CN105348506B - 谷氨酸‑tpgs嵌段共聚物的制备及其在靶向药物传递中的应用 - Google Patents
谷氨酸‑tpgs嵌段共聚物的制备及其在靶向药物传递中的应用 Download PDFInfo
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- CN105348506B CN105348506B CN201510869800.1A CN201510869800A CN105348506B CN 105348506 B CN105348506 B CN 105348506B CN 201510869800 A CN201510869800 A CN 201510869800A CN 105348506 B CN105348506 B CN 105348506B
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- tpgs
- glutamic acid
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种谷氨酸‑TPGS共聚物的制备及该两亲性靶向材料修饰的脂质体在疾病靶向传递中的应用。所述的两亲性靶向材料,以谷氨酸作为靶头,聚乙二醇增加靶头的柔韧性,疏水性的α‑生育酚酯为与磷脂的锚钉部位。该靶向材料修饰的脂质体可作为多种抗肿瘤药物靶向传递的载体,并能通过表面修饰的谷氨酸与血脑屏障和肿瘤细胞膜上高表达的大中性氨基酸转运体1相互作用,有效提高脂质体的跨血脑屏障的能力及细胞摄取和抗肿瘤活性。该脂质体稳定性好,安全性高,靶向性佳,可用于静脉注射,有较大的市场应用前景。
Description
技术领域
本发明属于药物制剂新辅料和新剂型领域,涉及两亲性聚合物谷氨酸-TPGS的制备,及其作为靶向材料在主动靶向药物传递***中的应用。
背景技术
脑肿瘤的侵润性生长和血脑屏障严重影响了脑部肿瘤的临床治疗效果。化疗是脑瘤治疗的常用手段,但大多数的小分子药物和所有大分子药物的跨血脑屏障能力很差,许多活性高的抗肿瘤药物由于跨血脑屏障能力差在开发早期就宣布失败。因此,血脑屏障上高表达的一些受体和营养型转运体成为研究焦点,如:维生素转运体、氨基酸转运体、葡萄糖转运体。这些在肿瘤部位和血脑屏障上不可或缺的营养型转运体可以开发为脑肿瘤主动靶向治疗的新靶点。纳米载体由于能够提高抗癌药物的疗效并且减少药物副作用而被广泛用于靶向药物传递***,PEG化的纳米载体更能显示出一些独特的优越性,如:延长纳米制剂的体内循环时间、增加配体的柔韧性和靶向性等。以纳米载体为药物递送工具,以血脑屏障和肿瘤同时高表达转运体为靶点,是一种有效地脑部靶向药物传递***。
近几年来,越来越多目光转移至肿瘤转运体靶向的纳米粒制剂的研究,它们通过对纳米制剂进行转运体底物的表面修饰,底物在接触到转运体时,通过转运体对其表面的底物进行高亲和性识别、结合,然后内陷、入胞。纳米制剂可以依靠肿瘤细胞膜上高表达的转运体达到提高细胞摄取量,增加抑瘤效果的目的。除此之外,一些营养型转运体同时在血脑屏障上高表达,靶向纳米制剂首先依靠血脑屏障上高表达的转运体促进药物的跨血脑屏障能力,再通过相同的靶点对脑瘤进一步进行靶向。在此,我们旨在开发靶向血脑屏障和脑胶质瘤上高表达的中性氨基酸转运体1(LAT1)的纳米制剂,研究其跨血脑屏障能力和脑胶质瘤的靶向能力。
发明内容
本发明的目的在于提供一种具有高跨血脑屏障能力、肿瘤靶向性、延长药物半衰期、既可以自身自组装形成胶束又可以作纳米制剂修饰剂的两亲性材料-谷氨酸-TPGS。
本发明第二个目的在于提供上述谷氨酸-TPGS嵌段共聚物的制备方法。
本发明的第三个目的是提供谷氨酸-TPGS嵌段共聚物在靶向药物传递中的作用。
本发明通过以下技术方案实现上述目的:
谷氨酸-TPGS嵌段共聚物以谷氨酸作为靶头,聚乙二醇为亲水端,提供靶头的柔韧性,疏水性的α-生育酚酯为疏水端,与其它药物载体内核的锚钉部位。是一种稳定性好、靶向性佳的主动靶向材料。
