CN102603866B - 基于寡肽的pH敏感型两性离子及其在药剂中的应用 - Google Patents
基于寡肽的pH敏感型两性离子及其在药剂中的应用 Download PDFInfo
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- CN102603866B CN102603866B CN201210067847.2A CN201210067847A CN102603866B CN 102603866 B CN102603866 B CN 102603866B CN 201210067847 A CN201210067847 A CN 201210067847A CN 102603866 B CN102603866 B CN 102603866B
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Abstract
本发明涉及药用功能辅料与制剂领域。具体涉及一类基于寡肽pH敏感型两性离子脂质(I)或(II)。本发明的寡肽两性离子脂质衍生物在不同的pH条件下表面电荷不同,能够在生理环境pH近中性的条件带较强的负电荷,使得脂质体具有良好的血液相容性,而到达肿瘤部位时,在肿瘤弱酸性的环境下,寡肽两性离子脂质体表面电荷发生反转,由原来的正电性反转成正电性,带正电荷的载体易于与肿瘤细胞表面结合,可有效地通过内吞途径实现肿瘤细胞靶向。在溶酶体中,阳离子载体继续发挥质子海绵作用或溶酶体膜裂解作用,这两种作用可以保证载体的完整性,使载体可以安全逃逸到达胞质或其他细胞器。
Description
技术领域
本发明涉及药用功能辅料与制剂领域。具体涉及一类具有寡肽pH敏感型两性离子脂质及其制备方法,还涉及其作为药物载体如组装成脂质体或作为阳离子载体的包覆材料在制剂中的应用。
背景技术
脂质体作为药物载体具有使药物靶向网状内皮系统、延长药效、降低药物毒性、提高疗效、避免耐受性、改变给药途径等优点。但脂质体作为药物载体仍存在对有些疾病的靶向特征不理想、体内稳定性和贮存稳定性欠佳等缺点,因而限制了脂质体的临床应用和工业化生产。近年来人们研制出长循环脂质体、前体脂质体、聚合膜脂质体等新型脂质体以提高脂质体的稳定性;设计开发了温度敏感脂质体、pH敏感脂质体、免疫脂质体、磁性脂质体等新型脂质体以提高脂质体的靶向性。
pH敏感脂质体是基于肿瘤间质处的pH值比正常组织低的特点而设计的,一种具有细胞内靶向和控制药物释放作用的脂质体。其原理是pH值降低导致脂肪酸羧基的质子化,引起六角晶相(非相层结构)的形成而使膜融合,将包封的药物释放入胞质并主动靶向病变组织,避免网状内皮系统清除及溶酶体的降解,增加了组织对药物的摄取量。应用不同的膜材或通过调节脂质组成比例,可获得具不同pH敏感性的脂质体。这种脂质体通常采用对pH敏感的类脂,如二棕榈酰磷脂酰胆碱(dipalmitoyl phosphatidylcholine,DPPC)和十七烷酸磷脂为膜材。这种pH敏感而引起膜融合的特性,易使载体发生破坏,使其中的药物泄露出来。
发明内容
本发明公开了一类pH敏感型两性离子脂质材料,该材料由谷氨酸(或天冬氨酸)-组氨酸与酸酐基(六氢苯酐,柠糠酸酐,马来酸酐、邻苯二甲酸酐,甲基四氢邻苯二甲酸酐,四氢化邻苯二甲酸酐,甲基六氢苯酐)组成两性离子亲水头基,由链双长链烷烃(正癸醇-正二十醇,油醇,亚油醇)疏水尾(结构式I);另外,此结构的组氨酸可由碱性氨基酸赖氨酸或精氨酸替代。
或由甘氨酸(或苯丙氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,色氨酸,蛋氨酸,脯氨酸;丝氨酸,苏氨酸,天冬酰胺,谷氨酰胺,酪氨酸)-组氨酸与酸酐基(六氢苯酐,柠糠酸酐,马来酸酐、邻苯二甲酸酐,甲基四氢邻苯二甲酸酐,四氢化邻苯二甲酸酐,甲基六氢苯酐)组成两性离子亲水头基,由单链烷烃(胆固醇,正癸醇-正二十醇,油醇,亚油醇)组成疏水尾(结构式II)。另外,此结构的赖氨酸可以由碱性氨基酸赖氨酸或精氨酸替代。
本发明的基于寡肽的pH敏感型两性离子的结构式(I)或(II)的脂质衍生物如下:
其中:
n=1或2;
R2=-(CH2)x-CH3,x=7-19、-(CH2)x-CH=CH-(CH2)y-CH3,x=8,y=8或
-(CH2)x-CH=CH-CH2-CH=CH-(CH2)y-CH3,x=8,y=5;
