CN107198789B - 一种纳米铂聚合物及其制备方法和应用 - Google Patents

一种纳米铂聚合物及其制备方法和应用 Download PDF

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CN107198789B
CN107198789B CN201710505619.1A CN201710505619A CN107198789B CN 107198789 B CN107198789 B CN 107198789B CN 201710505619 A CN201710505619 A CN 201710505619A CN 107198789 B CN107198789 B CN 107198789B
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杨革
梁鑫鑫
孙阳
刘金锋
巩志金
李媛
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Guangzhou Boshipai Biotechnology Co ltd
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Abstract

本发明公开了一种纳米铂聚合物及其制备方法和应用，所述的纳米铂聚合物的原料包括纳米铂，壳寡糖，聚γ‑谷氨酸，丙二醇，交联剂EDC/NHS，本发明制备得到的纳米铂聚合物，可应用到医疗产品当中，尤其是在伤口敷料方面的应用。与现有的技术相比，本发明所获得的纳米铂聚合物药物，具有良好的生物相容性，抑菌性，首选纳米铂作为药物，丙二醇作为润滑剂，药物包裹率较高，较高的可降解性，溶胀性能较好，原料廉价易得，生产工艺简单。

Description

一种纳米铂聚合物及其制备方法和应用
技术领域
本发明属于医学技术领域，涉及一种纳米铂聚合物及其制备方法和应用。
背景技术
聚γ-谷氨酸（γ-PGA），是由D-谷氨酸或者L-谷氨酸通过α-氨基和γ-羧基酰化反应形成酰胺键聚合在一起的一种高分子聚合物，含有大量的游离的羧基，是一种阴离子聚合物，能发生交联、鳌合，衍生化等反应，分子量范围在10KD～10000KD，通过一定的降解条件，可形成小分子量的γ-PGA，本实验室提取的γ-PGA，分子量大约3000KD，经过酸性降解条件，降解为70KD左右的分子量。
聚γ-谷氨酸水凝胶因其生物可降解性、高吸水性及保湿性、pH敏感性、生物相容性、可修饰性等，在组织工程、药物缓释、食品工业、污水处理、各种伤口的创面敷料中，具有相当广泛的应用。与传统的伤口敷料相比，水凝胶伤口敷料因其高生物相容性、生物可降解性、高保湿性，抑菌性能较好等，成为伤口敷料的研究热点。
在各种伤口敷料中，比较常用的先进敷料可分为四种，湿式伤口敷料、抗菌敷料、主动式伤口照护敷料、负压治疗用敷料。其中，抗菌类敷料占敷料应用市场的10%，并因其高效的抗菌性能、生物相容性、可降解性等，逐渐打开在各种敷料产品的市场。抗菌类敷料的研究，主要集中在银离子抗菌敷料、铜离子抗菌敷料等。
在水凝胶伤口敷料中，主要研究结合了银离子、铜离子、铅离子、汞离子等离子聚合物，以及结合各类药物的水凝胶的抑菌性能、生物相容性，对伤口的高效止血、促进伤口愈合的能力。但采用纳米铂作为抑菌物质，将其应用到水凝胶医药产品上，还未有此方面的研究及应用。
发明内容
本发明提供一种纳米铂聚合物及其制备方法，所获得的纳米铂聚合物，具有良好的生物相容性，抑菌性。
本发明还提供上述纳米铂聚合物在水凝胶医药产品上，尤其在烧伤、创伤、溃疡等造成的创伤方面的敷料的应用。
本发明技术方案如下：
一种纳米铂聚合物，具有致密的三维网状结构，纳米铂的包封率为95.46～99.89%，负载率为93.5～97.5%，吸水度为31.5～38.4g/g；所述纳米铂聚合物制备原料包括：纳米铂，壳寡糖，聚γ-谷氨酸，丙二醇和EDC/NHS交联剂。
进一步地，所述的纳米铂，粒度为20～30nm。
进一步地，纳米铂与聚γ-谷氨酸、壳寡糖的质量比为1:10～15:25～40。
进一步地， EDC/NHS交联剂为 EDC和NHS溶于去离子水中配制成的0.1M交联剂溶液， EDC与NHS在水中的摩尔比为1:1，用量为200～600μL/ 0.01～0.05g纳米铂，优选400μL/0.02g纳米铂。
进一步地，丙二醇用量为1～3mL/ 0.01～0.05g纳米铂，优选为2mL/0.02g纳米铂。
一种上述纳米铂聚合物的制备方法，步骤包括：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）将聚γ-谷氨酸，加入到去离子水中，搅拌溶解，配制为0.0014～0.016g/mL的透明溶液，然后向透明溶液中加入EDC/NHS交联剂和纳米铂溶液，搅拌均匀，得到聚γ-谷氨酸溶液；