所述的谷氨酸-TPGS嵌段共聚物的结构式通式如下:
所述的靶向材料,,n为11-110,聚乙二醇的分子量为500-5000,优选为500-1000。
其制备过程:将羧基和氨基保护的谷氨酸,如:N-苄氧羰基-L-谷氨酸-1-苄酯(Z-Glu-OBzl,Ⅰ),溶于适量二氯甲烷、二甲基亚砜等有机良溶剂中,在催化剂的作用下,如:1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和4-二甲氨基吡啶(DMAP),避光冰浴1h-2h,然后与TPGS(Ⅱ)在30℃N2保护下反应12h-48h,经分离纯化得到淡黄色固体的Ⅲ。Ⅲ化合物经过钯碳还原反应,脱掉谷氨酸的保护基团,再经过进一步分离纯化得到最终化合物-谷氨酸-TPGS嵌段共聚物(Glu-TPGS,Ⅳ)。
该嵌段共聚物为淡黄色固体,易溶于二氯甲烷、N、N-二甲基甲酰胺、二甲基亚砜等有机溶剂。
所述的谷氨酸-TPGS嵌段共聚物是一种稳定性好、靶向性佳的主动靶向材料。
所述的谷氨酸-TPGS嵌段共聚物可以用于修饰包载紫杉烷类、喜树碱类、蒽醌类抗肿瘤药或二氢吡啶类、非甾体抗炎药中的任一物质或其衍生物;基因类药物为DNA或SiRNA的脂质体,其修饰方法可采用薄膜分散法制备,并采用下述步骤:将磷脂、胆固醇和谷氨酸-TPGS嵌段共聚物(30-40:1-2:2-4,w/w/w)完全溶解于适量的二氯甲烷中,在适当温度下,旋干成膜,加入2-5mL水化剂水化,并探头超声后,得到具有脑靶向性的脂质体。
本发明具有以下有益效果:制备一种新型的靶向性强的两亲性聚合物-谷氨酸-TPGS嵌段共聚物,载体制备过程温和,易操作。所制备谷氨酸-TPGS修饰的脂质体,制备简便,粒径较小且均一,包封率高,稳定性好,靶向性佳。体外细胞实验和体内跨血脑屏障能力证明本发明的谷氨酸-TPGS修饰的脂质体具有较好的跨血脑屏障能力和肿瘤靶向性。
附图说明
图1为本发明实施例1的谷氨酸-TPGS嵌段共聚物结构的1HNMR谱图
图2为本发明实施例2的谷氨酸-TPGS修饰的多西他赛脂质体(DTX-TGL)的动态光散射测定胶束粒径图和透视电镜图
图3为本发明实施例2谷氨酸-TPGS修饰的多西他赛脂质体/和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)的DSC图
A:多西他赛,B:多西他赛物理混合物C:TPGS修饰的多西他赛脂质体,D:TPGS-Glu修饰的多西他赛脂质体
图4为本发明实施例2的谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)的血浆稳定性试验
DTX-TL TPGS修饰的多西他赛脂质体粒径变化
DTX-TGL TPGS-Glu修饰的多西他赛脂质体粒径变化
-DTX-TL PDI TPGS修饰的多西他赛脂质体多分散指数变化
-DTX-TGL PDI TPGS-Glu修饰的多西他赛脂质体多分散指数变化
图5为本发明实施例2的谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)的稀释稳定性试验
DTX-TL TPGS修饰的多西他赛脂质体粒径变化
DTX-TGL TPGS-Glu修饰的多西他赛脂质体粒径变化
-DTX-TL PDI TPGS修饰的多西他赛脂质体多分散指数变化
-DTX-TGL PDI TPGS-Glu修饰的多西他赛脂质体多分散指数变化
图6为本发明实施例2谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)的体外释放试验
DTX-TL 7.4 TPGS修饰的多西他赛脂质体在pH7.4的释放
DTX-TGL 7.4TPGS-Glu修饰的多西他赛脂质体在pH7.4的释放
