CN112426535A - 一种肿瘤靶向药物纳米晶递送系统 - Google Patents

一种肿瘤靶向药物纳米晶递送系统 Download PDF

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CN112426535A
CN112426535A CN202010816519.2A CN202010816519A CN112426535A CN 112426535 A CN112426535 A CN 112426535A CN 202010816519 A CN202010816519 A CN 202010816519A CN 112426535 A CN112426535 A CN 112426535A
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陆伟跃
刘瑜
王俊
黄广建
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Abstract

本发明属药物制剂领域，涉及一种肿瘤靶向药物纳米晶递送系统及其制备方法和在制药中的应用。本发明的肿瘤靶向药物纳米晶递送系统由抗肿瘤药物纳米晶核心和包被材料组成，由一种或多种生物相容的磷脂、维生素E聚乙二醇1000琥珀酸酯、叶酸‑聚乙二醇‑磷脂酰乙醇胺和甲氧基聚乙二醇‑磷脂酰乙醇胺按照一定比例混合包覆在难溶性抗肿瘤药物纳米结晶上，所得的肿瘤靶向药物纳米晶递药系统可稳定地分散在水性环境中，实验证实，该肿瘤靶向药物纳米晶递药系统能有效抑制肿瘤细胞生长，在动物模型瘤旁注射后能有效缩小肿瘤体积。本发明为实体瘤术前辅助化疗提供了一种可瘤旁注射的新制剂形式。

Description

一种肿瘤靶向药物纳米晶递送系统
技术领域
本发明属药物制剂领域，涉及一种肿瘤靶向药物纳米晶递送系统及其制备方法，和在肿瘤术前辅助化疗中的应用。
背景技术
根据2019年国家癌症中心的最新全国癌症统计数据显示，恶性肿瘤已经成为严重威胁我国人群健康的主要公共卫生问题之一，所致死亡约占全部疾病死因的24％，每年所致医疗花费超过2200亿，防控形势严峻。肺癌、肝癌、上消化系统肿瘤及结直肠癌、女性乳腺癌等是主要恶性肿瘤类型。
针对上述实体瘤的现行临床首选方案大多是以手术为主的综合治疗方案。目前，临床上对术前辅助化疗越来越重视。术前辅助化疗，又称新辅助化疗，指的是在肿瘤切除术前先进行全身性化疗，为手术提供便利，并改进对肿瘤复发及转移的控制。例如，在胃癌手术中，部分患者在术前已经出现亚临床转移病灶，且存在肿瘤组织和正常组织的黏连，很难完全清除，即便是采用扩大淋巴结清扫范围的D2根治术，也难以明显提高患者生存率。丁志等发现在胃癌切除手术之前进行新辅助化疗，能够有效地降低肿瘤临床分期，减少阳性淋巴结数量，提高手术清除率，降低术后复发率(《术前辅助化疗对胃癌患者手术并发症及生活质量的影响》，《解放军医药杂志》2019,第5期:第22-25页)。再如，在乳腺癌的治疗中，传统的根治术治疗乳腺癌，手术创伤大，手术所致的乳房缺失会明显影响患者生活质量，而新辅助化疗可使乳腺原发肿瘤降期，提高保乳手术比率，提高患者术后生活质量(《新辅助化疗后保乳手术治疗乳腺癌的临床效果》，《中国医药科学》，2019,第2期:第207-210页)。