R3=-(CH2)n-CH3,n=7-19、-(CH2)n-CH=CH-(CH2)m-CH3,n=8,m=8、
本发明的寡肽两性离子脂质衍生物制备方法包括:
a.将单羧基氨基酸或二元羧基氨基酸和对甲苯磺酸溶于甲苯(或苯,或环己烷)中,回流1h~3h。加入脂肪醇,回流5h~15h。冷却至室温,减压蒸馏去除甲苯(或苯,或环己烷)。用二氯甲烷(或三氯甲烷,或乙酸乙酯)溶解后,5%~15%碳酸氢钠溶液(或碳酸钠,或碳酸钾)、水洗涤,有机层无水硫酸钠(或无水硫酸镁)干燥后浓缩,甲醇(或乙醇,或丙酮)重结晶,得到脂肪醇-单羧基氨基酸(1)或脂肪醇-二元羧基氨基酸(2)。反应式如下:
脂肪醇-单羧基氨基酸的合成反应式1:
脂肪醇-二元羧基氨基酸的合成反应式2:
b.将Boc-L-His (Tos)-OH,N,N-二环己基碳二亚胺(DCC)和N-羟基丁二酰亚胺(NHS)溶于N,N-二甲基甲酰胺(DMF)(或氯仿)中,室温搅拌1h~3h;将1或2和三乙胺溶于DMF(或氯仿)中,室温搅拌1h~3h后,加入上述混合溶液中,室温搅拌10h~24h。反应结束后,反应液加入水中,抽滤,将滤出物溶于二氯甲烷(或氯仿,或乙酸乙酯),滤去不溶物,浓缩二氯甲烷(或氯仿,或乙酸乙酯)溶液;乙酸乙酯(或丙酮)溶解,除去析出DCU,重复此操作,直至DCU完全去除。甲醇(或乙醇,或丙酮)重结晶,得到白色粉末状固体。将上述得到的白色粉末状固体溶解在三氟醋酸和二氯甲烷混合溶液中,室温搅拌0.5h~4h;反应结束后,加入5%~15%碳酸氢钠溶液(或碳酸钠,或碳酸钾)调pH值至中性,收集有机层,无水硫酸钠(或无水硫酸镁)干燥后浓缩,得到脂肪醇-单羧基氨基酸-组氨酸(含保护基)(3)或脂肪醇-二元羧基氨基酸-组氨酸(含保护基)(4)。反应式如下:
脂肪醇-单羧基氨基酸-组氨酸(含保护基)的合成反应式3:
脂肪醇-二元羧基氨基酸-组氨酸(含保护基)的合成反应式4:
c.将3或4,酸酐和三乙胺溶于氯仿(或二氯甲烷,或四氢呋喃)中,室温搅拌6h~20h。反应结束后,5%~15%碳酸氢钠溶液(或碳酸钠,或碳酸钾)、饱和食盐水、水洗涤,无水硫酸钠(或无水硫酸镁)干燥有机层,浓缩后,乙醇(或丙酮、或甲醇)重结晶,得到白色粉末状固体。取上述白色粉末状固体和1-羟基苯并三唑(HOBt)溶解在四氢呋喃中,室温反应4h~8h,反应液浓缩,过滤除去析出物,浓缩滤液,二氯甲烷/甲醇柱层析,得到得到脂肪醇-单羧基氨基酸-组氨酸-酸酐基(5)或脂肪醇-二元羧基氨基酸-组氨酸-酸酐基(6)。反应式如下:
脂肪醇-单羧基氨基酸-组氨酸-酸酐基的合成反应式5:
脂肪醇-二元羧基氨基酸-组氨酸-酸酐基的合成反应式6:
本发明的寡肽两性离子脂质材料为白色至黄色粉末,易溶于二氯甲烷和氯仿,可以与不同量的磷脂、胆固醇制备寡肽两性离子脂质体,并其粒径在100-300nm之间,均能够在pH 7.4至pH 4.5发生电荷反转,由表面负电荷变为正电荷。并加入蔗糖冻干保护剂对寡肽两性离子脂质体冻干,冻干后的寡肽离子脂质体仍具有电荷反转能力。该寡肽两性离子脂质材料具有很强的质子缓冲能力,在酸性的溶酶体环境下特别是pH5.5-4.5能够发生质子海绵作用,发挥溶酶体逃逸作用,如图1所示。
本发明还公开了一种空白脂质体,含脂质体基质和权利要求1的脂质衍生物。脂质体基质为磷脂。脂质体基质还可以含胆固醇。
本发明还公开了一种药物脂质体,其中脂质体基质为磷脂。这种寡肽两性离子脂质体对难溶性药物能够得到很好的包载,包封率在80%以上,例如对坦西莫斯(Temsirolimus)的包载,寡肽两性离子脂质体的包封率为93.33±1.69%,冻干复溶后包封率基本没有变化。所述的难溶性药物优选:坦西莫斯、喜树碱类(优选喜树碱、10-羟基喜树碱、9-硝基喜树碱或SN-38)、紫杉醇、多西紫杉醇、藤黄酸、环孢素A、足叶乙苷、替尼泊甙、依托泊甙、长春酰胺、尼莫地平、硝苯地平、尼群地平、阿霉素、柔红霉素、丝裂霉素、甲氨喋呤、冬凌草素、藤黄酸、三尖杉酯碱、高三尖杉酯碱、灯盏花素、银杏内酯、水飞蓟素、靛玉红,本发明的寡肽两性离子脂质体对上述药物均有很好的包载。
由于市售坦西莫斯制剂中含有一定量的表面活性剂聚乙二醇400和吐温80,这些表面活性剂导致了一些不良反应,通过细胞实验比较了脂质体和这些表面活性剂的细胞毒性,结果表明聚乙二醇400在各个浓度对L02肝正常细胞的毒性较小,细胞存活率基本都在100%,而吐温80在1mg/mL以上浓度表现出较强的细胞毒性。中聚乙二醇和吐温80的配比接近1∶1(w∶w),聚乙二醇400+吐温80的混合溶液与吐温80相比,毒性更强。而本发明的寡肽两性离子脂质体、空白普通脂质体仅在浓度为10mg/mL表现出一定毒性,而10mg/mL以下浓度,对L02细胞基本无毒。如图2所示。
