CN101766818B - 多糖金磁复合微粒载药体及其制备方法 - Google Patents
多糖金磁复合微粒载药体及其制备方法 Download PDFInfo
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- CN101766818B CN101766818B CN2008102365404A CN200810236540A CN101766818B CN 101766818 B CN101766818 B CN 101766818B CN 2008102365404 A CN2008102365404 A CN 2008102365404A CN 200810236540 A CN200810236540 A CN 200810236540A CN 101766818 B CN101766818 B CN 101766818B
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Abstract
本发明涉及一种以金磁微粒为核心，以葡聚糖，环糊精及其衍生物等可生物降解的多糖为材料，合成具有更好生物相容性和载药性的多糖金磁复合微粒载药体及其制备方法。该多糖金磁复合微粒载药体是由多糖金磁复合微粒与药物溶液直接混合，通过物理吸附，将药物负载于金磁复合微粒上形成的载药复合体。该多糖金磁复合微粒载药体的制备方法包括：制备多糖金磁复合微粒、制备多糖金磁复合微粒载药体。解决了现有金磁复合微粒载药体制备方法不具体，载药量等理化指标不明确等技术问题，所制备的用于载药的多糖金磁复合微粒分散性好，粒径均一，有更好生物相容性，多糖金磁复合微粒载药体具有良好的药物缓释和控释效应，合成方法简单，具体，可操作性强。
Description
技术领域
本发明涉及一种金磁复合微粒载药体及其制备方法，特别涉及一种以金磁微粒为核心，以天然或人工合成的可生物降解的多糖，如葡聚糖，环糊精及其衍生物为材料，合成具有更好生物相容性和载药性的多糖金磁复合微粒载药体及其制备方法。
背景技术
磁性药物微球作为第四代靶向制剂，有利于提高药物疗效，降低毒副作用，为化疗药物的临床应用开辟了新途径。它是将抗肿瘤药物和磁性物质共同包埋或吸附于高分子材料，特别是具有生物相容性的生物大分子中制成稳定制剂。该制剂注入体内后在足够强的外磁场作用下逐渐集中于肿瘤部位，药物载体通过酶的催化或理化条件如pH，渗透压或温度的改变而降解，缓慢释放化疗药物，使肿瘤部位保持较高的血药浓度，相应减少了全身其他部位的药物水平，从而起到高效、缓释、低毒的作用。
磁性微球由磁性材料、载体材料两部分组成。通常应用的磁性物质有：纯铁粉、羰基铁、磁铁矿、铁钴合金等，尤以Fe3O4磁流体居多，粒度要求越小越好，一般直径在10～30nm，另外还应具有非常良好的磁响应性。常用的载体材料包括白蛋白、明胶、壳聚糖、葡聚糖、淀粉等天然高分子，以及聚碳酸酯、聚烷基氰基丙烯酸酯、聚乙烯吡咯烷酮、聚乳酸及其共聚物等合成高分子。它们能够降低系统毒性并且增加生物相容性，减少内皮细胞的清除作用。另外，这些双功能材料一方面可以与磁性粒子通过化学键合或物理吸附结合，另一方面也可以和药物结合，从而具有一定的药物缓释控释作用。
1996年，德国的Lubbe等首先完成了世界上第一例应用磁性药物靶向治疗的临床实验，在14个晚期实体瘤患者的磁靶向治疗中，发现患者对磁靶向药物的耐受性很好。2002年美国FeRx公司磁导向载体一阿霉素(MTC-DOX)技术已通过美国FDA认证，主要用于肝癌(肝细胞癌-HCC)的治疗，在2002年11月“分子靶向和癌症治疗”的年会上，FeRx公司报道了靶向治疗肝细胞癌的I/II期临床试验结果，预示了这项新技术在治疗肝癌上的巨大潜力。Liang等氨基修饰的超顺磁性氧化铁纳米粒子作为一种新型的生物磁性靶向的载体，研究其在磁靶向性肝癌治疗中的应用。中南大学张阳德教授等以磁性阿霉素白蛋白对移植性肝癌的治疗研究中表明磁性阿霉素白蛋白在外加磁场作用下具有良好的治疗效果。慕蓉进行了载阿霉素磁性壳聚糖微球靶向治疗大鼠移植性肝癌的研究，结果显示磁性壳聚糖载药具有良好的靶向疗效。有关纳米金在生物医学中的应用也有很多报道。