CN104548123B - 一种酰化改性明胶栓塞微球的制备 - Google Patents
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Abstract
将明胶微球进行反应改性，通过酰化反应引入羧基，然后用反相悬浮交联法制备成微球，制备成含离子交换基团的载药栓塞微球，微球形态规整，粒径在100μm到700μm之间，粒径可调。该微球负载抗癌药物阿霉素，24h内载药率最高可达35.9％，而纯明胶微球载药率仅为8.6％，其原因是改性反应后成功引入了功能性基团，增加了离子交换载药方式，直接提高了载药率和载药速率；微球经过弱碱处理后载药率进一步提高，并具备缓释特点，本研究产物在介入法治疗肿瘤领域具有光明应用前景。
Description
技术领域
一种酰化改性明胶栓塞微球的制备，属于医用高分子材料领域。
背景技术
蒽环类药物，阿霉素(doxorubicin,ADM)以抗肿瘤谱广,活性强，对恶性肿瘤细胞有好的疗效而引起关注，但其直接给药时毒性较大,限制了它在肿瘤治疗领域的应用，因此作为潜在的载体材料之一，明胶以其良好的生物相容性，价格低廉，且可生物降解,逐渐受到青睐。
目前临床应用的明胶海绵血管栓塞剂虽然可以生物降解，但是形状不规则，使用不方便，只能起到机械栓塞作用，不能结合化疗药物。已经报道的载药明胶微球都是只通过物理包覆的方式负载阿霉素，存在载药量过低，载药速率慢，使用过程中容易突释等问题。
明胶是一种蛋白质类高聚物，基本组成单位是氨基酸，分子中含有大量氨基和羧基。其中氨基带正电荷，对于同为正电荷的盐酸阿霉素分子具有排斥作用，不利于药物负载。本专利解决此问题的思路是将功能基团的电荷转换，由正电荷变成负电荷。因此为了提高明胶微球的载药率和载药速度，本发明研究以明胶微球为基体，通过酰化反应对其进行改性，将明胶分子中的氨基转化成羧基，合成了含有离子交换基团的载药栓塞微球，微球形态规整，粒径集中分布在100μm到700μm之间。该微球负载抗癌药物阿霉素，24h内载药率最高可达35.9％，而纯明胶微球载药率仅为8.6％，同时研究结果进一步表明羧酸基团以-COONa形式存在时载药率要明显高于以-COOH的存在形式，且微球改性后具备良好的缓释特点，本研究产物在介入法治疗肿瘤领域具有光明应用前景。
发明内容
本发明提供一种酰化改性明胶栓塞微球的制备方法。通过酰化改性使微球中具有离子交换功能基团-COOH，具有与盐酸阿霉素离子交换作用，使药物快速负载到微球上，增大负载率，并稳定性良好，适宜保存。用柔性高分子交联剂交联微球，改善了微球的物理性能，增加了安全性。
本发明的有益效果：
①通过酰化改性合成了含有离子交换功能基团的明胶栓塞微球，微球制备条件容易控制，原料低廉易得，便于日后工业生产。微球主要通过凝胶网络中(-COOH)与盐酸阿霉素的氨基形成离子交换作用来负载药物；使微球的载药量4h内迅速达到32％以上，解决了常规微球通过物理包埋所造成的药物流失和载药量不足的弊端。
②用柔性双环氧化合物做交联剂制备微球，改善了微球的物理性能，增加了使用安全性。。
③本发明制备的酰化改性微球具有良好的生物相容性，微球可以进行生物降解，且微球改性后具备良好的缓释特点。
附图说明
图1酰化改性明胶栓塞微球的光学显微镜照片
图2扫面电镜观察到的微球内部切面结构
图3曲线a、b分别是酰化改性后和改性前微球的载药动力学曲线对比
图4曲线a、b分别是酸化前后微球的载药动力学曲线对比
图5曲线a、b分别是酰化改性前后微球的累积释放曲线对比
具体实施方式
实施例1：酰化改性明胶栓塞微球的制备
交联剂选择聚乙二醇双缩水甘油醚，改性剂以丁二酸酐为例，是先成球再功能化反应：将4.5g明胶溶于15mL去离子水配成22.5w％的浓度，将混合液加入到4倍体积的石蜡油中，按油相体积的2％加入乳化剂司潘80，机械搅拌下，添加交联剂聚乙二醇双缩水甘油醚混合均匀，在30℃下搅拌反应7小时，用无水乙醇破乳，用去离子水反复浸泡洗涤，最后真空干燥得到微球；将改性剂溶于吡啶配成浓度为25％的溶液，再将干燥微球后的微球浸泡在改性剂的吡啶中，磁力搅拌反应5小时，反应结束后过滤出微球，用无水乙醇洗涤残留改性剂，再用去离子水反应浸泡洗涤除去未反应的残留物，最后真空干燥得到微球。
实施例2：微球中羧基含量的测定
按照GB/T601 2002制备所需试剂，采用返滴定法，将0.5g样品溶解置于干燥的三口烧瓶中(空白实验不加样品)，用移液管加入0.1mol/L的KOH-乙醇标准溶液25mL，加入2～3滴酚酞，置于磁力搅拌器上振荡，用0.1mol/L的盐酸标准溶液进行滴定，等红色消失后，记录此时消耗的体积V2(空白样品消耗盐酸溶液体积为V1)，羧基含量按下式进行计算:
