CN105749326A - 一种多肽抗菌自组装复合材料及其制备方法 - Google Patents
一种多肽抗菌自组装复合材料及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种多肽抗菌自组装复合材料及其制备方法，所述多肽抗菌自组装复合材料为CIPFmoc?7AAP/PTA。制备方法包括：将CIP加入到PTA水溶液中，得到混合溶液；然后将混合溶液加入到Fmoc?7AAP的1,1,1,3,3,3,?六氟?2?丙醇溶液中，静置，离心，冷冻干燥，即得。本发明的抗感染自组装复合材料，有较好的载药及药物缓释效果，可以用于药物控制释放研究，形成创造促进伤口愈合的微环境，有着很好的实用价值。
Description
技术领域
本发明属于自组装复合材料及其制备领域，特别涉及一种多肽抗菌自组装复合材料及其制备方法。
背景技术
敷料是指用于物品主料之外的辅属材料，主要指止血纱布，随着对创面愈合过程的病理生理的深入研究，人们对创面愈合过程的理解也越来越深刻，从而导致了医用创面敷料的不断改进与发展。今天，新型的创面护理用敷料相对于早期而言，已经发生了革命性的变化，而且多种不同性能的医用敷料可供临床护理人员选用。目前，藻酸盐敷料是国际最先进的医用敷料，抗菌敷料，是一种新型的广谱抗菌敷料，主要成分为聚氨酯泡棉、羧甲基纤维素钠、银等，新型医用敷料(含银抗菌敷料、生物活性敷料、人工皮肤等)普及进程也将加快，利用多肽自组装技术构建的各种功能性材料在药物控制释放、组织工程支架材料以及医疗等领域内有着巨大的应用前景。
环丙沙星(Ciprofloxacin，CIP)为合成的第三代喹诺酮类抗菌药物，具广谱抗菌活性，作用于细菌细胞DNA螺旋酶的A亚单位，抑制DNA的合成和复制而导致细菌死亡，杀菌效果好，几乎对所有细菌的抗菌活性均较诺氟沙星及依诺沙星强2～4倍，对于肠杆菌、绿脓杆菌、流感嗜血杆菌、淋球菌、链球菌、军团菌、金黄色葡萄球菌具有抗菌作用，应用广泛。然而，环丙沙星也有着传统抗癌药物的不良反应，主要不良反应为胃肠道反应，也有些神经系统反应，如：头痛头晕失眠等，有过敏反应，另外还有体弱、肌肉痛、腱鞘炎、光敏感、短暂的肾功能损害，包括短暂的肾衰竭，静脉炎或血栓性静脉炎等问题。因此，开发一种新型理想的抗感染敷料，同时又能实现高效载环丙沙星及其可控释放的生物材料很有必要。
发明内容
本发明所要解决的技术问题是提供一种多肽抗菌自组装复合材料及其制备方法，该方法操作简单、反应条件温和；多肽自组装载药材料药物包封率高，且具有较好的释放特性。
本发明的一种多肽抗菌自组装复合材料，多肽抗菌自组装复合材料为CIP@Fmoc-7AAP/PTA；其中，Fmoc-7AAP和PTA总质量与CIP的质量比为5:1～1:1；Fmoc-7AAP和PTA的质量比为1:20～1:80。
本发明的一种多肽抗菌自组装复合材料的制备方法，包括：
将CIP加入到PTA水溶液中，得到混合溶液；然后将混合溶液加入到七肽Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液中，静置，离心，冷冻干燥，得到CIP@Fmoc-7AAP/PTA载药复合物，即多肽抗菌自组装复合材料；其中，混合溶液加入到Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液后Fmoc-7AAP和PTA总质量与CIP的质量比为5:1～1:1；Fmoc-7AAP和PTA的质量比为1:20～1:80。
所述PTA水溶液中PTA的浓度为0.025×10-3～0.8×10-3M；七肽Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液中Fmoc-7AAP的浓度为0.03～0.48M。
所述七肽Fmoc-7AAP的序列为Fmoc-Ile-Gln-Ser-Pro-His-Phe-Phe。
所述静置的时间为4h～5h。
所述离心转速为10000rpm，离心时间为5～10分钟。
所述CIP@Fmoc-7AAP/PTA的溶液及Fmoc-7AAP/PTA的PBS溶液用于药物释放，测其药物释放量；其中，CIP@Fmoc-7AAP/PTA的PBS溶液中含CIP浓度为0～40μM，配制的Fmoc-7AAP/PTA的PBS溶液的浓度为0～l00mg/ml。CIP@Fmoc-7AAP/PTA的溶液用于大肠杆菌培育，测其抗菌性能。
有益效果
(1)本发明利用Fmoc-7AAP和PTA自组装过程中对CIP的化学吸附及物理包裹，制备了含CIP的多肽自组装复合材料，制备方法简单、实验条件温和；
(2)本发明所使用的载体材料本身具有很好的生物相容性和可降解性，所制备的含环丙沙星多肽自组装复合材料药物包封率高；
(3)本发明所制备的含环丙沙星多肽自组装复合材料，通过调控环境的pH值使CIP@Fmoc-HP/PTA微球的敷料具有不同的药物释放量。
附图说明
图1为实施例1中环丙沙星的标准曲线；
图2为实施例1中不同pH值下载体的降解和药物的释放图；
图3为实施例2中整理有CIP@Fmoc-HP/PTA微球的棉纱布的SEM图；
图4为实施例3中CIP@Fmoc-HP/PTA微球的敷料对大肠杆菌产生的抑菌圈。
具体实施方式
下面结合具体实施例，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。此外应理解，在阅读了本发明讲授的内容之后，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。
实施例1
