CN106619568B - 一种铂纳米晶复合纳米材料的制备方法及产品 - Google Patents
一种铂纳米晶复合纳米材料的制备方法及产品 Download PDFInfo
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- CN106619568B CN106619568B CN201611130427.9A CN201611130427A CN106619568B CN 106619568 B CN106619568 B CN 106619568B CN 201611130427 A CN201611130427 A CN 201611130427A CN 106619568 B CN106619568 B CN 106619568B
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Abstract
本发明涉及一种铂纳米晶复合纳米材料的制备方法,包括如下步骤:1)将乙酰丙酮铂溶解在油胺和油酸中,真空条件下在50~100℃下搅拌;升温至150~250℃,继续注入三乙基硼氢化锂,反应1~60分钟,不良溶剂沉淀,得到小尺寸铂纳米晶;2)将步骤1)中得到的小尺寸铂纳米晶采用薄膜分散法或乳化溶剂挥发法,进行两亲性高分子的组装修饰,得到铂纳米晶复合纳米材料。本发明还涉及一种铂纳米晶复合纳米材料,具备良好的抗肿瘤活性,不仅可以克服肿瘤耐药,而且对正常组织有良好的生物安全性。
Description
技术领域
本发明涉及铂纳米晶材料制备领域,具体涉及一种铂纳米晶复合纳米材料的制备方法及产品。
背景技术
目前,尽管国内外医疗水平不断提高,但恶性肿瘤仍严重威胁人类的生命安全。世界卫生组织(WHO)等权威机构已发布统计数据,在肝、肺、食道和胃等多种恶性肿瘤中,中国新增病例和死亡人数均居世界首位。
自1978年被美国FDA批准以来,顺铂广泛应用于头颈癌、卵巢癌、睾丸癌、膀胱癌、肺癌及结肠直肠癌等多种肿瘤的治疗。由于细胞内的氯离子浓度较低,顺铂进入细胞后,其配体氯会被水分子取代,形成的正电铂离子能够与细胞内DNA、RNA和蛋白质等亲核分子作用。其中,DNA为顺铂的主要作用靶点,顺铂多与DNA中的嘌呤碱基的N7位点结合,形成Pt-DNA加合物。
但是,普遍耐药以及严重的毒副作用限制了顺铂在临床治疗的持续应用。临床中很多病人存在先天或者获得性顺铂耐药性。癌症病人在给予顺铂之后,肿瘤细胞会从各个通路抵御顺铂的作用,导致获得性耐药,如:1)通过调节细胞膜转运体,使顺铂分子入胞量减少;2)增大细胞浆内含硫蛋白的解毒效应;3)DNA修复加快;4)提高细胞对DNA损伤的耐受性等。另外,顺铂会导致包括肾小管损伤在内的较为严重的肾毒性、胃肠道毒性、血液毒性和耳毒性等。而且病人体内顺铂的累积也是潜在的危险因素。
而近些年来,第二代、第三代铂类药物层出不穷,如卡铂、奥沙利铂、沙伯以及吡铂等,虽然有一些改进,但至今没有任何一种铂类药物能取代顺铂。因此,许多的研究人员致力于研究新型的铂类复合材料来解决顺铂相关的一系列问题。
发明内容
本发明的目的在于针对现有技术的不足,提供一种铂纳米晶复合纳米材料的制备方法及产品,所得到的铂纳米晶复合纳米材料具备良好的抗肿瘤活性,不仅可以克服肿瘤耐药,而且对正常组织有良好的生物安全性。