Priyabrata Mukherjee等人将纳米金和血管内皮细胞生长因子偶联，治疗慢性淋巴细胞性白血病。研究表明，单独使用一定剂量的纳米金不会引起细胞大量凋亡；而偶联血管内皮细胞的纳米金可显著得引起细胞凋亡。这些发现证实了运用纳米金载药系统治疗人类恶性疾病的优点。Giulio等胶体金作为负载肿瘤抑制因子的载体用于靶向给药的疗效，毒性等研究，表明胶体金对细胞没有明显的伤害，而负载肿瘤抑制因子的胶体金对肿瘤细胞有明显杀伤作用。姚翠萍等人将免疫胶体金与牛肠碱性磷酸酯酶特异抗体结合，然后用激光照射后，治疗人类恶性淋巴瘤细胞Karpas299；结果表明，激光照射后，结合金微粒的Karpas299细胞死亡率达到95％以上，而没有结合金微粒的KG1细胞基本上没有发生变化。表明金微粒对人体细胞没有明显的伤害。Zharov等设计了一套系统，把40nm的金微粒通过抗体与MDA-MB-231乳腺癌细胞上的抗原结合，然后用激光照射细胞微粒结合体，可以观察到在纳米簇周围产生大量的气泡从而导致肿瘤细胞的死亡。El-Sayed等利用免疫胶体金对癌症细胞诊断进行了先行性的研究，得到一定的反响。以上研究表明，将磁性微粒与纳米金结合起来用于肝癌靶向治疗，可以把磁性微粒的磁靶向性和金元素本身具有增强机体非特异性免疫反应能力结合起来，起到靶向给药和提高机体免疫力的作用，有着巨大的应用前景。
美国专利(Pat.No.7226636 B2)报道了一种金包被的磁性纳米粒子的合成过程。该专利公开了合成方法，即在适宜的液体溶液中，向磁流体悬液中加入一定量的还原性的金的化合物和还原性介质，反应一定的时间，就可以合成金包被的磁性纳米粒子。英国专利(Pat.GB2415374A)报道了一种合成克级核壳型磁性纳米粒子的方法，该专利中的核是γ-Fe2O3，壳层是金。美国专利Pat.No.7232471 B2报道了一种环糊精修饰的纳米金的合成方法。中国专利ZL03124061.5和ZL 03153486.4公开了本申请人的核壳型和组装型金磁微粒的合成方法，但未涉及金磁微粒的进一步修饰和在靶向给药中的应用。
本课题组2006年申请的专利：超顺磁性载药体及其制备方法(专利申请号：200610104757.0)中，涉及了金磁复合微粒载药体的制备过程及用于靶向治疗，但权利要求涉及面宽，一些指标较为笼统，保护性不强，没有给出具体的超顺磁性复合微粒的粒径，磁化饱和强度，磁响应性，载药率，包封率等，并且没有具体的多糖金磁复合微粒载药体的制备方法和理化指标。
发明内容
本发明的目的：
为了解决背景技术中存在的上述技术问题，本发明提供了一种生物相容性好，无毒副作用，有一定的粒径，具有好的药物缓释和控释作用，包封率符合药典规定的具有超顺磁性的多糖金磁复合微粒载药体及其制备方法。
本发明的技术方案：
多糖金磁复合微粒载药体，其特殊之处在于：是由多糖金磁复合微粒与药物溶液直接混合，通过物理吸附，将药物负载于金磁复合微粒上，形成的载药复合体，该多糖金磁复合微粒是由组装型或核壳型金磁微粒与天然或人工合成的多糖类高分子材料混和，通过化学键合或物理吸附，将高分子聚合物包被于金磁微粒上形成的，或者是以金磁微粒为核心，通过交联剂的交联作用，使多糖分子连成网状结构形成的。
金磁微粒包括核壳型和组装型。核壳型金磁微粒由磁性材料的核心部分(Fe3O4)和包覆于其表面的胶体金外壳部分组成，粒径为约为40纳米；组装型金磁微粒是将磁性材料的核心部分(Fe3O4)经硅烷化修饰，再通过Au-S键，将胶体金外壳部分包覆于核心部分表面，粒径约为3-5微米。
天然或人工合成的多糖分子具有良好的生物相容性，无毒副作用，可生物降解等特点，包括葡聚糖，环糊精及其衍生物等。
其中葡聚糖包括分子量为10000，20000，30000，40000，50000和70000六种。
环糊精是一类两端开口直径不同的圆锥状中空筒型环状多糖化合物。环糊精及其衍生物的最大特点是具有特定的空腔，不同尺度的空腔，可以与特定大小和性状的小分子作用形成包合物。由6、7、8个葡萄糖分子通过1，4-糖苷键连接而成的的环糊精分别称为α，β，γ-环糊精。环糊精衍生物包括羟丙基-α-环糊精，羟丙基-β-环糊精，羟丙基-γ-环糊精，甲基-β-环糊精等。