但是，目前已有的新辅助化疗并无专属制剂，大多采用术后化疗的常规制剂，全身给药，副作用大，病灶局部浓度低，药效发挥不充分。即便是采用局部瘤旁给药，若仍用术后化疗所用的注射液，药物仍会从局部毛细血管网迅速吸收进入全身循环。因此，急需开发能够有效停留在注射部位、充分发挥辅助化疗效果而控制甚至减小肿瘤大小的瘤旁注射新制剂。
近年来，药物纳米晶这一纳米制剂新形式因其高载药量特征引起了广泛的关注。药物纳米晶是在少量稳定剂(表面活性剂或聚合物)存在的条件下将纳米级药物颗粒分散在水中的一种亚微胶体分散系。目前已有多个品种产品上市，如帕尔制药生产的醋酸甲地孕酮纳米晶口服制剂等。
主动靶向是提高肿瘤组织靶向效率的重要策略。其主要针对肿瘤组织中高表达的受体或转运体，利用与特异性受体或转运体具有识别、结合能力的配体或抗体作为靶向分子，将药物或纳米递药系统递送至肿瘤组织或细胞中，提高药物被肿瘤组织或细胞的摄取量，增强抗肿瘤效果。将靶向分子连接到纳米晶表面，可赋予纳米晶对肿瘤细胞的靶向性。
发明内容
本发明的目的在于基于现有技术的现状，提供一种肿瘤靶向药物纳米晶递送系统。本发明所述药物纳米晶可通过瘤旁注射的途径，有效停留在注射部位并被肿瘤细胞摄取，充分发挥术前辅助化疗效果。
本发明提供的肿瘤靶向药物纳米晶递送系统由药物纳米晶核心和表面包被材料组成。
所述的包载药物纳米晶的肿瘤靶向递送系统是聚合物胶束、脂质圆盘、脂质体、纳米粒。
所述的药物纳米晶核心为难溶性抗肿瘤药物或抗肿瘤药物的难溶性盐或抗肿瘤药物的难溶性复合物形成的纳米结晶。
所述的抗肿瘤药物选自紫杉烷类药物、喜树碱类药物、蒽环类药物、分子靶向药物和具有抗癌作用的天然活性成分。
所述的紫杉烷类药物选自紫杉醇、多西他赛、卡巴他赛、阿齐他赛及其他具有紫杉烷骨架的衍生物，所述的喜树碱类药物可选自喜树碱、拓扑替康、伊立替康、9-羟基喜树碱、9-硝基喜树碱、9-氨基喜树碱，所述的蒽环类药物可选自阿霉素、柔红霉素、阿柔比星、表阿霉素、伊达比星、戊柔比星、米托蒽醌等，所述的分子靶向药物可选自伊马替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、尼洛替尼、拉帕替尼、帕唑帕尼、埃克替尼、凡德他尼、维罗非尼、克唑替尼、阿西替尼、伯舒替尼、卡博替尼、普纳替尼、瑞戈非尼、拉多替尼、达拉非尼、曲美替尼、阿法替尼、依鲁替尼、色瑞替尼、阿来替尼、阿帕替尼、尼达尼布、乐伐替尼、奥希替尼、奥莫替尼等，其他抗肿瘤药物可选自姜黄素、长春碱、长春新碱、长春瑞滨、长春地辛、雷帕霉素、驮瑞塞尔、依维莫司、佐他莫司等。
本发明中，肿瘤靶向药物纳米晶递送系统的表面包覆层由磷脂、胆固醇、维生素E聚乙二醇1000琥珀酸酯、甲氧基聚乙二醇-磷脂酰乙醇胺和靶向分子修饰的聚乙二醇-磷脂酰乙醇胺按照一定比例构成。
所述的磷脂选自大豆磷脂或大豆卵磷脂、卵黄磷脂或卵黄卵磷脂、二肉豆蔻酰基卵磷脂或二肉豆蔻酰磷脂酰胆碱或二肉豆蔻酰磷脂酰乙醇胺、二棕榈酰基卵磷脂或二棕榈酰磷脂酰胆碱或二棕榈酰磷脂酰乙醇胺或二棕榈酰磷脂酰甘油、二硬脂酰基磷脂酰胆碱或二硬脂酰磷脂酰胆碱或二硬脂酰磷脂酰乙醇胺或二硬脂酰磷脂酰甘油、二油酰基卵磷脂或二油酰磷脂酰胆碱或二油酰磷脂酰乙醇胺或二油酰磷脂酰甘油等中的一种或两种及其以上混合物。
所述的靶向分子修饰的聚乙二醇-磷脂酰乙醇胺为修饰聚乙二醇-磷脂酰乙醇胺的靶向分子为可特异性靶向肿瘤的配体和/或抗体。
优选地，配体靶向分子可选自叶酸、RGD肽、iRGD肽、VAP肽、A7R肽、RW肽、mn肽、RAP肽、F3肽、LYP-1肽、tLYP-1肽、透明质酸、Angiopep-2、转铁蛋白、TAT肽、多聚精氨酸、多聚赖氨酸等；抗体靶向分子为chTNT、anti-MUC1、anti-MUC4、anti-MUC16、anti-HER2、anti-EGFR、抗-TfR抗体等。