本发明所提供的技术方案为:
一种铂纳米晶复合纳米材料的制备方法,包括如下步骤:
1)将乙酰丙酮铂溶解在油胺和油酸中,真空条件下在50~100℃下搅拌;升温至150~250℃,继续注入三乙基硼氢化锂,反应1~60分钟,不良溶剂沉淀,得到小尺寸铂纳米晶;
2)将步骤1)中得到的小尺寸铂纳米晶采用薄膜分散法或乳化溶剂挥发法,进行两亲性高分子的组装修饰,得到铂纳米晶复合纳米材料。
上述技术方案中,步骤1)中所得的小尺寸铂纳米晶的粒径为1~10nm,经过步骤2)后得到的铂纳米晶复合纳米材料的粒径为1~600nm。小尺寸铂纳米晶与铂纳米晶复合纳米材料所属的粒径范围,便于应用于肿瘤治疗。
铂纳米晶复合纳米材料借助小尺寸铂纳米晶、功能性高分子以及肿瘤组织固有的特征微环境,实现对肿瘤细胞内DNA的大规模杀伤,进而高效杀伤肿瘤细胞。首先,功能性高分子以及高通透性和滞留效应(EPR效应)可以实现肿瘤组织靶向。入胞后,刺激介导纳米材料解体为很多个小尺寸铂纳米晶,其极大的比表面积显著加快铂离子溢出速率;其次,肿瘤微酸环境以及内涵体的较大酸度会进一步促使铂纳米晶表面溶解腐蚀,释放出大量铂离子,扩散至细胞核内破坏DNA,进而导致肿瘤细胞死亡。利用功能性高分子靶向传递和微环境响应性解体伴随pH调控铂离子释放,联合使用多种策略,不仅增强对肿瘤的杀伤,同时也降低对正常组织的毒副作用。
所述两亲性高分子可以选用功能性高分子,具体优选为市售的两亲性高分子或合成的高分子聚合物(如刺激响应的高分子聚合物或连接肿瘤靶向分子的高分子聚合物)。
所述市售两亲性高分子选自泊洛沙姆、聚乙烯吡咯烷酮、聚乙烯醇、吐温、维生素E聚乙二醇琥珀酸酯、聚乳酸-羟基乙酸共聚物、聚乳酸、司盘、磷脂、聚乙二醇、十二烷基硫酸钠、十六烷基三甲基溴化铵、白蛋白、脂蛋白、蓖麻油聚氧乙烯醚、脂肪酸聚氧乙烯酯、脂肪酸聚氧乙烯醚、烷基酚聚氧乙烯醚和多元醇酯中的一种或多种。
所述刺激响应的高分子聚合物选自肿瘤pH响应的高分子聚合物、肿瘤ROS响应的高分子聚合物、肿瘤酶响应的高分子聚合物、光响应的高分子聚合物、热响应的高分子聚合物、磁响应的高分子聚合物和超声响应的高分子聚合物中的一种或多种。
所述肿瘤pH响应的高分子聚合物选自通过物理吸附或化学合成内含咪唑、哌啶、原酸酯键、马来酸二甲酯键、肟键、缩醛/缩酮键、腙键、酰胺或酰腙键的一种或多种的亲水-疏水嵌段高分子聚合物。
所述肿瘤ROS响应的高分子聚合物选自通过物理吸附或化学合成内含二硒键、琥珀酰亚胺-硫醚键、二硫键的一种或多种的亲水-疏水嵌段高分子聚合物。
所述肿瘤酶响应的高分子聚合物选自通过物理吸附或化学合成内含对基质金属蛋白酶、前列腺特异性抗原、组织蛋白酶B、分泌型磷脂酶A2、α-淀粉酶、赖氨酰基氧化酶、β-葡萄糖醛酸苷酶、成纤维细胞活化蛋白敏感的一种或多种的亲水-疏水嵌段高分子聚合物。
所述连接肿瘤靶向分子选自叶酸、透明质酸、蛋白、多肽、抗体、核酸适配体、DNA和RNA中的一种或多种。
作为优选,所述步骤1)中真空条件下在50~100℃下搅拌0.5~2h。
作为优选,所述步骤1)中乙酰丙酮铂、油胺、油酸和三乙基硼氢化锂的投料比为20~200mg:2~20ml:0.01~0.5ml:0.05~1ml。
作为优选,所述步骤2)中的薄膜分散法的制备过程:将小尺寸铂纳米晶分散在良溶剂中,室温下搅拌并加入两亲性高分子,减压蒸发,水化,得到铂纳米晶复合纳米材料。所述水化时优选使用pH缓冲液,进一步优选为PBS缓冲液。