图7为本发明实施例2的谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)对脑胶质瘤细胞C6的细胞毒72h
DTX-TL TPGS修饰的多西他赛脂质体
DTXTGL TPGS-Glu修饰的多西他赛脂质体
DTX-Sol 多西他赛DMSO溶液剂
图8为本发明实施例2的谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)对脑胶质瘤细胞C6的细胞毒96h
DTX-TL TPGS修饰的多西他赛脂质体
DTX-TGL TPGS-Glu修饰的多西他赛脂质体
OTX-Sol 多西他赛DMSO溶液剂
图9为本发明实施例2的谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的香豆素6脂质体(C6-TGL/C6-TL)的脑胶质瘤细胞C6摄取情况
C6TL TPGS修饰的香豆素6脂质体
C6TGL TPGS-Glu修饰的香豆素6脂质体
图10为本发明实施例2的谷氨酸-TPGS密度对谷氨酸-TPGS修饰的香豆素6脂质体的脑胶质瘤细胞C6摄取情况
图11为本发明实施例2的不同氨基酸底物对谷氨酸-TPGS修饰的香豆素6脂质体与脑胶质瘤C6细胞膜上中性大氨基酸转运体1(LAT1)摄取的影响
图12为本发明实施例2谷氨酸-TPGS/TPGS修饰的DIR脂质体的跨血脑屏障能力
DIR:DIR溶液剂 TGL:TPGS-Glu修饰的DIR脂质体
TL:TPGS修饰的DIR脂质体。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将发明限制在所述的实施例范围之中。
实施例1
谷氨酸-TPGS嵌段共聚物的制备。
将羧基和氨基保护的谷氨酸,如:N-苄氧羰基-L-谷氨酸-1-苄酯(Z-Glu-OBzl,Ⅰ),溶于适量二氯甲烷中,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和4-二甲氨基吡啶(DMAP),避光冰浴1h,然后与TPGS(Ⅱ)在30℃N2保护下反应12h,经分离纯化得到淡黄色固体的Ⅲ。Ⅲ化合物经过钯碳还原反应,脱掉谷氨酸的保护基团,再经过进一步分离纯化得到最终化合物-谷氨酸-TPGS嵌段共聚物(Glu-TPGS,Ⅳ)。反应式如下:
步骤中聚乙二醇的分子量为1000,但是并不限于此,本发明的聚乙二醇亦可是一端为羟基修饰的聚乙二醇,但是并不局限于以上物质。聚乙二醇的分子量可以为500-5000范围内。
采用核磁共振测定1H-NMR氢谱来确定实施例1中靶向材料的结构,选用的溶剂为d-DMSO,结果如图1。4.2ppm为谷氨酸上-CH-上的H,3.52-3.75ppm间的质子峰为PEG中的H。3.0ppm以下为维生素E琥珀酸酯中的典型质子H峰。
实施例2
薄膜分散法制备载多西他赛或香豆素6的谷氨酸-TPGS修饰的脂质体和TPGS修饰的脂质体
称取1mg多西他赛或香豆素6,溶于适量二氯甲烷中,加入2mg实施例1制备的谷氨酸-TPGS或TPGS,以及30mg的大豆磷脂和1mg的胆固醇。旋干成膜,加入2mL的去离子水水化30min,探头超声300W,5min,采用微柱离心法除去未包裹的药物。
将实施例2中制备的脂质体通过动态光散射和透视电镜测定脂质体的粒径大小和形态。结果如图2,脂质体的粒径约为80nm,粒径分布窄;透视电镜图表明载药脂质体为粒径均一的球形。
表1为本发明实施例2的谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)对脑胶质瘤细胞C6在72h和96h的IC50值。
表1多西他赛溶液剂,TPGS修饰的多西他赛脂质体和TPGS-Glu修饰的多西他赛脂质体对C6胶质瘤细胞的IC50值。
实施例3
谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)的DSC图