所述的靶向分子修饰的聚乙二醇-磷脂酰乙醇胺和甲氧基聚乙二醇，其中的聚乙二醇分子量为2000～5000。
本发明提供了上述肿瘤靶向药物纳米晶递送系统的制备方法，包括：
1)核心药物纳米晶的制备，在稳定剂存在的条件下，将难溶性抗肿瘤药物或抗肿瘤药物的难溶性盐或抗肿瘤药物的难溶性复合物分散成纳米结晶。
2)核心药物纳米晶的表面包覆，即将包覆材料分散入步骤1)所得的纳米结晶混悬液，以获得具有热力学稳定性和肿瘤靶向性的药物纳米晶递送系统。
更具体的，为实现上述目的，本发明采用的技术方案为：
1)制备核心药物纳米晶，采用下述四种方法中任一种，所述方法分别为：
1-1)水化法：将药物和稳定剂按一定比例溶解在易挥发有机溶剂中，挥发除去有机溶剂，形成混合固形物。加入适宜的缓冲盐溶液，通过温和振摇的方式将混合固形物分散入缓冲盐溶液中(该过程简称为“水化”)，必要时对颗粒进行高压均质，即得纳米级别的药物结晶。
经试验优选:稳定剂可采用维生素E聚乙二醇1000琥珀酸酯等，用量是药物质量的1～5倍。
1-2)沉淀法：制备核心药物纳米晶，具体步骤为：将含有药物的有机溶剂，以滴加或微流控的方法加入含有稳定剂的水溶液中，在冰浴的条件下搅拌至出现淡蓝色乳光后，旋转蒸发除去有机溶剂，必要时对颗粒进行高压均质，即得纳米级别的药物结晶。
经试验优选：配制药物溶液中的有机溶剂选自甲醇、乙醇、乙腈、N,N-二甲基乙酰胺、丙酮、环己酮中的一种或几种，所述稳定剂包括泊洛沙姆188、维生素E聚乙二醇1000琥珀酸酯或天然卵磷脂中一种或几种，用量是药物质量的1～5倍。
1-3)介质研磨法：先将药物混悬于溶有表面活性剂或稳定剂的蒸馏水中。然后将均匀的混悬液用二氧化锆研磨珠在行星式球磨机或高能水冷式球磨仪内进行研磨，制得纳米结晶。最后，在纳米结晶混悬液中加入冻干保护剂，经冻干得到药物纳米结晶粉。
经试验优选：所述稳定剂包括泊洛沙姆188、维生素E聚乙二醇1000琥珀酸酯或天然卵磷脂中一种或几种，用量是药物质量的1～5倍。
1-4)高压均质法：将药物溶解于有机溶剂中，配制成一定浓度的溶液，将稳定剂溶于反溶剂中，得到含有稳定剂的反溶剂，以含有稳定剂的反溶剂作为水相，将有机相注入水相，以速度为3000～10000rpm，剪切5～10min，得初级混悬液，将所得的初级混悬液用高压均质机循环均质，得纳米晶混悬液。
经试验优选：药物的浓度为1～30mg/mL。配制药物的溶剂选自甲醇、乙醇、乙腈、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、丙酮、正丙醇、异丙醇、环己酮、二氯甲烷中的一种或几种。所述稳定剂包括泊洛沙姆188、维生素E聚乙二醇1000琥珀酸酯或天然卵磷脂中一种或几种，用量是药物质量的1～5倍。
2)对上述药物纳米晶进行表面包被，具体包括：
2-1)将一种或多种生物相容的磷脂、胆固醇、维生素E聚乙二醇1000琥珀酸酯、靶向分子修饰的聚乙二醇-磷脂酰乙醇胺和甲氧基聚乙二醇-磷脂酰乙醇胺磷脂材料按照一定比例共同溶于易挥发有机溶剂，挥发除去有机溶剂，形成固态混合物。将该固态混合物分散入步骤1)所得的纳米结晶混悬液中。其中磷脂可选自大豆磷脂、大豆卵磷脂、二棕榈酰基卵磷脂、二肉豆蔻酰基卵磷脂、二硬脂酰磷脂酰胆碱、1,2-二油酰基卵磷脂、1,2-二油酰基卵乙醇胺、二棕榈酰磷脂酰胆碱、二肉豆蔻酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺、二棕榈酰磷脂酰甘油、二肉豆蔻酰磷脂酰胆碱、二棕榈酰磷脂酰乙醇胺、二硬脂酰磷脂酰甘油等磷脂中的一种或两种及其以上混合物。