本发明的药物和脂质衍生物(I)或(II)的药载质量比优选1∶40~1∶60。
本发明的脂质衍生物可用作脂质体修饰剂。
本发明的寡肽两性离子脂质衍生物部分取代普通磷脂制备的寡肽两性离子脂质体在不同的pH条件下表面电荷不同,能够在生理环境pH近中性(pH 7.4)的条件带较强的负电荷,使得脂质体具有良好的血液相容性,而到达肿瘤部位时,在肿瘤弱酸性的环境下(pH7.0-6.5),寡肽两性离子脂质体表面电荷发生反转,由原来的正电性反转成正电性,带正电荷的载体易于与肿瘤细胞表面结合,可有效地通过内吞途径实现肿瘤细胞靶向。在溶酶体中,阳离子载体继续发挥质子海绵作用或溶酶体膜裂解作用,这两种作用可以保证载体的完整性,使载体可以安全逃逸到达胞质或其他细胞器。
本发明的脂质衍生物可以作为阳离子载体的包覆材料,在生理环境pH近中性(pH 7.4)的条件带较强的负电荷,依赖静电作用力,包覆于阳离子载体表面,组装成在血液中性环境呈负电性的纳米载体。该载体经静脉注射可以稳定地携带药物靶向肿瘤。在肿瘤细胞外微酸性环境(pH 7.0-6.5),包覆材料自发地由负电性转为正电性,与阳离子载体发生静电排斥,包覆层从阳离子载体上脱离,因其正电性易于被肿瘤细胞内吞,并在溶酶体偏酸性环境发挥质子海绵作用,安全逃逸至胞质。
根据肿瘤外环境较低pH的要求,以坦西莫司为模型药物,构建高度具有pH响应的寡肽两性离子脂质体。在中性pH亲水头基呈负电性,脂质体与血液相容。在肿瘤细胞外微弱酸性环境中亲水头基迅速发生pH响应,转成阳离子性质,实现细胞对脂质体的内吞。并且在内涵体或溶酶体更酸性的条件下继续发生质子化,带有更强的正电荷,同时结构中含有具备溶酶体逃逸功能的基团,能够实现溶酶体逃逸,将药物有效地释放到胞浆内,实现肿瘤靶向,提高药物递送效率,降低药物毒副作用的效果。
附图说明
图1是两性离子脂质体和普通脂质体的质子缓冲能力
图2是两性离子脂质体、普通脂质体、聚乙二醇400和吐温80对L02肝正常细胞的毒性
具体实施方式:
实施例1
1,5-正二十醇-L-谷氨酸-组氨酸-丁二酸酐的制备
将谷氨酸(11.8g,80.2mmol)和对甲苯磺酸(18.3g,96.2mmol)溶于350mL甲苯中,回流1h。加入正二十醇(52.8g,176.7mol),回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(100mL×2),水洗涤(100mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体1,5-正二十醇-L-谷氨酸(EI2-Glu,32g,56.2%)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),N,N-二环己基碳二亚胺(DCC,10.3g,49.9mmol)和N-羟基丁二酰亚胺(NHS,2.9g,25.2mmol)溶于100mLN,N-二甲基甲酰胺(DMF)中,室温搅拌3h;将EI2-Glu(12g,16.9mmol)加入上述混合溶液中,室温搅拌12h。过滤,加入300ml二氯甲烷,水洗(100mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体(9.1g,49.2%)。将上述得到的白色粉末状固体溶解在15mL三氟醋酸和15mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到1,5-正二十醇-L-谷氨酸-组氨酸。将EI2-Glu-His(Tos)(2.3g,2.3mmol),丁二酸酐(0.23g,2.3mmol)和三乙胺(0.5g,4.5mmol)溶于30mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(10mL×2),水洗涤(10mL×1),无水硫酸钠干燥有机层,浓缩后,乙醇(70mL)重结晶,得到白色粉末状固体(1.44g,58.3%)。取上述白色粉末状固体(0.85g,0.8mmol)和1-羟基苯并三唑(HOBt,1.2g,9.2mmol)溶解在40mL四氢呋喃中,室温反应5h,反应液浓缩,二氯甲烷/甲醇(10∶1)柱层析,得到白色粉末状固体,1,5-正二十醇-L-谷氨酸-组氨酸-丁二酸酐(EI2-Glu-His-Suc,0.3g,42.9%)。