按照实例2制备谷氨酸-TPGS/TPGS修饰的多西他赛脂质体,并以甘露醇为冻干保护剂进行冻干,通过DSC分析DTX在脂质体中的存在状态,分析样品包括:DTX原料药,DTX原料药和空白脂质体物理混合物,冻干的DTX-TGL和DTX-TL。
图3结果表明DTX以无定型或分子态包裹在磷脂双分子层中。
实施例4
谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体
(DTX-TGL/DTX-TL)在血浆中的稳定性试验
按照实例2制备谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体,将脂质体置于含有10%FBS的DMEM高糖培养液中,通过动态光散射测定脂质体在0h,1h,2h,4h,6h,8h,10h,12h和24h的粒径。
图4结果表明谷氨酸-TPGS/TPGS修饰的多西他赛脂质体具有较好的血浆稳定性。
实施例5
谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)的稀释稳定性
按照实例2制备谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体,将脂质体用PBS稀释不同倍数,并通过动态光散射测定脂质体的粒径。
图5结果表明谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体具有较好的稀释稳定性。
实施例6
谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体(DTX-TGL/DTX-TL)体外释放试验
采用透析法考察实例2制备谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体的体外释药特征。移取含150μg的载药胶束溶液于透析袋中,透析袋两端夹紧,分别置于含有30mL pH 7.4PBS(含0.5%Tween 80)的释放介质的锥形瓶中,在37℃恒温振荡器中以100r/min进行体外释放度考察。分别在1、2、4、6、8、10、12、24h和48h取样2mL,同时补充2mL新鲜释放介质,样品经0.45μm微孔滤膜过滤,取20μL进行HPLC测定。
图6结果表明谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体释药缓慢,有利于更多的药物达到肿瘤部位。
实施例7
细胞毒性实验
将处于对数生长期的脑胶质瘤细胞(C6)以3.5×104/孔/0.1mL的DMEM高糖培养液埋于96孔板中,24h后将实施例2制备的谷氨酸-TPGS修饰的多西他赛脂质体和TPGS修饰的多西他赛脂质体以不同浓度分别加入各孔,每孔加入100μL含脂质体溶液,每个浓度3个平行孔,置培养箱中孵育。培养72h和96h后,取出96孔板,每孔加入20μL的5mg/mL MTT,培养箱中孵育4h,甩板,将96孔板倒扣于滤纸中充分吸干残留液体,每孔加入150μL DMSO于振荡器中振荡10min,酶标仪测定各孔492nm处的吸光度。计算抑制率:
抑制率(%)=(1-A加药孔/A对照孔)×100%
MTT法测定脂质体细胞毒性结果如图7和图8,不同浓度载药脂质体作用于C6细胞株72h和96h后,细胞抑制率随药物浓度和孵化时间增加而增大,并且对细胞的抑制作用由于谷氨酸的靶向作用而增强。表1所计算得到的各制剂的IC50值也体现出谷氨酸修饰脂质体的优势。
实施例8
细胞摄取实验
将LAT1高表达的C6细胞以2×105/孔/0.1mL的1640培养液和DMEM培养液埋于96孔板中,24h后将实施例2制备的谷氨酸-TPGS修饰的香豆素6脂质体和TPGS修饰的香豆素6脂质体,由HBSS缓冲液稀释相同的香豆素6的浓度加入各孔中,每孔100μL,平行3孔,置培养箱中孵育1h和3h。弃上清,每孔加入50μl 0.5%TrtionX-100(含0.2N NaOH)的PBS溶液并置摇床中作用1h。随后,在激发波长为458nm,发射波长为525nm测定细胞内荧光强度,并对每孔进行蛋白含量测定,并计算摄取量。为了筛选最适宜的靶向密度,同时制备具有不同谷氨酸-TPGS密度修饰的香豆素6脂质体,按照上述进行细胞摄取考察。