3）将壳寡糖加入到步骤2）的聚γ-谷氨酸溶液中，搅拌均匀，再加入丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.5～1倍体积的去离子水，混均匀，2～8℃反应15h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，再用磷酸缓冲液浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
本发明纳米铂聚合物，还可以通过下述方法制备，步骤包括：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）聚γ-谷氨酸，加入到去离子水中，搅拌溶解，配制为0.0014～0.016g/mL的透明溶液，然后加入EDC/NHS交联剂，2～8℃反应5h；
3）向反应后溶液中加入纳米铂溶液，搅拌均匀，然后缓慢加入壳寡糖，轻轻搅拌后，再加入丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.5～1倍体积的去离子水，混均匀，2～8℃反应10h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，再用磷酸缓冲液浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
本发明纳米铂聚合物的应用，可用于医疗产品，尤其适用于创伤、烧伤等伤口中做伤口敷料。
纳米铂是一种金属元素，在纳米级别当中，铂不仅具有抗菌、杀菌作用，其更大优点在于还具有抗癌抗肿瘤、促进细胞的扩增以及损伤细胞的修复等方面的应用，将其应用到水凝胶敷料方面，结合铂的优势，加上聚γ-谷氨酸水凝胶的生物活性性能，能够加快伤口的愈合，缩短时间，并且不易留下伤疤。
本发明纳米铂聚合物，纳米铂以共价键修饰结合聚合物形成水凝胶的生物相容性高分子，与现有的技术相比，本发明所获得的纳米铂聚合物，具有良好的生物相容性，抑菌性，抑菌效率、细胞毒性、生物相容性等比其他现有的聚合物药物存在更大的优越性，可应用到医疗产品当中，尤其是伤口敷料方面。本发明制备方法简单，首选纳米铂作为药物，超声混合纳米铂加入溶液中，药物包裹率较高，较高的可降解性，溶胀性能较好，原料廉价易得。
具体实施方式
下面结合具体实施方案，来进一步阐述本发明。并认为，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。
实施例1（方法一）
一种纳米铂聚合物的制备方法，步骤为：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）将0.1g聚γ-谷氨酸粉末置于50mL烧杯中，溶于45mL去离子水中，配制为透明溶液，然后加入200μL EDC/NHS交联剂（EDC与NHS的摩尔比为1:1）和0.02g纳米铂溶液（纳米铂粒度为20～30nm），搅拌均匀，得到聚γ-谷氨酸溶液；
3）将2.5g壳寡糖粉末缓慢加入到步骤2）的聚γ-谷氨酸溶液中，轻轻搅拌均匀，再加入1mL丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.75倍体积的去离子水，混均匀，2～8℃反应15h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，再用磷酸缓冲液浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
实施例1所得到的纳米铂聚合物，具有致密的三维网状结构，纳米铂的包封率为99.89%，负载率为97.5%，对大肠杆菌，芽孢杆菌、金黄色葡萄球菌的抑菌效率都非常好，其中，对大肠杆菌的抑菌效率达到89.3%，对芽孢杆菌的抑菌效率达到88.9%，对金黄色葡萄球菌的抑菌效率到达94.6%，经MTT细胞毒性实验证明，与阴性对照材料的比值接近1，说明细胞毒性较低，且生物相容性较好，符合医疗产品的相关规定。
实施例2（方法一）
一种纳米铂聚合物的制备方法，步骤为：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）取0.15g聚γ-谷氨酸粉末于50mL烧杯中，溶于45mL去离子水中，配制为透明溶液，然后加入300μL EDC/NHS交联剂和0.03g纳米铂溶液，超声搅拌均匀，得到聚γ-谷氨酸溶液；
3）将2.5g壳寡糖粉末缓慢加入到步骤2）的聚γ-谷氨酸溶液中，轻轻搅拌均匀，再加入1.5mL丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.8倍体积的去离子水，混均匀，2～8℃低温反应15h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