(1)准确称取2mg环丙沙星，溶解于100ml PBS中，配制成0.02mg/ml的环丙沙星母液，将该溶液逐倍稀释到0.01、0.005、0.0025和0.00125mg/ml。图1为环丙沙星的标准曲线，从图上可知浓度范围在0.00125-0.02mg/mL以内，CIP在PBS缓冲液中的浓度-吸光度均具有很好的线性关系，拟合后线性相关系数分别为R2＝0.999。
(2)称取6mg环丙沙星，用6ml PBS溶解，配制浓度为1mg/mL的环丙沙星溶液，分别取10μl浓度为1，0.5，0.25，0.125，0.0625mg/mL环丙沙星的PTA混合溶液迅速加入到10μl的Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液中，静置4h后离心，收集上清液，再用去离子水重复洗涤三次。其中，PTA水溶液中PTA的浓度为0.165×10-3M；七肽Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液中Fmoc-7AAP的浓度为0.102M。Fmoc-7AAP和PTA总质量与CIP的质量比为4:1，Fmoc-7AAP和PTA的质量比为1:60。
(3)收集所有步骤2中离心洗涤后的上清液，用紫外-可见分光光度计测其在波长271nm处的吸光度，通过标准曲线方程计算出未上载的量，计算出CIP的上载率和包封率。表1为不同条件下CIP的上载率和包封率，当CIP浓度为0.5mg/ml时上载率和包封率均较高，为本实验最佳载药条件。图2为不同pH值下Fmoc-7AAP/PTA载体的降解和CIP药物的释放。
将CIP@Fmoc-7AAP/PTA微球用PBS溶液分散后放入透析袋，并置于PBS环境的溶出仪中，测定药物释放。其中，CIP@Fmoc-7AAP/PTA的PBS溶液中含CIP浓度为0.005mg/ml。
表1不同条件下CIP的上载率和包封率
| 浓度(mg/mL) | 上载率(％) | 包封率(％) |
| 1 | 30.48 | 48.76 |
| 0.5 | 20.06 | 64.2 |
| 0.25 | 11.48 | 73.44 |
| 0.125 | 4.32 | 54.11 |
| 0.0625 | 2.02 | 51.68 |
实施例2
(1)将漂白棉纱布剪成直径2cm规格的试样，取环丙沙星的PTA水溶液迅速加入到Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液中，同时将已经准备好的棉布样品放入其中浸没，再将CIP整理到含Fmoc-HP/PTA微球的棉纱布，其中，Fmoc-7AAP和PTA总质量与CIP的质量比为4:1。
(2)静置数小时后，用镊子将棉纱布取出放入恒温干燥箱中30℃干燥，即得到整理有CIP@Fmoc-HP/PTA微球的棉纱布。图3为整理有CIP@Fmoc-HP/PTA微球的棉纱布的SEM图，从图上可以看到织物上附有较多微球。
实施例3
(1)采用美国临床实验室标准化研究所的纸片扩散法研究纳米纤维的抗菌活性(MIC)。在评估中，大肠杆菌(革兰氏阴性；ATCC 25922)被选定为代表的微生物，并培养在Lauria肉汤(LB)和营养肉汤琼脂平板(NB)。
(2)将实施例2中整理有CIP@Fmoc-HP/PTA微球的棉纱布用75％的乙醇蒸汽处理24h进行灭菌。然后取100μl微生物溶液培养在琼脂培养皿上面，并把每个样品放置在琼脂平板的表面。
(3)所有的样品均在37℃条件下培育24小时，最后观察和测量抑菌圈。图4为CIP@Fmoc-HP/PTA微球的敷料对大肠杆菌产生的抑菌圈，抑菌圈直径在6cm左右，表明CIP@Fmoc-HP/PTA微球的敷料具有很好的抑菌效果。
Claims (6)
1.一种多肽抗菌自组装复合材料，其特征在于，多肽抗菌自组装复合材料为CIP@Fmoc-7AAP/PTA；其中，Fmoc-7AAP和PTA总质量与CIP的质量比为5:1～1:1；Fmoc-7AAP和PTA的质量比为1:20～1:80。
2.一种多肽抗菌自组装复合材料的制备方法，包括：
将环丙沙星CIP加入到磷钨酸PTA水溶液中，得到混合溶液；然后将混合溶液加入到七肽Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液中，静置，离心，冷冻干燥，得到CIP@Fmoc-7AAP/PTA载药复合物，即多肽抗菌自组装复合材料；其中，混合溶液加入到Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液后Fmoc-7AAP和PTA总质量与CIP的质量比为5:1～1:1；Fmoc-7AAP和PTA的质量比为1:20～1:80。
3.根据权利要求2所述的一种多肽抗菌自组装复合材料的制备方法，其特征在于，所述PTA水溶液中PTA的浓度为0.025×10-3～0.8×10-3M；七肽Fmoc-7AAP的1,1,1,3,3,3,-六氟-2-丙醇溶液中Fmoc-7AAP的浓度为0.03～0.48M。
4.根据权利要求2所述的一种多肽抗菌自组装复合材料的制备方法，其特征在于，所述七肽Fmoc-7AAP的序列为Fmoc-Ile-Gln-Ser-Pro-His-Phe-Phe。
5.根据权利要求2所述的一种多肽抗菌自组装复合材料的制备方法，其特征在于，所述静置的时间为4h～5h。
6.根据权利要求2所述的一种多肽抗菌自组装复合材料的制备方法，其特征在于，所述离心转速为10000rpm，离心时间为5～10分钟。
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