以最优处方制得的紫杉醇纳米晶粒径集中在120nm附近，进行磷脂包被后，平均粒径在160nm左右，室温储存6个月内粒径基本不变，载药量为30％左右；对人胃腺癌细胞株(SGC-7901)、人结肠癌(HT-29)、人乳腺癌细胞株(MCF-7)和人肺癌细胞(A549)均显示明显的肿瘤细胞生长抑制效果。在荷SGC-7901裸鼠肿瘤模型上进行的药效研究结果表明，磷脂包被的紫杉醇纳米晶递送系统瘤旁注射后能有效控制肿瘤体积，在瘤体积～100mm3单次给药时，肿瘤抑制率为100％，当瘤体积达到300mm3后单次给药，2周后瘤体积是初始瘤体积的15.69±24.76％(n＝6)，肿瘤体积缩小近6倍，动物体重变化和脏器系数与对照组相近。
2-2)如采用微沉淀法、介质研磨法或高压均质法，可以在分散介质中加入稳定剂及包被材料，实现包被材料在纳米级别结晶颗粒表面的包覆。
本发明具有以下优点：
1)将难溶性抗肿瘤药物制成纳米晶，实现了良好的水分散性好、通针性、稳定性和符合实用需求的高载药量。
2)将靶向分子修饰在纳米晶表面，赋予其针对肿瘤细胞的靶向性，提高了肿瘤细胞对药物纳米晶的摄取，瘤旁注射后能够有效缩小肿瘤体积，在肿瘤术前辅助化疗方面具有良好应用潜力。
附图说明
图1透射电镜照片(标尺＝200nm)：A.紫杉醇纳米晶核心；B.叶酸修饰主动靶向紫杉醇纳米晶(两步法制备)。
图2粒径分布：A.紫杉醇纳米晶核心；B.叶酸修饰主动靶向紫杉醇纳米晶(两步法制备)。
图3叶酸修饰主动靶向紫杉醇纳米晶的储存稳定性(25℃放置)：新鲜制备(A)、放置3个月(B)和放置6个月(C)(两步法制备)。
图4叶酸修饰主动靶向紫杉醇纳米晶(两步法制备)叶酸修饰比例(叶酸-聚乙二醇-磷脂酰乙醇胺占包被材料比例)对肿瘤细胞生长抑制效果的影响(受试细胞株：SGC-7901)。
图5叶酸修饰主动靶向紫杉醇纳米晶(两步法制备)等制剂单次瘤旁注射给药(剂量20mg/kg)后的肿瘤生长抑制曲线(荷SGC-7901模型肿瘤裸鼠)：A.给药时间：瘤体积达100mm3；B.给药时间：瘤体积达300mm3。
图6叶酸修饰主动靶向紫杉醇纳米晶(两步法制备)等制剂单次瘤旁注射给药(剂量20mg/kg)后的动物体重变化曲线(荷SGC-7901模型肿瘤裸鼠)：A.给药时间：瘤体积达100mm3；B.给药时间：瘤体积达300mm3。
图7叶酸修饰主动靶向紫杉醇纳米晶(两步法制备)等制剂在瘤体积达300mm3后单次瘤旁注射给药(剂量20mg/kg)12小时(A)和48小时(B)后前哨淋巴结和肿瘤组织内药物浓度(n＝4，mean±SD)。
图8粒径分布：叶酸修饰主动靶向羟基喜树碱纳米晶(水化法制备，实施例2)。
图9粒径分布：叶酸修饰主动靶向姜黄素纳米晶(水化法制备，实施例3)。
图10粒径分布：叶酸修饰主动靶向紫杉醇/拉帕替尼纳米晶(水化法制备，实施例4)。
图11粒径分布：叶酸修饰主动靶向拉帕替尼纳米晶(高压均质法制备，实施例5)。
图12粒径分布：叶酸修饰主动靶向多西他赛纳米晶(沉淀法制备，实施例6)。
图13粒径分布：叶酸修饰主动靶向阿帕替尼纳米晶(介质研磨法制备，实施例7)。
具体实施方式
以下借助非限制性实施例进一步描述本发明。
实施例1、叶酸修饰磷脂包被紫杉醇纳米晶递送系统制备及表征