实施例2所得到的纳米铂聚合物，具有致密的三维网状结构，纳米铂的包封率为96.3%，负载率为95.7 %，对大肠杆菌，芽孢杆菌、金黄色葡萄球菌的抑菌效率都非常好，其中，对大肠杆菌的抑菌效率达到93.7%，对芽孢杆菌的抑菌效率达到90 .5%，对芽孢杆菌的抑菌效率到达96%，经MTT细胞毒性实验证明，与阴性对照材料的比值接近1，说明细胞毒性较低，生物相容性较好，符合医疗产品的相关规定。
实施例3（方法一）
一种纳米铂聚合物的制备方法，步骤为：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）取0.15g聚γ-谷氨酸粉末于50mL烧杯中，溶于45mL去离子水中，配制为透明溶液，然后加入400μL EDC/NHS交联剂和0.04g纳米铂溶液，搅拌均匀，得到聚γ-谷氨酸溶液；
3）将3g壳寡糖粉末缓慢加入到步骤2）的聚γ-谷氨酸溶液中，轻轻搅拌均匀，再加入2mL丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.85倍体积的去离子水，混均匀，2～8℃低温反应15h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
实施例3所得到的纳米铂聚合物，具有致密的三维网状结构，纳米铂的包封率为95.8%，负载率为94.7%，对大肠杆菌，芽孢杆菌、金黄色葡萄球菌的抑菌效率都非常好，其中，对大肠杆菌的抑菌效率达到87.4%，对芽孢杆菌的抑菌效率达到95 .1%，对金黄色葡萄球菌的抑菌效率到达98.3%，经MTT细胞毒性实验证明，与阴性对照材料的比值接近1，说明细胞毒性较低，生物相容性较好，符合医疗产品的相关规定。
实施例4（方法二）
一种纳米铂聚合物的制备方法，步骤为：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）取0.15g聚γ-谷氨酸粉末于50mL烧杯中，溶于45mL去离子水中，配制为透明溶液，然后加入400μL EDC/NHS交联剂，2～8℃反应5h；
3）向反应后溶液中加入0.02g纳米铂溶液，超声搅拌均匀，然后缓慢加入3g壳寡糖，轻轻搅拌后，再加入2mL丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.75倍体积的去离子水，混合均匀，2～8℃反应10h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，再用磷酸缓冲液浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
实施例4所得到的纳米铂聚合物，具有致密的三维网状结构，纳米铂的包封率为98.4%，负载率为96.8%，对大肠杆菌，芽孢杆菌、金黄色葡萄球菌的抑菌效率都非常好，其中，对大肠杆菌的抑菌效率达到95.4%，对芽孢杆菌的抑菌效率达到96 .1%，对金黄色葡萄球菌的抑菌效率到达 97.4 %，经MTT细胞毒性实验证明，与阴性对照材料的比值接近1，说明细胞毒性较低，生物相容性较好，符合医疗产品的相关规定。
对比例1：
一种纳米银聚合物的制备方法，将实施例1中原料纳米铂替换为纳米银，步骤同实施例1。
对比例1所得到的纳米银聚合物，结构为较大的孔状、网状结构，纳米银的包封率为 93.6%，负载率为91.8%，对大肠杆菌的抑菌效率84.7%，对芽孢杆菌的抑菌效率82.3%，对金黄色葡萄球菌的抑菌效率83.6%，经MTT细胞毒性实验证明，与阴性对照材料的比值接近0.8。
对比例2：
一种纳米银聚合物的制备方法，将实施例4中原料纳米铂替换为纳米银，步骤同实施例4。
对比例2所得到的纳米银聚合物，结构为较大的孔状、网状结构，纳米银的包封率为91.4%，负载率为90.3%，对大肠杆菌的抑菌效率84.8%，对芽孢杆菌的抑菌效率86.2%，对金黄色葡萄球菌的抑菌效率87.8%，经MTT细胞毒性实验证明，与阴性对照材料的比值对比例1纳米银聚合物，接近0.8。
本发明纳米铂聚合物对伤口的影响
用实验室提供的荷兰鼠作为实验研究对象，利用实施例3得到得到的纳米铂聚合物药物、对比例1纳米银聚合物、市场销售的普通伤口敷料，涂抹于伤口处，对其伤口进行处理。结果发现，本发明在半小时内即可完全止血，且较对比例1纳米银聚合物相比，明显缩短伤口恢复时间一周。与市场销售的普通伤口敷料相比，本发明得到的纳米铂聚合物药物，伤口恢复的时间更是明显缩短，止血效果显著提高。此外，由于本发明纳米铂聚合物药物还具有抑菌性，会抑制伤口处的发炎状况，并且因其药物具有保湿性，当伤口恢复如初时，便于从伤口处剥离下来，不会破坏伤口。