药物是单药，或是两种、两种以上的复合药物，可以是抗癌化疗药物、蛋白药物、基因药物或抗生素类药物，其中抗癌化疗药物包括盐酸阿霉素、5-氟尿嘧啶、顺铂、洛铂、卡铂、甲氨喋呤、阿糖胞苷；蛋白药物包括肿瘤抑制因子；基因药物包括核酸疫苗；抗生素类药物包括阿克拉霉素、红霉素、盐酸多西环素。
制备该多糖金磁复合微粒载药体的方法，其特殊之处在于：包括以下步骤
步骤1)制备多糖金磁复合微粒
步骤1.1)配制多糖溶液
将浓度为0.5-4mol/L碱溶液加入到多糖中，配制成浓度为20～100mg/ml的多糖溶液；
步骤1.2)合成多糖金磁复合微粒
取金磁微粒和浓度为0.5～4mol/L的碱溶液加入到步骤1.1)制得的多糖溶液中得到混合体系，将该混合体系边反应边搅拌，合成多糖金磁复合微粒悬液；其中步骤1.1)中多糖与步骤1.2)所加金磁微粒的量比为5～40∶1；
步骤1.3)清洗
将步骤1.2)制得的多糖金磁复合微粒悬液反复磁分离，弃去上清，直到最后溶液pH为7；
步骤2)制备多糖金磁复合微粒载药体
步骤2.1)清洗
取多糖金磁复合微粒置于离心管中，磁分离，弃去上清；
步骤2.2)载药
加入浓度为0.5～1.0mg/ml的药物溶液，补加超纯水，置于恒温摇床震荡，反应完成后磁分离，弃去上清，冷冻干燥，制得多糖金磁复合微粒载药体，其中所加药物溶液与多糖金磁复合微粒的质量比为1～4∶20。
上述步骤1.2)的混合体系升温到35～45℃后再加入交联剂或碱溶液，再升温至50～60℃，反应5～8h，其中所加交联剂或碱溶液占混合体系的比例为10％～20％；将步骤1.3)制得的多糖金磁复合微粒悬液中先加入乙醇，经磁分离清洗，除去残余的有机相，再用超纯水反复清洗，直到溶液pH为7。
上述步骤1.1)在20～40℃条件下进行，可用电动搅拌器加速溶解，转速为300～900转/分钟，搅拌时间为5～20min为宜；步骤1.2)中搅拌速度为300～900转/分钟，反应时间为4～8h为宜；步骤2.1)磁分离的时间为5～15min为宜；步骤2.2)恒温震荡的温度为25～40min，震荡的转速为100～200转/分钟，震荡时间为4～20h为宜，磁分离的时间为5～15min为宜。
上述步骤2.2)的药物溶液为阿霉素溶液时，离心管要用铝箔包裹好。
上述多糖是葡聚糖、环糊精或羟丙基-β-环糊精等环糊精衍生物；碱溶液是NaOH或NH4OH，其中NaOH溶液的浓度为0.5～4mol/L，NH4OH溶液的浓度为10～18％。；交联剂为甲醛、戊二醛或环氧氯丙烷；药物为单药，或是两种、两种以上的复合药物，可为抗癌化疗药物、蛋白药物、基因药物或抗生素类药物；抗癌化疗药物包括盐酸阿霉素、5-氟尿嘧啶、顺铂、洛铂、卡铂、甲氨喋呤、阿糖胞苷；蛋白药物包括肿瘤抑制因子；基因药物包括核酸疫苗；抗生素类包括阿克拉霉素，红霉素，盐酸多西环素。
药物和多糖金磁复合微粒通过物理吸附结合，不改变药物的结构和性质；并可根据需要，改变条件合成不同粒径和金磁复合微粒。
本发明的优点：
1、用于载药的多糖金磁复合微粒分散性好，粒径均一，如用葡聚糖包被的金磁复合微粒，粒径为220nm，粒径均一，无聚集现象。
2、用于载药的多糖金磁复合微粒具有更好生物相容性。
3、合成方法简单，具体，可操作性强；并可根据需要，改变条件合成不同粒径的多糖金磁复合微粒。
4、该多糖金磁复合微粒载药体具有良好的药物缓释和控释效应，如载阿霉素葡聚糖超顺磁性金磁复合微粒，体外实验表明，在2h，24h，和72h天的累积释药率分别为18.1％，51.4％和77.1％。
5、该多糖金磁复合微粒用于药物载体时包封率和载药率高，如葡聚糖超顺磁性金磁复合微粒最高可达93％以上，最高载药率载药可达15.8％，符合中国药典的要求。
附图说明
图1是220nm葡聚糖金磁复合微粒的粒径分布图。
图2是220nm葡聚糖金磁复合微粒扫描电镜图。
图3葡聚糖金磁复合微粒的磁饱和强度图。
图4是阿霉素投入量与阿霉素磁性毫微粒载药量、包封率的关系图。
图5是载阿霉素葡聚糖金磁复合微粒的释药曲线。
具体实施方式：