1H-NMR(CDCl3,500MHz,δppm):0.88(t,6H,CH2CH3),1.25-1.61(m,68H,CH2(stearyl)),2.05(m,2H,NHCHCH2),2.19(m,2H,NHCHCH2CH2),2.39-2.63(m,4H,COOCH2CH2COO),2.88-3.25(q,2H,NHCHCH2),4.02-4.15(t,4H,COOCH2),4.50(q,1H,NHCH),4.99(q,1H,NHCH),7.83(d,1H,CH2C=CH),8.18(d,1H,N=CH).
13CNMR(CDCl3+CD3OD,75MHz,ppm):16.5(CH3),26.2(CH2),28.9(CH2),29.6(CH2),30.0(CH2),30.8(CH2),32.2(CH2),49.8(CH2),59.4(CH2),65.4(CHNH),66.2(CHNH),77.8(OCH2),118.70(CH-NH),131.7(CH=CH),134.9(CH=NH),171.9(NHCHCO),172.2(NHCHCO),173.6(COOCH2),173.7(CONH),176.8(CHCOOH).
实施例2
1,5-正十八醇-L-谷氨酸-组氨酸-柠糠酸酐(SA2-Glu-His-CTA)的制备
将谷氨酸(11.8g,80.2mmol)和对甲苯磺酸(18.3g,96.2mmol)溶于350mL甲苯中,回流1h。加入十八醇(47.8g,176.7mol),回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(100mL×2),水洗涤(100mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体1,5-十八醇-L-谷氨酸(SA2-Glu,29g,55.4%)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),DCC(10.3g,49.9mmol)和NHS(2.9g,25.2mmol)溶于100mLDMF中,室温搅拌3h;将SA2-Glu(11g,16.9mmol)加入上述混合溶液中,室温搅拌12h。过滤,加入300ml二氯甲烷,水洗(100mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体(8.9g,50.8%)。将上述得到的白色粉末状固体溶解在15mL三氟醋酸和15mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到1,5-十八醇-L-谷氨酸-组氨酸(SA2-Glu-His(Tos),7.5g,93.2%)。取SA2-Glu-His(Tos)(4.6g,4.9mmol),柠糠酸酐(0.55g,4.9mmol)和三乙胺(1.0g,9.9mmol)溶于75mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(10mL×2),水洗涤(10mL×1),无水硫酸钠干燥有机层,浓缩后,甲醇(180mL)重结晶,得到淡黄色粉末状固体(1.5g,29%)。取上述白色粉末状固体(1.5g,1.4mmol)和HOBt(2.3g,16.5mmol)溶解在50mL四氢呋喃中,室温反应5h,反应液浓缩,二氯甲烷/甲醇(15∶1)柱层析,得到白色粉末状固体,1,5-十八醇-L-谷氨酸-组氨酸-柠糠酸酐(SA2-Glu-His-CTA,0.4g,31.6%)。
1H-NMR(CDCl3,500MHz,δppm):0.86-0.87(t,6H,CH2CH3),1.25-1.61(m,64H,CH2(stearyl)),1.98(d,3H,CH=C-CH3),2.02(m,2H,NHCHCH2),2.37(m,2H,NHCHCH2CH2),2.91-3.38(q,2H,NHCHCH2),4.05-4.11(t,4H,COOCH2),4.45(q,1H,NHCH),4.8(q,1H,NHCH),5.9(s,1H,CH=C-CH3),7.03(d,1H,CH2C=CH).