将3mg紫杉醇、4mg维生素E聚乙二醇1000琥珀酸酯和7.5mg柠檬酸溶于适量无水乙醇，置于梨形瓶中旋转蒸发，挥去乙醇，在瓶底形成薄膜，加入5mL碳酸氢钠溶液(4mg/mL)，在室温下振摇水化，将所得混悬液在8000rpm转速下离心15分钟，弃去上清，收集沉淀，以纯水分散，即得具有淡蓝色乳光的核心纳米结晶分散液。
称取卵磷脂(1.15mg)、胆固醇(0.58mg)、十八烷基胺(0.36mg)、维生素E聚乙二醇1000琥珀酸酯(0.58mg)、甲氧基聚乙二醇-磷脂酰乙醇胺(0.70mg)和叶酸-聚乙二醇-磷脂酰乙醇胺(0.70mg)，溶于适量二氯甲烷，置于梨形瓶中旋转蒸发，挥去二氯甲烷，在瓶底形成薄膜，加入前述核心纳米结晶分散液，在室温下振摇水化，将所得混悬液在8000rpm转速下离心10分钟，除去未反应的磷脂，即得叶酸修饰主动靶向紫杉醇纳米晶，在透射电镜呈近球形(图1)，平均粒径168.0nm，PDI0.166(图2)，在25℃储存6个月粒径基本不变，稳定性良好(图3)。
将前述叶酸修饰主动靶向紫杉醇纳米晶递送系统以乙腈定量溶解，以高效液相色谱分析其载药量和包封率。色谱条件为：Agilent 1100(美国)液相色谱仪，
Figure BDA0002632914700000101
C18色谱柱(250mm×4.6mm，粒径：5μm，迪马科技公司，北京)，流动相为乙腈:纯水v:v70:30，流速0.7mL/min，检测波长227nm。根据以下公式计算包封率(EE)和载药量(DL)：
Figure BDA0002632914700000111
Figure BDA0002632914700000112
经计算，叶酸修饰主动靶向紫杉醇纳米晶中紫杉醇的载药量为29.37±1.64％，包封率为79.58±1.78％。
在人胃腺癌细胞株(SGC-7901)上以MTT法测试了叶酸修饰主动靶向紫杉醇纳米晶递送系统的肿瘤细胞生长抑制效果，以软件GraphPadPrism对数据进行分析。结果表明，叶酸修饰主动靶向紫杉醇纳米结晶对肿瘤细胞生长的抑制效果优于无叶酸修饰的紫杉醇纳米结晶(以类似的材料包被，但以甲氧基聚乙二醇-磷脂酰乙醇胺等摩尔代替叶酸-聚乙二醇-磷脂酰乙醇胺)，且以叶酸-聚乙二醇-磷脂酰乙醇胺占包膜材料比例为1％时具有最优的对肿瘤细胞生长的抑制效果(图4)。
进一步的，选用体重20±2g的裸鼠共56只，饲养在SPF级。收集培养的SGC-7901细胞，用PBS制成约3×107个/mL的细胞悬液，取0.1mL注入裸鼠右侧腋下。其中28只在肿瘤体积达到约100mm3时随机分成4组，每组7只。另外28只待肿瘤体积达到约300mm3时，同样随机分成4组，每组7只。瘤旁注射生理盐水，泰素(Taxol)，0％FA(即非叶酸修饰紫杉醇纳米晶递送系统)和1％FA(即叶酸修饰紫杉醇纳米晶递送系统，其中叶酸-聚乙二醇-磷脂酰乙醇胺占包被材料比例为1％)，其中后三组紫杉醇剂量均为20mg/kg。于注射药物当天、第2天、第4天、第6天、第8天、第10天和第12天测量肿瘤大小，记录体重。
按下列公式计算肿瘤体积：
Figure BDA0002632914700000121
(a：肿瘤的长径；b：肿瘤的短径)