多糖金磁复合微粒载药体，是由多糖金磁复合微粒与药物溶液直接混合，通过物理吸附，将药物负载于金磁复合微粒上，形成的载药复合体，该多糖金磁复合微粒是由组装型或核壳型金磁微粒与天然或人工合成的多糖类高分子材料混和，通过化学键合或物理吸附，将高分子聚合物包被于金磁微粒上形成的，或者是以金磁微粒为核心，通过交联剂的交联作用，使多糖分子连成网状结构形成的。
多糖是葡聚糖、环糊精或环糊精衍生物；
药物是抗癌化疗药物、蛋白药物、基因药物或抗生素类药物；抗癌化疗药物包括盐酸阿霉素、5-氟尿嘧啶、顺铂、洛铂、卡铂、甲氨喋呤、阿糖胞苷；蛋白药物包括肿瘤抑制因子；基因药物包括核酸疫苗；抗生素类药物包括阿克拉霉素、红霉素、盐酸多西环素。
多糖金磁复合微粒载药体的制备方法，包括以下步骤
步骤1)制备多糖金磁复合微粒
步骤1.1)配制多糖溶液
将浓度为0.5-4mol/L碱溶液加入到多糖中，配制成浓度为20～100mg/ml的多糖溶液；
步骤1.2)合成多糖金磁复合微粒
取金磁微粒和浓度为0.5～4mol/L的碱溶液加入到步骤1.1)制得的多糖溶液中得到混合体系，将该混合体系边反应边搅拌，合成多糖金磁复合微粒悬液；
其中步骤1.1)中多糖与步骤1.2)所加金磁微粒的量比为5～40∶1；
当多糖为葡聚糖时，可将步骤1.2)的混合体系升温到35～45℃后再加入交联剂或碱溶液，再升温至50～60℃，反应5～8h，所加交联剂或碱溶液占混合体系的比例为10％～20％；将步骤1.3)制得的多糖金磁复合微粒悬液中先加入乙醇经磁分离清洗，除去残余的有机相，再用超纯水反复清洗，直到溶液pH为7。
步骤1.3)清洗
将步骤1.2)制得的多糖金磁复合微粒悬液反复磁分离，弃去上清，直到最后溶液pH为7；
步骤2)制备多糖金磁复合微粒载药体
步骤2.1)清洗
取多糖金磁复合微粒置于离心管中，磁分离，弃去上清；
步骤2.2)载药
加入浓度为0.5～1.0mg/ml的药物溶液，补加超纯水，置于恒温摇床震荡，反应完成后磁分离，弃去上清，冷冻干燥，制得多糖金磁复合微粒载药体，所加药物溶液与多糖金磁复合微粒的质量比为1～4∶20。
步骤1.1)在20～40℃条件下进行，可用电动搅拌器加速溶解，转速为300～900转/分钟，搅拌时间为5～20min；步骤1.2)中搅拌速度为300～900转/分钟，反应时间为4～8h；步骤2.1)磁分离的时间为5～15min；步骤2.2)恒温震荡的温度为25～40min，震荡的转速为100～200转/分钟，震荡时间为4～20h，磁分离的时间为5～15min。
步骤2.2)的药物溶液为阿霉素溶液时，离心管要用铝箔包裹好。
上述多糖是葡聚糖、环糊精或环糊精衍生物；碱溶液是NaOH或NH4OH；交联剂为甲醛、戊二醛或环氧氯丙烷；药物可为抗癌化疗药物、蛋白药物、基因药物或抗生素类药物；抗癌化疗药物包括盐酸阿霉素、5-氟尿嘧啶、顺铂、洛铂、卡铂、甲氨喋呤、阿糖胞苷；蛋白药物包括肿瘤抑制因子；基因药物包括核酸疫苗；抗生素类药物包括阿克拉霉素，红霉素，盐酸多西环素。
该多糖金磁复合微粒用于药物载体时包封率和载药率高，如葡聚糖超顺磁性金磁复合微粒最高可达93％以上，载药量载药可达15.9％，符合中国药典的要求。
该多糖金磁复合微粒载药体具有良好的药物缓释和控释效应，如载阿霉素葡聚糖超顺磁性金磁复合微粒，体外实验表明，在2h，24h，和72h天的累积释药率分别为18.1％，51.4％和77.1％。
以下结合实施例对发明作进一步详细说明
具体实施例1
本实例中的多糖为葡聚糖，药物为阿霉素。
在25℃条件下，将100mg的葡聚糖加入100ml二颈烧瓶中，加入1ml的超纯水和1ml 1mol/L NaOH溶液，开动电动搅拌器，转速为300转/分钟，搅拌10min，使葡聚糖彻底溶解；然后边搅拌边将2ml(10mg/ml)的核壳型金磁微粒加入二颈烧瓶中，再加入2ml 1mol/L NaOH溶液，300转/分钟，反应6h。反应完后，将反应后的悬液倒到入一个干净的烧杯，然后将烧杯放在5000高斯的磁铁上，磁分离，弃去上清；再加入一定量的超纯水，混匀，再磁分离，弃去上清，重复三次，直到最后溶液的PH为7。经检测其粒径为2.1μm左右；磁化饱和强度为42emu/g。