作为优选,所述步骤2)中的乳化溶剂挥发法的制备过程:将小尺寸铂纳米晶分散在良溶剂中,室温下搅拌并加入到两亲性高分子水溶液中,超声,减压蒸发,得到铂纳米晶复合纳米材料。
作为优选,所述步骤2)中小尺寸铂纳米晶与两亲性高分子的质量投料比为1:1~50。通过调控二者之间的质量投料比,一方面,实现对刺激的灵敏响应,即于肿瘤部位实现刺激介导的分解组装;另一方面,控制铂纳米晶复合纳米材料中装载的小尺寸铂纳米晶数量。
作为优选,所述两亲性高分子选自泊洛沙姆、聚乙烯吡咯烷酮、聚乙烯醇、吐温、维生素E聚乙二醇琥珀酸酯和聚乳酸-羟基乙酸共聚物中的一种或几种。
作为优选,所述两亲性高分子为通过物理吸附或化学合成的刺激响应的高分子聚合物,或者通过物理吸附或化学合成连接肿瘤靶向分子的高分子聚合物。
进一步优选,所述两亲性高分子选自泊洛沙姆-叶酸复合高分子、硬脂胺-聚(天冬氨酸-咪唑)高分子、脱氧胆酸-SS-透明质酸高分子或疏水阳离子穿透肽-MMP2敏感肽-聚乙二醇高分子。
作为优选,所述步骤1)中不良溶剂选自丙酮、乙醇、乙酸乙酯、甲醇、甲基吡咯烷酮、中链醇、乙腈、二甲基甲酰胺和二甲基亚砜中的一种或多种。
作为优选,所述步骤2)中良溶剂选自二氯甲烷、三氯甲烷、正己烷、环己烷和二氧六环中的一种或多种。
本发明还提供一种上述的制备方法得到的铂纳米晶复合纳米材料。
同现有技术相比,本发明的有益效果体现在:
(1)首先通过合成小尺寸铂纳米晶,由于其表面的铂离子溢出速率可由pH调控。在中性环境中,铂纳米晶表面铂离子溢出速率很慢;而偏酸环境会加速表面腐蚀释放大量铂离子。在肿瘤治疗中,肿瘤微酸环境以及内涵体的较大酸度会促使铂纳米晶表面溶解腐蚀,释放出大量铂离子,扩散至细胞核内破坏DNA,进而导致肿瘤细胞死亡;而到达正常组织的铂纳米晶因释放铂离子少,毒性很低。
(2)铂纳米晶复合纳米材料使用功能性高分子对小尺寸铂纳米晶进行组装修饰。借助功能性高分子以及高通透性和滞留效应(EPR效应)实现对肿瘤细胞的靶向,进而高效杀伤肿瘤细胞。
(3)铂纳米晶复合纳米材料不仅可以克服肿瘤耐药,而且对正常组织有良好的生物安全性。
(4)本发明涉及反应体系温和,条件可控,具有良好的临床转化可能性。
附图说明
图1为实施例1中的小尺寸铂纳米晶的X射线衍射图;
图2为实施例1中的小尺寸铂纳米晶的透射电子显微镜照片;
图3为实施例3中的铂纳米晶复合纳米材料的动态光散射粒度分布图;
图4为实施例4中的pH敏感铂纳米晶复合材料在pH7.4和pH5.5的透射电子显微镜照片;
图5为铂纳米晶复合材料在不同pH下对肿瘤细胞的细胞毒性;
图6为静脉注射铂纳米晶复合材料的平均血药浓度-时间曲线。
具体实施方式
下述实施例中的方法,如无特别说明,均为常规方法。
室温温度范围为20-25℃。
下面结合具体的实施例和说明书附图详细阐述本发明小尺寸铂纳米晶和铂纳米晶复合纳米材料的制备及其在肿瘤治疗中的应用。
实施例1
小尺寸铂纳米晶的合成:将80mg乙酰丙酮铂与7ml油胺,0.09ml油酸,真空条件下在70℃搅拌1小时,以5℃/min的速度升至170℃;将0.2ml三乙基硼氢化锂注射到反应体系中,老化5分钟,丙酮沉淀,离心得到小尺寸铂纳米晶。