于给药12天后处死动物，记录体重。完整剥离腋部肿瘤移植物，称重，计算肿瘤抑制率。由图5A和6A可知，瘤体积达到100mm3开始给药，1％FA组能够完全抑制肿瘤生长，抑瘤率为100％(图5A)，制剂组与对照组的体重差异很小(图6A)。由图5B和6B可知，在瘤体积达到300mm3开始给药时，1％FA组有3只裸鼠的肿瘤完全抑制，抑瘤率达到了90％(图5B)。各组对体重的影响无显著且持续的差异(图6B)。图7为瘤体积达到300mm3时给药12小时(图7A)和48小时(图7B)后肿瘤前哨淋巴结和肿瘤内部的药物浓度，1％FA组在提高肿瘤组织和淋巴结内药物浓度方面优势显著，这与其更好的抑瘤效果相符。
实施例2、叶酸修饰磷脂包被羟基喜树碱纳米晶递送系统
将3mg羟基喜树碱、4mg维生素E聚乙二醇1000琥珀酸酯和7.5mg柠檬酸溶于适量无水乙醇，置于梨形瓶中旋转蒸发，挥去乙醇，在瓶底形成薄膜，加入5mL碳酸氢钠溶液(4mg/mL)，在室温下振摇水化，将所得混悬液在8000rpm转速下离心15分钟，弃去上清，收集沉淀，以纯水分散，即得具有淡蓝色乳光的核心纳米结晶分散液。
称取卵磷脂(1.15mg)、胆固醇(0.58mg)、维生素E聚乙二醇1000琥珀酸酯(0.58mg)、甲氧基聚乙二醇-磷脂酰乙醇胺(0.70mg)和叶酸-聚乙二醇-磷脂酰乙醇胺(0.70mg)，溶于适量二氯甲烷，置于梨形瓶中旋转蒸发，挥去二氯甲烷，在瓶底形成薄膜，加入前述核心纳米结晶分散液，在室温下振摇水化，将所得混悬液在8000rpm转速下离心10分钟，除去未反应的磷脂，即得叶酸修饰主动靶向羟基喜树碱纳米晶，平均粒径237.3nm，PDI0.207(图8)。
实施例3、叶酸修饰磷脂包被姜黄素纳米晶递送系统
将3mg姜黄素、4mg维生素E聚乙二醇1000琥珀酸酯和7.5mg柠檬酸溶于适量无水乙醇，置于梨形瓶中旋转蒸发，挥去乙醇，在瓶底形成薄膜，加入5mL碳酸氢钠溶液(4mg/mL)，在室温下振摇水化，将所得混悬液在8000rpm转速下离心15分钟，弃去上清，收集沉淀，以纯水分散，即得具有淡蓝色乳光的核心纳米结晶分散液。
称取卵磷脂(1.15mg)、胆固醇(0.58mg)、维生素E聚乙二醇1000琥珀酸酯(0.58mg)、甲氧基聚乙二醇-磷脂酰乙醇胺(0.70mg)和叶酸-聚乙二醇-磷脂酰乙醇胺(0.70mg)，溶于适量二氯甲烷，置于梨形瓶中旋转蒸发，挥去二氯甲烷，在瓶底形成薄膜，加入前述核心纳米结晶分散液，在室温下振摇水化，将所得混悬液在8000rpm转速下离心10分钟，除去未反应的磷脂，即得叶酸修饰主动靶向姜黄素纳米晶，平均粒径176.3nm，PDI0.254(图9)。
实施例4、叶酸修饰磷脂包被紫杉醇/拉帕替尼复合纳米晶递送系统
将2mg紫杉醇、1mg拉帕替尼、4mg维生素E聚乙二醇1000琥珀酸酯和7.5mg柠檬酸溶于适量无水乙醇，置于梨形瓶中旋转蒸发，挥去乙醇，在瓶底形成薄膜，加入5mL碳酸氢钠溶液(4mg/mL)，在室温下振摇水化，将所得混悬液在8000rpm转速下离心15分钟，弃去上清，收集沉淀，以纯水分散，即得具有淡蓝色乳光的核心纳米结晶分散液。
称取卵磷脂(2.3mg)、胆固醇(1.15mg)、十八烷基胺(0.72mg)、维生素E聚乙二醇1000琥珀酸酯(1.15mg)、甲氧基聚乙二醇-磷脂酰乙醇胺(0.49mg)和叶酸-聚乙二醇-磷脂酰乙醇胺(1.12mg)，溶于适量二氯甲烷，置于梨形瓶中旋转蒸发，挥去二氯甲烷，在瓶底形成薄膜，加入前述核心纳米结晶分散液，在室温下振摇水化，将所得混悬液在8000rpm转速下离心10分钟，除去未反应的磷脂，即得叶酸修饰主动靶向紫杉醇/拉帕替尼复合纳米晶，平均粒径157.9nm，PDI0.201(图10)。
实施例5、叶酸修饰磷脂包被拉帕替尼纳米晶递送系统