在5ml的离心管中加入2mg金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml。盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，180rpm震荡；反应4小时后取出离心管，10min磁分离，取20ul上清。在紫外分光光度计下测480纳米的吸收值，计算得出该葡聚糖金磁复合微粒的载药率可达12.5％。
载药量按以下公式计算：
载药率＝(总的阿霉素质量-上清中阿霉素质量)/磁粒质量×100％
具体实施例2
本实例中的多糖为葡聚糖，药物为阿霉素。
在25℃条件下，将100mg的葡聚糖加入100ml二颈烧瓶中，加入2ml10mg/ml的金磁微粒，开动电动搅拌器，转速为300转/分钟，搅拌10min，使葡聚糖彻底溶解并与金磁微粒充分混合。然后边搅拌边向二颈烧瓶中逐滴加入3ml 18％NH4OH，升温至60℃，以300转/分钟的速度继续搅拌，反应30min。反应完后，将反应后的悬液倒入一个干净的烧杯，然后将烧杯放在5000高斯的磁铁上，磁分离，弃去上清；再加入一定量的超纯水，混匀，再磁分离，弃去上清，重复三次，直到最后溶液的PH为7。经检测其粒径为0.22μm左右，见图1；磁化饱和强度38.8emu/g，见图3。
在5ml的离心管中加入2mg金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml。盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，以180rpm的转速震荡；反应4小时后取出离心管，磁分离10min，取20ul上清。在紫外分光光度计下测480纳米的吸收值，计算出该葡聚糖金磁复合微粒的载药量可达12.05％，见图4。
具体实施例3
本实例中的多糖为葡聚糖，交联剂为环氧氯丙烷，药物为阿霉素。
在25℃条件下，将100mg的葡聚糖加入100ml二颈烧瓶中，接着加入1ml1mol/L NaOH溶液，开动电动搅拌器，以300rpm的转速搅拌10min，使葡聚糖完全溶解；然后边搅拌边向二颈烧瓶中加入2ml 10mg/ml的金磁微粒，反应1h。然后将反应体系升温到40℃，再加入2ml环氧氯丙烷，再升温至55℃，继续反应6小时。反应完后，将反应后的悬液倒入一个干净的烧杯，然后将烧杯放在5000高斯磁铁上，磁分离，弃上清；再加入一定量的乙醇，磁分离，清洗三次，除去残余的有机相，再用超纯水清洗三次，直到溶液PH为7。经检测其粒径为4.2μm左右；磁化饱和强度为48.5emu/g。
在5ml的离心管中加入2mg金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml。盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，180rpm震荡；反应4小时后取出离心管，10min磁分离，取20ul上清。在紫外分光光度计下测480纳米的吸收值，计算出该葡聚糖金磁复合微粒的载药量可达12.8％。
具体实施例4
本实例中的多糖为环糊精，药物为阿霉素。
在25℃条件下，将100mg环糊精加入100ml二颈烧瓶中，接着加入1mllmol/L NaOH溶液，开动电动搅拌器，以300rpm的转速搅拌10min，使环糊精彻底溶解。边搅拌边加入2ml 10mg/ml的金磁微粒，升温到40℃时，加入0.8ml16.5％NH4OH。再继续加热至50℃并反应5h。反应完后，将反应后的悬液倒入一个干净的烧杯，然后将烧杯放在5000高斯的磁铁上，磁分离，弃上清；再加入一定量的超纯水，混匀，再磁分离，弃上清，重复三次，直到最后溶液的pH为7。经检测其粒径为0.32μm左右，见图1；磁化饱和强度为38.5emu/g。
在5ml的离心管中加入2mg金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml。盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，以180rpm的转速震荡；反应4小时后取出离心管，磁分离10min，取20ul上清。在紫外分光光度计下测480纳米的吸收值，计算出该环糊精金磁复合微粒的载药量可达9.05％。