对得到的小尺寸铂纳米晶进行X射线衍射分析,结果如附图1所示;对小尺寸铂纳米晶用透射电镜进行形貌表征,结果如附图2所示,粒径在2~4nm。
实施例2
小尺寸铂纳米晶的合成:将80mg乙酰丙酮铂与5ml油胺,0.05ml油酸,真空条件下在70℃搅拌2小时,以5℃/min的速度升至170℃;将0.2ml三乙基硼氢化锂注射到反应体系中,老化30分钟,丙酮沉淀,离心得到铂纳米晶。得到的铂纳米粒尺寸在4~6nm。
实施例3
铂纳米晶复合纳米材料的制备:将1.2mg小尺寸铂纳米晶(按照本实施例2方法制得)和20mg泊洛沙姆P188分散在氯仿中,室温搅拌1h,减压蒸发除去有机溶剂。加入3ml PBS(pH 7.4)水化,即得铂纳米晶复合纳米材料。
利用动态光散射分析得到的铂纳米晶复合纳米材料的粒度分布,结果如附图3所示。
实施例4
pH敏感铂纳米晶复合材料的制备:将1.2mg小尺寸铂纳米晶(按照本实施例1方法制得)和20mg泊洛沙姆-叶酸复合高分子(F127-FA)分散在氯仿中,边搅拌边加入15mg硬脂胺-聚(天冬氨酸-咪唑)的甲醇溶液(氯仿:甲醇=10:1,v/v),室温搅拌1h,减压蒸发除去有机溶剂。加入3ml PBS(pH7.4)水化,得肿瘤pH敏感的铂纳米晶复合纳米材料。
使用透射电镜对得到的pH敏感的铂纳米晶复合材料在pH 7.4和pH 5.5进行形貌表征,结果如附图4所示。结果显示,该种铂纳米晶复合材料有良好的pH响应性。
实施例5
铂纳米晶复合纳米材料的制备:将1.2mg小尺寸铂纳米晶(按照本实施例2方法制得)和20mg疏水脱氧胆酸-SS-透明质酸(HA-SS-DOCA)分散在氯仿中,室温搅拌1h,减压蒸发除去有机溶剂。加入3ml PBS(pH 7.4)水化,即得肿瘤ROX敏感的铂纳米晶复合纳米材料。
实施例6
铂纳米晶复合纳米材料的制备:将1.2mg小尺寸铂纳米晶(按照本实施例2方法制得)分散在氯仿中,滴入20mg疏水阳离子穿透肽-MMP2敏感肽-聚乙二醇(PepFect14-GPLGIAGQ-PEG)的水溶液中,探头超声(3分钟,150W),即得肿瘤酶敏感的铂纳米晶复合纳米材料。
实施例7
铂纳米晶复合纳米材料的制备:将1.2mg小尺寸铂纳米晶(按照本实施例1方法制得)分散在氯仿中,滴入20mg维生素E聚乙二醇琥珀酸酯的水溶液中,探头超声(3分钟,150W)形成均匀乳液。减压蒸发除去有机溶剂,即得铂纳米晶复合纳米材料。
性能实验
一、铂纳米晶复合材料对人源肿瘤细胞系的细胞毒性
1、材料:肿瘤细胞株(肝癌HCCLM3);
2、方法:取对数生长期的人源肿瘤细胞,用新鲜的培养基将细胞密度调至1×104cells/ml,接种于96孔扳内,200μl/well,于37℃,5%CO2的培养箱内培养。细胞贴壁培养12-24h后换成含有铂纳米晶复合材料(按照本实施例4方法制得)的新鲜培养液。细胞加药后继续培养24h,吸出培养液并用200μl PBS洗。然后向96孔扳内加入MTT溶液(200μl/well),于37℃下共同孵育1~4h,吸出培养液,加入200μl DMSO,震荡摇匀后,测定其光密度OD值。
数据处理,利用酶标仪相应软件进行数据处理,计算每一种样品3~5个孔OD值的平均值,利用平均值按如下公式计算细胞成活率(Cell Viability%)。