称取0.6g泊洛沙姆188溶于10mL纯水中，加入0.2g卵磷脂、0.2g甲氧基聚乙二醇-磷脂酰乙醇胺和0.2g叶酸-聚乙二醇-磷脂酰乙醇胺，于40℃高速剪切分散均匀，加入将拉帕替尼/二氯甲烷溶液(0.3g拉帕替尼溶于0.5mL二氯甲烷)，先于40℃高速剪切分散均匀，再进行高压均质处理，即得具有淡蓝色乳光的叶酸修饰磷脂包被拉帕替尼纳米晶递送系统，平均粒径195.4nm，PDI0.173(图11)。
实施例6、叶酸修饰磷脂包被多西他赛纳米晶递送系统
称取0.06g泊洛沙姆188溶于1mL纯水中，加入0.02g卵磷脂、0.02g甲氧基聚乙二醇-磷脂酰乙醇胺和0.02g叶酸-聚乙二醇-磷脂酰乙醇胺，于40℃高速剪切分散均匀，在微流控条件下，与1mL的多西他赛乙醇溶液(5mg/mL)混合，得淡蓝色乳光胶体分散液，旋蒸挥干乙醇，即得具有淡蓝色乳光的叶酸修饰磷脂包被多西他赛纳米晶递送系统。平均粒径120.4nm，PDI0.173(图12)。
实施例7、叶酸修饰磷脂包被阿帕替尼纳米晶递送系统
称取0.6g泊洛沙姆188溶于10mL纯水中，加入0.2g卵磷脂、0.2g甲氧基聚乙二醇-磷脂酰乙醇胺和0.2g叶酸-聚乙二醇-磷脂酰乙醇胺，于40℃高速剪切分散均匀，加入400mg阿帕替尼原料药粉末，加适量二氧化锆珠，以高能水冷式球磨仪进行介质研磨，1200rpm，研磨两次，各30分钟，工作温度35℃。以筛网筛去二氧化锆珠，即得叶酸修饰磷脂包被阿帕替尼纳米晶递送系统，平均粒径215.6nm，PDI0.199(图13)。

Claims (16)

1.一种肿瘤靶向药物纳米晶递送系统，其特征在于，由含有抗肿瘤药物的核和包被材料形成的壳构成，具有核壳型结构。
2.根据权利要求1所述的肿瘤靶向药物纳米晶递送系统，其特征在于，含有抗肿瘤药物的核为药物纳米结晶。
3.根据权利要求1所述的肿瘤靶向药物纳米晶递送系统，其特征在于，含有抗肿瘤药物的核为聚合物胶束、脂质圆盘、脂质体或纳米粒。
4.根据权利要求2所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的药物纳米结晶采用两步法制备：第一步为在稳定剂存在的条件下，难溶性抗肿瘤药物或抗肿瘤药物的难溶性盐或抗肿瘤药物的难溶性复合物制备成纳米结晶；第二步将包被材料分散入前述纳米结晶分散液中，即得。
5.根据权利要求2所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的药物纳米结晶还采用介质研磨法、高压均质法或微沉淀法制备。
6.根据权利要求1～5任一所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的抗肿瘤药物选自紫杉烷类药物、喜树碱类药物、蒽环类药物、分子靶向药物和其他抗肿瘤药物中的一种或组合；其中，所述的紫杉烷类药物选自紫杉醇、多西他赛、卡巴他赛、阿齐他赛及其他具有紫杉烷骨架的衍生物，所述的喜树碱类药物选自喜树碱、9-羟基喜树碱、9-硝基喜树碱或9-氨基喜树碱；所述的蒽环类药物选自阿霉素、柔红霉素、阿柔比星、表阿霉素、伊达比星、戊柔比星、米托蒽醌；所述的分子靶向药物选自伊马替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、尼洛替尼、拉帕替尼、帕唑帕尼、埃克替尼、凡德他尼、维罗非尼、克唑替尼、阿西替尼、伯舒替尼、卡博替尼、普纳替尼、瑞戈非尼、拉多替尼、达拉非尼、曲美替尼、阿法替尼、依鲁替尼、色瑞替尼、阿来替尼、阿帕替尼、尼达尼布、乐伐替尼、奥希替尼或奥莫替尼；其他抗肿瘤药物选自姜黄素、长春碱、长春新碱、长春瑞滨、长春地辛、雷帕霉素、依维莫司或佐他莫司。