Claims (7)

1.一种纳米铂聚合物，其特征在于：具有致密的三维网状结构，纳米铂的包封率为95.46～99.89%，负载率为93.5～97.5%，吸水度达到31.5～38.4g/g；所述纳米铂聚合物制备原料包括：纳米铂，壳寡糖，聚γ-谷氨酸，丙二醇和EDC/NHS交联剂；
所述的聚γ-谷氨酸的平均分子量为70KD；
所述的纳米铂与聚γ-谷氨酸、壳寡糖的质量比为1:10～15:25～40；
所述的EDC/NHS交联剂为 EDC和NHS溶于去离子水中配制成的0.1M交联剂溶液，EDC与NHS在水中的摩尔比为1:1，用量为200～600μL/ 0.01～0.05g纳米铂；
所述的丙二醇用量为1～3mL/ 0.01～0.05g纳米铂。
2.根据权利要求1所述的纳米铂聚合物，其特征在于：所述的纳米铂，粒度为20～30nm；
3.根据权利要求1所述的纳米铂聚合物，其特征在于：EDC/NHS交联剂用量为400μL/0.02g纳米铂。
4.根据权利要求1所述的纳米铂聚合物，其特征在于：丙二醇用量为2mL/0.02g纳米铂。
5.一种权利要求1～4任一项所述纳米铂聚合物的制备方法，其特征在于，步骤包括：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）将聚γ-谷氨酸，加入到去离子水中，搅拌溶解，配制为0.0014～0.016g/mL的透明溶液，然后向透明溶液中加入EDC/NHS交联剂和纳米铂溶液，搅拌均匀，得到聚γ-谷氨酸溶液；
3）将壳寡糖加入到步骤2）的聚γ-谷氨酸溶液中，搅拌均匀，再加入丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.5～1倍体积的去离子水，混均匀，2～8℃反应15h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，再用磷酸缓冲液浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
6.一种权利要求1～4任一项所述纳米铂聚合物的制备方法，其特征在于，步骤包括：
1）按配比取各原料，将纳米铂加入到去离子水中，超声10min，混合均匀，配制为0.1g/mL纳米铂溶液；
2）聚γ-谷氨酸，加入到去离子水中，搅拌溶解，配制为0.0014～0.016g/mL的透明溶液，然后加入EDC/NHS交联剂，2～8℃反应5h；
3）向反应后溶液中加入纳米铂溶液，搅拌均匀，然后缓慢加入壳聚糖，轻轻搅拌后，再加入丙二醇，搅拌形成均一混合溶液；
4）向步骤3）的混合液中缓慢加入0.5～1倍体积的去离子水，混均匀，2～8℃反应10h，形成均一的水凝胶聚合物；
5）将聚合物用0.5M 的NaOH水溶液浸泡4h，然后用磷酸缓冲液洗涤后，再用磷酸缓冲液浸泡4h，直至pH为7，冷冻干燥，得纳米铂聚合物。
7.根据权利要求1～4任一项所述的纳米铂聚合物，其特征在于：作为医疗产品在创伤、烧伤伤口中做伤口敷料。
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