13C-NMR(CDCl3+CD3OD,75MHz,δppm):14.0(CH3),22.6(CH2),25.9(CH2),28.5(CH2),28.6(CH2),29.3(CH2),30.8(CH2),32.2(CH2),49.8(CH2),59.4(CH2),65.4(CHNH),66.2(CHNH),77.8(OCH2),118.70(CH-NH),131.7(CH=CH),134.9(CH=NH),171.9(NHCHCO),172.2(NHCHCO),173.6(COOCH2),173.7(CONH),176.8(CHCOOH).
实施例3
1,5-正十二醇-L-谷氨酸-组氨酸-六氢苯酐的制备
将谷氨酸(11.8g,80.2mmol)和对甲苯磺酸(18.3g,96.2mmol)溶于350mL甲苯中,回流1h。加入正十二醇(3.3g,176.7mol),回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(100mL×2),水洗涤(100mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体1,5-正十二醇-L-谷氨酸(DO2-Glu,17g,44.1%)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),DCC(10.3g,49.9mmol)和NHS(2.9g,25.2mmol)溶于100mLDMF中,室温搅拌3h;将DO2-Glu(8.1g,16.9mmol)加入上述混合溶液中,室温搅拌12h。过滤,加入300ml二氯甲烷,水洗(100mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体(7.2g,48.0%)。将上述得到的白色粉末状固体溶解在15mL三氟醋酸和15mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到1,5-正十二醇-L-谷氨酸-组氨酸。将DO2-Glu-His(Tos)(1.8g,2.3mmol),六氢苯酐(0.35g,2.3mmol)和三乙胺(0.5g,4.5mmol)溶于30mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(10mL×2),水洗涤(10mL×1),无水硫酸钠干燥有机层,浓缩后,乙醇(70mL)重结晶,得到白色粉末状固体(1.1g,51.6%)。取上述白色粉末状固体(0.88g,0.8mmol)和HOBt(1.2g,9.2mmol)溶解在40mL四氢呋喃中,室温反应5h,反应液浓缩,二氯甲烷/甲醇(10∶1)柱层析,得到白色粉末状固体,1,5-正十二醇-L-谷氨酸-组氨酸-六氢苯酐(DO2-Glu-His-HHPA,0.17g,27.4%)。
1H-NMR(CDCl3,500MHz,δppm):0.88(t,6H,CH2CH3),1.25-1.61(m,52H,CH2(stearyl)),2.05(m,2H,NHCHCH2),2.19(m,2H,NHCHCH2CH2),1.75-2.86(m,10H,CH2(HHPA)),2.88-3.25(q,2H,NHCHCH2),4.02-4.15(t,4H,COOCH2),4.50(q,1H,NHCH),4.99(q,1H,NHCH),7.83(d,1H,CH2C=CH),8.18(d,1H,N=CH).
13CNMR(CDCl3+CD3OD,75MHz,ppm):16.5(CH3),26.2(CH2),28.9(CH2),29.6(CH2),30.0(CH2),30.8(CH2),32.2(CH2),49.8(CH2),59.4(CH2),65.4(CHNH),66.2(CHNH),77.8(OCH2),118.70(CH-NH),131.7(CH=CH),134.9(CH=NH),171.9(NHCHCO),172.2(NHCHCO),173.6(COOCH2),173.7(CONH),176.8(CHCOOH).