具体实施例5
本实例中的多糖为羟丙基-β-环糊精，药物为阿霉素。
将150mg羟丙基-β-环糊精加入100ml二颈烧瓶中，开动电动搅拌器，以300rpm的转速搅拌10min，使羟丙基-β-环糊精彻底溶解。边搅拌边加入2ml10mg/ml的金磁微粒，继续搅拌，然后升温到40℃时，加入0.8ml 16.5％NH4OH。再继续加热至50℃并搅拌，反应5h。反应完后，得到的磁性复合微粒分散液用磁铁(5000高斯)磁分离，用超纯水反复洗涤后至上清pH约为7。经检测其粒径为420nm左右；磁化饱和强度40.5emu/g。
在5ml的离心管中加入2mg金磁复合微粒，5min磁分离，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml。盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，以180rpm的转速震荡；反应4小时后取出离心管，磁分离10min，取20ul上清。在紫外分光光度计下测480纳米的吸收值，计算出该羟丙基-β-环糊精金磁复合微粒的载药量为9.55％。
Claims (5)
1.一种多糖金磁复合微粒载药体的制备方法，包括以下步骤：
在25℃条件下，将100mg的葡聚糖加入100ml二颈烧瓶中，加入1ml的超纯水和1ml 1mol/L NaOH 溶液，开动电动搅拌器，转速为300转/分钟，搅拌10min，使葡聚糖彻底溶解；然后边搅拌边将2ml 10mg/ml的核壳型金磁微粒加入二颈烧瓶中，再加入2ml 1mol/L NaOH溶液，300转/分钟，反应6h；反应完后，将反应后的悬液倒入一个干净的烧杯，然后将烧杯放在5000高斯的磁铁上，磁分离，弃去上清；再加入一定量的超纯水，混匀，再磁分离，弃去上清，重复三次，直到最后溶液的pH 为7，得到多糖金磁复合微粒；
在5ml的离心管中加入2mg上述步骤得到的多糖金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml；盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，180rpm震荡；反应4小时后取出离心管，10min磁分离，弃去上清，冷冻干燥，制得多糖金磁复合微粒载药体。
2.一种多糖金磁复合微粒载药体的制备方法，包括以下步骤：
在25℃条件下，将100mg的葡聚糖加入100ml二颈烧瓶中，加入2ml 10mg/ml的金磁微粒，开动电动搅拌器，转速为300转/分钟，搅拌10min，使葡聚糖彻底溶解并与金磁微粒充分混合；然后边搅拌边向二颈烧瓶中逐滴加入3ml 18% NH4OH，升温至60℃，以300转/分钟的速度继续搅拌，反应30min；反应完后，将反应后的悬液倒入一个干净的烧杯，然后将烧杯放在5000高斯的磁铁上，磁分离，弃去上清；再加入一定量的超纯水，混匀，再磁分离，弃去上清，重复三次，直到最后溶液的pH为7，得到多糖金磁复合微粒；
在5ml的离心管中加入2mg上述步骤得到的多糖金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml；盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，以180rpm的转速震荡；反应4小时后取出离心管，磁分离10min，弃去上清，冷冻干燥，制得多糖金磁复合微粒载药体。
3.一种多糖金磁复合微粒载药体的制备方法，包括以下步骤：
在25℃条件下，将100mg的葡聚糖加入100ml二颈烧瓶中，接着加入1ml 1mol/L NaOH 溶液，开动电动搅拌器，以300rpm的转速搅拌10min，使葡聚糖完全溶解；然后边搅拌边向二颈烧瓶中加入2ml 10mg/ml的金磁微粒，反应1h；然后将反应体系升温到40℃，再加入2ml 环氧氯丙烷，再升温至55℃，继续反应6小时；反应完后，将反应后的悬液倒入一个干净的烧杯，然后将烧杯放在5000高斯磁铁上，磁分离，弃上清；再加入一定量的乙醇，磁分离，清洗三次，除去残余的有机相，再用超纯水清洗三次，直到溶液pH为7，得到多糖金磁复合微粒；