细胞成活率%=样品组OD值的平均值/空白对照组OD值的平均值×100%(CellViability%=ODsample/ODcontrol×100%)
结果见实施例附图5。
二、铂纳米晶复合材料在老鼠动物体内药代动力学研究
1、材料和方法
1.1、药品和试剂:铂纳米晶复合材料(按照本实施例3方法制得),规格10ml:3mg,自制;氯仿、甲醇、乙醇,分析级,国药集团化学试剂有限公司;实验用水,重蒸馏水。
1.2、动物:balb/c小鼠,体重(20±3)g,6只,雄性,由浙江大学试验动物中心提供。
2、给药方案与样品采集:
balb/c雄性小鼠实验前禁食12小时,按2mg/kg剂量于尾静脉注射铂纳米复合材料,给药后于0.0833,0.1667,0.25,0.5,0.75,1,2,4,6,8,12h,眼眶取血约0.1ml全血置于肝素化试管中,待测。
3、全血样品处理及分析:
精密吸取全血样品50μl,加入5ml 70%硝酸。室温溶解24h后,热台挥去浓硝酸,用2%稀硝酸稀释至5ml,于ICP-MS定量分析。静脉注射铂纳米复合材料的平均血药浓度-时间曲线见附图6。
以上所述实施例对本发明的技术方案和有益效果进行了详细说明,应理解的是以上所述仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改,补充和等同替换等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种铂纳米晶复合纳米材料的制备方法,其特征在于,包括如下步骤:
1)将乙酰丙酮铂溶解在油胺和油酸中,真空条件下在50~100℃下搅拌;升温至150~250℃,继续注入三乙基硼氢化锂,反应1~60分钟,不良溶剂沉淀,得到小尺寸铂纳米晶;所述小尺寸铂纳米晶的粒径为1~6nm;
所述步骤1)中乙酰丙酮铂、油胺、油酸和三乙基硼氢化锂的投料比为20~200mg:2~20ml:0.01~0.5ml:0.05~1ml;
2)将步骤1)中得到的小尺寸铂纳米晶采用薄膜分散法或乳化溶剂挥发法,进行两亲性高分子的组装修饰,得到铂纳米晶复合纳米材料;
所述步骤2)中小尺寸铂纳米晶与两亲性高分子的质量投料比为1:1~50;
所述两亲性高分子选自泊洛沙姆或维生素E聚乙二醇琥珀酸酯。
2.根据权利要求1所述的铂纳米晶复合纳米材料的制备方法,其特征在于,所述步骤2)中的薄膜分散法的制备过程:将小尺寸铂纳米晶分散在良溶剂中,室温下搅拌并加入两亲性高分子,减压蒸发,水化,得到铂纳米晶复合纳米材料。
3.根据权利要求1所述的铂纳米晶复合纳米材料的制备方法,其特征在于,所述步骤2)中的乳化溶剂挥发法的制备过程:将小尺寸铂纳米晶分散在良溶剂中,室温下搅拌并加入到两亲性高分子水溶液中,超声,减压蒸发,得到铂纳米晶复合纳米材料。
4.根据权利要求1所述的铂纳米晶复合纳米材料的制备方法,其特征在于,所述步骤1)中不良溶剂选自丙酮、乙醇、乙酸乙酯、甲醇、甲基吡咯烷酮、中链醇、乙腈、二甲基甲酰胺和二甲基亚砜中的一种或多种。
5.根据权利要求2或3所述的铂纳米晶复合纳米材料的制备方法,其特征在于,所述步骤2)中良溶剂选自二氯甲烷、三氯甲烷、正己烷、环己烷和二氧六环中的一种或多种。
6.一种如权利要求1~5任一所述的制备方法得到的铂纳米晶复合纳米材料。
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