7.根据权利要求1～5任一所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的包被材料为磷脂、胆固醇、维生素E聚乙二醇1000琥珀酸酯、甲氧基聚乙二醇-磷脂酰乙醇胺和靶向分子修饰的聚乙二醇-磷脂酰乙醇胺按照一定比例组成。
8.根据权利要求7所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的维生素E聚乙二醇1000琥珀酸酯、泊洛沙姆188、磷脂或三者的组合为稳定剂，用量是药物质量的1～5倍。
9.根据权利要求7所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的包被材料中，磷脂选自大豆磷脂或大豆卵磷脂、卵黄磷脂或卵黄卵磷脂、二肉豆蔻酰基卵磷脂或二肉豆蔻酰磷脂酰胆碱或二肉豆蔻酰磷脂酰乙醇胺、二棕榈酰基卵磷脂或二棕榈酰磷脂酰胆碱或二棕榈酰磷脂酰乙醇胺或二棕榈酰磷脂酰甘油、二硬脂酰基磷脂酰胆碱或二硬脂酰磷脂酰胆碱或二硬脂酰磷脂酰乙醇胺或二硬脂酰磷脂酰甘油、二油酰基卵磷脂或二油酰磷脂酰胆碱或二油酰磷脂酰乙醇胺或二油酰磷脂酰甘油中的一种或两种及其以上混合物。
10.根据权利要求7所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的包被材料中，靶向分子修饰的聚乙二醇-磷脂酰乙醇胺中的靶向分子为可特异性靶向肿瘤的配体和/或抗体；其中的配体靶向分子选自叶酸、RGD肽、iRGD肽、VAP肽、A7R肽、RW肽、mn肽、RAP肽、F3肽、LYP-1肽、tLYP-1肽、透明质酸、Angiopep-2、转铁蛋白、TAT肽、多聚精氨酸或多聚赖氨酸；抗体靶向分子为chTNT、anti-MUC1、anti-MUC4、anti-MUC16、anti-HER2、anti-EGFR、抗-TfR抗体。
11.根据权利要求7所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的包被材料中，靶向分子修饰的聚乙二醇-磷脂酰乙醇胺和甲氧基聚乙二醇中的聚乙二醇分子量为2000～5000。
12.根据权利要求7所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的包被材料中，磷脂、胆固醇、十八烷胺、维生素E聚乙二醇1000琥珀酸酯、甲氧基聚乙二醇-磷脂酰乙醇胺和靶向分子修饰的聚乙二醇-磷脂酰乙醇胺的摩尔比为30:(10～40):(0～40):(5～10):(1～5):(1～5)。
13.根据权利要求12所述的肿瘤靶向药物纳米晶递送系统，其特征在于，所述的包被材料中，磷脂、胆固醇、十八烷胺、维生素E聚乙二醇1000琥珀酸酯、甲氧基聚乙二醇-磷脂酰乙醇胺和靶向分子修饰的聚乙二醇-磷脂酰乙醇胺的摩尔比为30:30:27:8:4:1。
14.权利要求1～13任一所述的肿瘤靶向药物纳米晶递送系统在用于制备实体瘤的术前辅助化疗药物中的用途。
15.根据权利要求14所述的用途，其特征在于，所述的实体瘤为胃癌、结直肠癌、乳腺癌或肺癌。
16.根据权利要求14所述的用途，其特征在于，所述术前辅助化疗药物的给药方式为瘤旁注射。
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