在5ml的离心管中加入2mg上述步骤得到的多糖金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml；盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，180rpm震荡；反应4小时后取出离心管，10min磁分离，弃去上清，冷冻干燥，制得多糖金磁复合微粒载药体。
4.一种多糖金磁复合微粒载药体的制备方法，包括以下步骤：
在25℃条件下，将100mg环糊精加入100 ml二颈烧瓶中，接着加入1ml 1mol/L NaOH 溶液，开动电动搅拌器，以300rpm的转速搅拌10min，使环糊精彻底溶解；边搅拌边加入2 ml 10mg/ml的金磁微粒，升温到40℃时，加入0.8 ml 16.5% NH4OH；再继续加热至50℃并反应5 h；反应完后，将反应后的悬液倒入一个干净的烧杯，然后将烧杯放在5000高斯的磁铁上，磁分离，弃上清；再加入一定量的超纯水，混匀，再磁分离，弃上清，重复三次，直到最后溶液的pH 为7，得到多糖金磁复合微粒；
在5ml的离心管中加入2mg上述步骤得到的多糖金磁复合微粒，磁分离5min，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml；盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，以180rpm的转速震荡；反应4小时后取出离心管，磁分离10min，弃去上清，冷冻干燥，制得多糖金磁复合微粒载药体。
5.一种多糖金磁复合微粒载药体的制备方法，包括以下步骤：
将150 mg羟丙基-β-环糊精加入100 ml二颈烧瓶中，开动电动搅拌器，以300rpm的转速搅拌10min，使羟丙基-β-环糊精彻底溶解；边搅拌边加入2ml 10mg/ml的金磁微粒，继续搅拌，然后升温到40℃时，加入0.8 ml 16.5% NH4OH；再继续加热至50℃并搅拌，反应5 h；反应完后，得到的磁性复合微粒分散液用磁铁磁分离，用超纯水反复洗涤后至上清pH为7，得到多糖金磁复合微粒；
在5ml的离心管中加入2mg上述步骤得到的多糖金磁复合微粒，5min磁分离，弃上清；然后加入0.4ml浓度为1mg/ml的阿霉素溶液，再补加1.6ml超纯水至2ml；盖好离心管盖，用铝箔包裹好，置于37℃恒温摇床，以180rpm的转速震荡；反应4小时后取出离心管，磁分离10min，弃去上清，冷冻干燥，制得多糖金磁复合微粒载药体。
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| US13/142,820 US20120121717A1 (en) | 2008-12-30 | 2008-12-30 | DRUG-LOADED POLYSACCHARIDE-COATED GOLDMAG PARTICLES (DPGPs) AND ITS SYNTHESIS METHOD |
| PCT/CN2008/002130 WO2010078675A1 (zh) | 2008-12-30 | 2008-12-30 | 多糖金磁复合微粒载药体及其制备方法 |
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| WO2003041095A1 (en) * | 2001-11-05 | 2003-05-15 | Universidade Federal De Minas Gerais - Ufmg | Process of composites preparation between particulate materials and cyclodextrins and/or their derivatives products thereof |
| CN1542449A (zh) * | 2003-04-30 | 2004-11-03 | �����ɷ� | 一种核/壳型超顺磁性复合微粒及其制备方法与应用 |
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