实施例4
1,5-正辛醇-L-谷氨酸-组氨酸-马来酸酐的制备
将谷氨酸(11.8g,80.2mmol)和对甲苯磺酸(18.3g,96.2mmol)溶于350mL甲苯中,回流1h。加入正辛醇(22.9g,176.7mol),回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(100mL×2),水洗涤(100mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体1,5-正辛醇-L-谷氨酸(OC2-Glu,16g,53.9%)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),DCC(10.3g,49.9mmol)和NHS(2.9g,25.2mmol)溶于100mL DMF中,室温搅拌3h;将OC2-Glu(6.3g,16.9mmol)加入上述混合溶液中,室温搅拌12h。过滤,加入300ml二氯甲烷,水洗(100mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体(6.4g,48.9%)。将上述得到的白色粉末状固体溶解在15mL三氟醋酸和15mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到1,5-正辛醇-L-谷氨酸-组氨酸。将OC2-Glu-His(Tos)(1.55g,2.3mmol),马来酸酐(0.22g,2.3mmol)和三乙胺(0.5g,4.5mmol)溶于30mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(10mL×2),水洗涤(10mL×1),无水硫酸钠干燥有机层,浓缩后,乙醇(70mL)重结晶,得到白色粉末状固体(0.8g,47.1%)。取上述白色粉末状固体(0.59g,0.8mmol)和HOBt(1.2g,9.2mmol)溶解在40mL四氢呋喃中,室温反应5h,反应液浓缩,二氯甲烷/甲醇(10∶1)柱层析,得到白色粉末状固体,1,5-正辛醇-L-谷氨酸-组氨酸-马来酸酐(OC2-Glu-His-MA,0.13g,27.5%)。
1H-NMR(CDCl3,500MHz,δppm):0.88(t,6H,CH2CH3),1.25-1.61(m,64H,CH2(stearyl)),2.05(m,2H,NHCHCH2),2.19(m,2H,NHCHCH2CH2),1.75-2.86(m,10H,CH2(HHPA)),2.88-3.25(q,2H,NHCHCH2),4.02-4.15(t,4H,COOCH2),4.50(q,1H,NHCH),4.99(q,1H,NHCH),7.83(d,1H,CH2C=CH),8.18(d,1H,N=CH).
13CNMR(CDCl3+CD3OD,75MHz,ppm):16.5(CH3),26.2(CH2),28.9(CH2),29.6(CH2),30.0(CH2),30.8(CH2),32.2(CH2),49.8(CH2),59.4(CH2),65.4(CHNH),66.2(CHNH),77.8(OCH2),118.70(CH-NH),131.7(CH=CH),134.9(CH=NH),171.9(NHCHCO),172.2(NHCHCO),173.6(COOCH2),173.7(CONH),176.8(CHCOOH).
实施例5
1,5-正十八醇-L-谷氨酸-组氨酸-六氢苯酐的制备
将谷氨酸(11.8g,80.2mmol)和对甲苯磺酸(18.3g,96.2mmol)溶于350mL甲苯中,回流1h。加入十八醇(47.8g,176.7mol),回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(100mL×2),水洗涤(100mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体1,5-十八醇-L-谷氨酸(SA2-Glu,29g,55.4%)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),DCC(10.3g,49.9mmol)和NHS(2.9g,25.2mmol)溶于100mLDMF中,室温搅拌3h;将SA2-Glu(11g,16.9mmol)加入上述混合溶液中,室温搅拌12h。过滤,加入300ml二氯甲烷,水洗(100mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体(8.9g,50.8%)。将上述得到的白色粉末状固体溶解在15mL三氟醋酸和15mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到1,5-十八醇-L-谷氨酸-组氨酸(SA2-Glu-His(Tos),7.5g,93.2%)。取SA2-Glu-His(Tos)(2.0g,2.1mmol),六氢苯酐(0.32g,2.1mmol)和三乙胺(0.43g,4.2mmol)溶于30mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(10mL×2),水洗涤(10mL×1),无水硫酸钠干燥有机层,浓缩后,丙酮(70mL)重结晶,得到白色粉末状固体(1.5g,64.4%)。取上述白色粉末状固体(1.5g,1.4mmol)和HOBt(2.2g,16.4mmol)溶解在40mL四氢呋喃中,室温反应5h,反应液浓缩,二氯甲烷/甲醇(15∶1)柱层析,得到白色粉末状固体,1,5-十八醇-L-谷氨酸-组氨酸-六氢苯酐(SA2-Glu-His-HHPA,0.1g,5.1%)。
1H-NMR(CDCl3,500MHz,δppm):0.85-0.89(t,6H,CH2CH3),1.25-1.60(m,64H,CH2(stearyl)),1.77-3.18(m,10H,CH2(HHPA)),2.03(m,2H,NHCHCH2),2.18(m,2H,NHCHCH2CH2),3.02-3.18(q,2H,NHCHCH2),4.02-4.12(t,4H,COOCH2),4.49(q,1H,NHCH),4.94(q,1H,NHCH),7.87(d,2H,CH2C=CH,N=CH).
13C-NMR(CDCl3+CD3OD,75MHz,δppm):14.1(CH3),21.8(CH2),23.4(CH2),24.8(CH2),26.3(CH2),28.6(CH2),30.3(CH2),30.5(CHCONH),39.9(CHCOOH),52.3(CH),77.5(OCH2),126.0(CH-NH),129.7(CH=CH),141.2(CH=NH),171.2(NHCHCO),171.9(NHCHCO),173.4(COOCH2),173.7(CONH),179.8(CHCOOH).