ω＝(V1-V2)×C/m×100％
式中V1、V2分别为样品和空白试验所消耗盐酸标准溶液的体积，mL；c为盐酸标准溶液的摩尔浓度，mol/L；m为样品的质量，g；
实施例3：酰化改性微球的形态和粒径
取干燥后的酰化改性明胶栓塞微球于载玻片上，通过光学显微镜对微球的表面形貌进行观察，统计不同微球的粒径大小，绘制其分布趋势
实施例4：微球的SEM分析
将微球用超薄切片沿中心切开，切面部位向上粘在附有两面胶的样品台上，对样品表面进行喷金处理，扫描电镜加速电压调至1kV，高真空条件下观察微球的切面结构，
实施例5：酰化改性微球的载药量测定
称取微球样品10mg，置于含有4mL浓度为1mg/mL的阿霉素溶液中磁力搅拌，分别在不同载药时间后测定溶液在483nm处的吸光度，计算微球的载药量。
实施例6：微球酸化前后的载药率测定
称取一定质量的微球两份，将微球不至于等体积的水中，分别用碳酸钠和醋酸溶液调节体系的pH至7.4和5.0，浸提数小时，用超纯水洗涤，真空干燥。
实施例7：微球内部阿霉素的分布
使用激光共聚焦显微镜观察荧光强度与药物分布，对微球表层部分由外向内每隔10μm逐层拍照，氩离子光源，激发波长为488nm。结果显示：荧光强度从微球表层向中心逐渐变弱。表明药物外层分布多于内部。
实施例8：微球酰化前后的释放曲线对比
在250mL烧杯中加入50mL pH为7.4的PBS溶液，再添加精密称量的20mg的载药微球，控制水浴温度37±0.5℃，慢速磁力搅拌，每隔一定时间取样5mL通过紫外分光光度计检测介质中药物的浓度，并加入相同体积的新鲜释放介质以维持其总体积不变。
实施例9：微球的降解性能分析
选取实验制的载药微球的1个，加入到pH＝7.4的PBS溶液中，置于恒温水浴振荡器中，保持温度在37±0.5℃，选取不同时间点分别对微球的降解情况进行跟踪记录。结果表明5d后微球的形态基本没有改变，微球颜色略为变淡；10d后微球开始逐渐坍塌，表面出现伸展开的絮状的凝胶，周围溶液中也开始出现降解后的凝胶碎片，颜色也进一步变淡，12d后微球已经基本完全破裂，溶液中只可以观察到少量的浅黄色透明状凝胶。这是因为明胶分子上的氨基与丁二酸酐反应生成的酰胺键有较好的稳定性，使微球在降解初期保持了原有的形貌特征，然后酰胺键开始逐渐断裂，微球慢慢解体，原有的凝胶结构遭到破坏，最终断裂成少量的凝胶碎片。
实施例10：体外细胞毒性试验
微球的体外细胞毒性采用MTT法进行评估。用细胞培养液含10％胎牛血清的RPMI-1640培养基(RPMI-1640完全培养基)将对数生长期的3T3细胞配成浓度为6×103个/mL的细胞悬，每孔100μL，接种于96孔培养板，置于37℃、5％CO2培养箱中培养24h后，吸出每孔中的原培养液，阴性对照组、阳性对照组和实验组每孔分别加入100μL RPMI-1640完全培养基、含0.64％苯酚的RPMI-1640完全培养基、含样品浸提液(f)浓度为200mg/mL的RPMI-1640完全培养基，每组设4个复孔，继续置于37℃、5％CO2培养箱中培养48h，通过MTT法得到实验组细胞的相对增值率RGR值为100.6％，样品的细胞毒性反应等级为0级，表明所制备的酰化明胶微球无细胞毒性。
Claims (4)
1.一种改性明胶微球的制备方法，其特征是将4.5g明胶溶于15mL去离子水配成22.5w％的浓度，将混合液加入到4倍体积的石蜡油中，按油相体积的2％加入乳化剂司盘80，机械搅拌下，添加交联剂聚乙二醇双缩水甘油醚混合均匀，在30℃下搅拌反应7小时，用无水乙醇破乳，用去离子水反复浸泡洗涤，最后真空干燥得到微球；将丁二酸酐溶于吡啶配成浓度为25％的溶液，再将干燥后的微球浸泡在丁二酸酐的吡啶中，磁力搅拌反应5小时，反应结束后过滤出微球，用无水乙醇洗涤残留丁二酸酐，再用去离子水反应浸泡洗涤除去未反应的残留物，最后真空干燥得到微球。
2.一种权利要求1所述改性明胶微球的制备方法，其特征是明胶的分子量为4.7×104，丁二酸酐用量是明胶重量的30％。
3.一种权利要求1所述改性明胶微球的制备方法，其特征是聚乙二醇双缩水甘油醚的聚合度为4，其重量占明胶重量的20％～30％。
4.一种改性明胶微球在制备肿瘤血管栓塞剂中的应用，其特征是称取权利要求1、2、3中所述任意一种改性明胶微球样品10mg，置于含有4mL浓度为1mg/mL的阿霉素溶液中磁力搅拌，分别在不同载药时间后测定溶液在483nm处的吸光度，计算微球的载药量。
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