | 0.5 | 甘油 | 1.0 | I.30II.20 | 0.540 | 2(浸) |
TDI-甲苯二异氰酸酯
S -十二烷基硫酸钠
N -十六烷基三甲基溴化铵
Claims (12)
1.一种用于携载基因的蛋白质涂层医用载体，包括涂层、底物和基因，其特征在于它含有分子量大于一万的蛋白质和添加剂；用作所述涂层的涂液的蛋白质浓度是0.1％-40％、添加剂浓度为0-3.0％和溶剂；所述的添加剂是增塑剂、表面活性剂、抗凝血剂、抗血小板沉积剂、抗平滑肌细胞增生剂和/或防腐剂。
2.按照权利要求1所说的用于携载基因的蛋白质涂层医用载体，其特征在于所说的蛋白质是来源于动物或人的软、硬组织的明胶、胶原或白蛋白。
3.按照权利要求1所说的用于携载基因的蛋白质涂层医用载体，其特征在于所说的蛋白质是采用化学交联法或高能辐射交联法交联处理。
4.按照权利要求1所说的用于携载基因的蛋白质涂层医用载体，其特征在于所说的底物包括金属、塑料、骨或陶瓷；所说的底物制作成金属血管内支架、球囊导管、引导导管、高分子血管内支架、人造血管、鞘管、骨钉、人工关节或骨夹板。
5.按照权利要求4所说的用于携载基因的蛋白质涂层医用载体，其特征在于所说的金属是不锈钢、钛、钽、锆或记忆合金。
6.按照权利要求4所说的用于携载基因的蛋白质涂层医用载体，其特征在于所说的塑料是聚乙烯、聚氯乙烯、聚氨酯、聚对苯二甲酸乙二醇酯、聚对苯二甲酸丁二醇酯、聚酰胺、聚苯乙烯、聚碳酸酯、聚己内酯、聚丙交酯、聚乙交酯、聚二氧杂环己酮、或相应共聚物。
7.按照权利要求1所说的用于携载基因的蛋白质涂层医用载体，其特征在于所说的增塑剂是甘油、脂肪酸、醚类、矿物油或硅油；所说的表面活性剂是十二烷基硫酸钠、十二烷基磺酸钠、烷基季铵盐或吐温类；所说的抗凝血剂是肝素钠；所说的防腐剂是苯甲酸钠。
8.按照权利要求1所说的用于携载基因的蛋白质医用载体，其特征在于所说的底物可以是涂有涂层的底物，它们是聚氨酯涂层、异氰酸酸低聚物涂层、异氰酸酯与二元醇或多无醇加成物涂层、异氰酸酯单体涂层、环氧树脂涂层，或能使底物表面带活性基团包括异氰酸酯基、胺基、酰胺基、羟基、环氧基或醛基的涂层。
9.按照权利要求1所说的用于携载基因的蛋白质涂层医用载体，其特征在于所说的溶剂是水、二甲基甲酰胺和/或二甲基亚砜。
10.权利要求1所说的用于携载基因的蛋白质涂层医用载体的制作方法，其特征在于包括如下步骤：
A.先用溶剂将蛋白质溶解，再加入添加剂，搅拌混匀，配制成蛋白质浓度0.1％-40％、添加剂浓度为0-3.0％的蛋白质溶液；
B.采用化学交联法或高能辐射交联法交联处理；所说的化学交联剂是醛类、酮类、异氰酸酯类和/或环氧类化合物，用量为每100克蛋白质加入0.01-10克交联剂；所说的高能辐射交联法是用放射源产生的高剂量γ-射线来照射使其产生交联；
C.将蛋白质溶液均匀地涂于底物表面，涂覆的方法为浸泡5秒-2小时、刷、涂抹或喷涂；
D.将涂覆上蛋白质涂层的底物放入烘箱中、或在自然环境中进行干燥，温度为4-100℃，时间为0.3-100小时；
E.通过控制蛋白质溶液的浓度和涂抹次数即重复操作B-D步骤控制涂层的厚度，涂层厚度控制在0.1-100微米内即可。
11.按照权利要求10所说的用于携载基因的蛋白质涂层医用载体的制作方法，其特征在于配制成蛋白质浓度0.1％-10％、添加剂浓度为0.015-3.0％的蛋白质溶液。
12.按照权利要求10所说的用于携载基因的蛋白质涂层医用载体的制作方法，其特征在于所说的化学交联剂是甲醛、甲苯二异氰酸酯、戊二醛和/或丁二酮。
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Also Published As
| Publication number | Publication date |
|---|---|
| CN1126093A (zh) | 1996-07-10 |
| US6004943A (en) | 1999-12-21 |
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