实施例6
正十八醇-苯丙氨酸-组氨酸-邻苯二甲酸酐的制备
将苯丙氨酸(2.9g,17.6mmol)和对甲苯磺酸(3.6g,21.1mmol)溶于100mL甲苯中,回流1h。加入十八醇(4.7g,17.6mmol)回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(30mL×2),水洗涤(30mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体十八醇-苯丙氨酸(SA-Phe)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),DCC(10.3g,49.9mmol)和NHS(2.9g,25.2mmol)溶于100mLDMF中,室温搅拌3h;将SA-Phe(7g,16.8mmol)加入上述混合溶液中,室温搅拌12h。滤去DCU,加入150ml二氯甲烷,水洗(60mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体8g。将上述得到的白色粉末状固体溶解在10mL三氟醋酸和10mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到十八醇-苯丙氨酸-组氨酸(SA-Phe-L-His(Tos))。将SA-Phe-L-His(Tos)(4.2g,6.8mmol),邻苯二甲酸酐(1.0g,6.8mmol)和三乙胺(0.7g,7.5mmol)溶于25mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(10mL×2),水洗涤(10mL×1),无水硫酸钠干燥有机层,浓缩后,乙醇(45mL)重结晶,得到白色粉末状固体SA-Phe-L-His(Tos)-PA。取上述白色粉末状固体(2.1g,2.7mmol)和HCOONH4(0.5g,8.0mmol)加热溶解在40mL四氢呋喃中,加入钯/碳(0.2g),50℃条件下反应5h,抽滤除去钯/碳,浓缩反应液,二氯甲烷/甲醇柱层析,得到白色粉末状固体,十八醇-苯丙氨酸-组氨酸-邻苯二甲酸酐(SA-Phe-His(Tos)-PA,0.6g,33.1%)。1H-NMR(CDCl3,500MHz,δppm):0.96(t,3H,CH3),1.29(m,32H,CH2),1.57(m,2H,CH2),4.08(m,2H,CH2),3.04,3.29(m,2H,CHCH2),4.53(s,1H,CHNH),4.81(s,1H,CHNH),7.12-8.31(m,8H,CHbenzenering),7.83(d,1H,CH2C=CH),8.18(d,1H,N=CH).
13C-NMR(CDCl3+CD3OD,75MHz,δppm):14.1(CH3),20.7(CHCH2CH2),22.8(CH2),25.9(CH2),29.0(CH2),29.4(CH2),29.7(CH2),31.6(CHCH2),31.9(CH2),32.1(CH2CH2NH2),37.0(CHCH2),42.1(CH2NH2),53.4(CHNH),54.7(CHNH),65.3(CH2-O),126.0-139.5(CHbenzenering),131.7(CH=CH),134.9(CH=NH),167.6(C=O),169.4(COOH),171.1(CHCO),171.6(C=O).
实施例7
胆固醇-甘氨酸-组氨酸-甲基四氢邻苯二甲酸酐的制备
将甘氨酸(2.9g,38.8mmol)和对甲苯磺酸(8g,46.5mmol)溶于350mL甲苯中,回流1h。加入胆固醇(15g,38.8mmol)回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(100mL×2),水洗涤(100mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体胆固醇-甘氨酸(Chol-Gly)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),DCC(10.3g,49.9mmol)和NHS(2.9g,25.2mmol)溶于100mL DMF中,室温搅拌3h;将Chol-Gly(7.4g,16.8mmol)加入上述混合溶液中,室温搅拌12h。滤去DCU,加入300ml二氯甲烷,水洗(100mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体10g。将上述得到的白色粉末状固体溶解在15mL三氟醋酸和15mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到胆固醇-甘氨酸-组氨酸(Chol-Gly-His(Tos))。将Chol-Gly-His(Tos)(5.4g,6.8mmol),甲基四氢邻苯二甲酸酐(11g,6.8mmol)和三乙胺(0.7g,7.5mmol)溶于40mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(20mL×2),水洗涤(20mL×1),无水硫酸钠干燥有机层,浓缩后,乙醇(80mL)重结晶,得到白色粉末状固体Chol-Gly-His(Tos)-MT HPA。取上述白色粉末状固体(2.1g,2.08mmol)和HOBt(3.4g,24.9mmol)溶解在35mL四氢呋喃中,室温反应5h,反应液浓缩,二氯甲烷/甲醇柱层析,得到白色粉末状固体,胆固醇-甘氨酸-组氨酸-甲基四氢邻苯二甲酸酐(Chol-Gly-His-MTHPA,0.8g,48.1%)。
1H-NMR(CDCl3,500MHz,δppm):1.01(t,6H,CH3),1.06(t,3H,CH3),1.16(t,3H,CH3),1.25(m,4H,CH2),1.29(m,2H,CH2),1.64(m,CHCH3),1.47(m,1H,CHCH3),1.6,1.35(m,4H,CH2),1.4(m,1H,CH),1.24,1.49(m,2H,CH2),1.27,1.52(m,2H,CH2),1.26(m,3H,CH3),1.38,1.13(m,2H,CH2),1.4,1.65(m,2H,CH2),1.79,2.04(m,2H,CH2),2.08,2.33(m,2H,CH2),3.99(s,1H,CH-O),5.37(s,1H,C=CH),1.71(t,3H,CH3),2.74(s,1H,CHCOOH),2.91(s,1H,CHCO),2.08,2.33(m,4H,CH2CH2),3.04,3.29(m,2H,CHCH2),4.16(s,1H,CHNH),4.92(s,1H,CHNH),7.83(d,1H,CH2C=CH),8.18(d,1H,N=CH).