细胞摄取的结果见图9,图10,在LAT1高表达瘤株中,谷氨酸-TPGS修饰的香豆素6脂质体的细胞摄取量均比TPGS修饰的香豆素6脂质体高。并且随着靶向材料修饰密度的增加,细胞摄取增加,在10%细胞摄取达到最大。
实施例9
不同氨基酸底物对LAT1介导的谷氨酸-TPGS修饰的香豆素6脂质体摄取的影响实验
将LAT1高表达的C6细胞以2×105/孔/0.1mL的1640培养液和埋于96孔板中,24h后将实施例2制备的谷氨酸-TPGS修饰的香豆素6脂质体,由HBSS缓冲液稀释后,与不同氨基酸混合均匀后,加入各孔中,每孔100μL,平行3孔,置37℃中孵育3h。弃上清,每孔加入50μl0.5%TrtionX-100(含0.2N NaOH)的PBS溶液并置摇床中作用1h。随后,在激发波长为458nm,发射波长为525nm测定细胞内荧光强度,并对每孔进行蛋白含量测定,并计算摄取量。
摄取影响实验结果见图11,结果表明作为LAT1高亲和性底物,亮氨酸和苯丙氨酸对脂质体和LAT1的结合过程有明显的抑制作用,证明靶向脂质体能识别并结合LAT1,促进细胞摄取。
实施例10
谷氨酸-TPGS修饰的DIR脂质体和TPGS修饰的DIR脂质体的跨血脑屏障能力
采用活体成像法考察实例2制备谷氨酸-TPGS/TPGS修饰的DIR脂质体和DIR溶液剂的跨血脑屏障能力。以2mg/kg尾静脉给予KM小鼠载有DIR的脂质体,8h后,将小鼠的心,肝,脾,肺,肾和脑取出,通过活体成像仪观察脂质体的分布情况。
跨血脑屏障能力实验结果见图12,结果表明作为谷氨酸-TPGS修饰的脂质体具有更好的跨血脑屏障能力。
Claims (9)
1.谷氨酸-TPGS嵌段共聚物,其特征在于:以聚乙二醇为亲水端,α-生育酚酯为疏水端,谷氨酸为靶头,结构通式如下:
其中,n为11-110,聚乙二醇的分子量为500-5000。
2.根据权利要求1所述谷氨酸-TPGS嵌段共聚物的制备方法,其特征在于采用如下步骤制备:
将羧基和氨基保护的谷氨酸,溶于适量二氯甲烷、二甲基亚砜的有机良溶剂中,在催化剂的作用下,避光冰浴1h-2h,然后与TPGS在30℃N2保护下反应12h-48h,经分离纯化得到淡黄色固体;
将此淡黄色固体经过钯碳还原反应,脱掉谷氨酸的保护基团,再经过进一步分离纯化得到最终化合物-谷氨酸-TPGS嵌段共聚物。
3.根据权利要求2所述的制备方法,其特征在于,羧基和氨基保护的谷氨酸为N-苄氧羰基-L-谷氨酸-1-苄酯。
4.根据权利要求2所述的制备方法,其特征在于,所述的催化剂为1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐或4-二甲氨基吡啶中的一种或两种。
5.权利要求1所述的谷氨酸-TPGS嵌段共聚物在药物传递***中的应用。
6.权利要求1所述的谷氨酸-TPGS嵌段共聚物作为药物载体或修饰剂在血脑屏障及肿瘤主动靶向递送中的应用。
7.权利要求1所述的谷氨酸-TPGS嵌段共聚物作为药物载体或修饰剂在靶向中性大氨基酸转运体1中的应用。
8.一种载药纳米粒,其特征在于,以权利要求1所述的谷氨酸-TPGS嵌段共聚物为修饰剂,以脂质体为药物储库。
9.根据权利要求8所述的载药纳米粒,其特征在于:脂质体中的药物为疏水性药物、亲水性药或基因类药物,所述的疏水性药物为紫杉烷类、喜树碱类、蒽醌类抗肿瘤药或二氢吡啶类、非甾体抗炎药中的任一物质或该物质的衍生物;亲水性药物为阿霉素、羟基喜树碱、顺铂类;基因类药物为DNA或SiRNA。
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