13C-NMR(CDCl3+CD3OD,75MHz,δppm):19.4(CH3),20.7(CH3),23.1(CH3),23.2(CH3),24.7(CH2),26.8(CH2),27.3(CH2),28.2(CHCH3),28.5(CH2),30.0(CH2),30.2(CH2),30.3(CH2C=CH),30.6
(CH2),31.9(CH2),35.8(CHCH3),36.1(CH2),37.2(CH2),37.5(C-CH3),39.9(CH2),38.6(CH2),39.3(CHCO),41.1(CH2NH),42.4(CHCOOH),44.0(C-CH),50.8(CH),53.3(CHNH),58.3(CH),56.5(CH),73.9(CH-O),119.6(C=CH),121.9(CH=C),123.4(C=CH),131.7(CH=CH),134.9(CH=NH),133.5(CH=N),134.0(CH=C-CH3),135.5(C=CH),140.9(C=CH),169.6(C=O),172.1(CONH),175.1(CONH),178.5(COOH).
实施例8
正十二醇-亮氨酸-组氨酸-四氢邻苯二甲酸酐的制备
将亮氨酸(2.9g,22.1mmol)和对甲苯磺酸(4.6g,26.6mmol)溶于100mL甲苯中,回流1h。加入正十二醇(4.1g,22.1mmol)回流12h。反应结束后,减压蒸馏去除甲苯。浓缩物用适量二氯甲烷溶解,5%碳酸氢钠溶液洗涤(30mL×2),水洗涤(30mL×1),有机层无水硫酸钠干燥后浓缩,甲醇重结晶,得到白色粉末状固体正十二醇-亮氨酸(DO-Leu)。将Boc-L-His(Tos)-OH(6.9g,16.8mmol),DCC(10.3g,49.9mmol)和NHS(2.9g,25.2mmol)溶于100mL DMF中,室温搅拌3h;将DO-Leu(5.0g,16.8mmol)加入上述混合溶液中,室温搅拌12h。滤去DCU,加入150ml二氯甲烷,水洗(60mL×3)除DMF,干燥二氯甲烷层,浓缩物用甲醇重结晶,得到白色粉末状固体(6.3g,54.1%)。将上述得到的白色粉末状固体溶解在10mL三氟醋酸和10mL二氯甲烷混合溶液中,室温搅拌4h;反应结束后,加入5%碳酸氢钠溶液调pH值至中性,收集有机层,无水硫酸钠干燥后浓缩,得到正十二醇-亮氨酸-组氨酸(DO-Leu-L-His(Tos))。将DO-Leu-L-His(Tos)(4.0g,6.8mmol),四氢邻苯二甲酸酐(1.03g,6.8mmol)和三乙胺(0.7g,7.5mmol)溶于25mL氯仿中,室温搅拌15h。反应结束后,饱和食盐水洗涤(10mL×2),水洗涤(10mL×1),无水硫酸钠干燥有机层,浓缩后,乙醇(45mL)重结晶,得到白色粉末状固体DO-Leu-L-His (Tos)-THPA。取上述白色粉末状固体(2.1g,2.7mmol)和HCOONH4(0.5g,8.0mmol)加热溶解在40mL四氢呋喃中,加入钯/碳(0.2g),50℃条件下反应5h,抽滤除去钯/碳,浓缩反应液,二氯甲烷/甲醇柱层析,得到白色粉末状固体,正十二醇-苯丙氨酸-组氨酸-邻苯二甲酸酐(DO-Leu-L-His-THPA,0.3g,25.4%)。
1H-NMR(CDCl3,500MHz,δppm):0.96(t,3H,CH3),1.01(t,6H,CH3),1.29(m,18H,CH2),1.57(m,2H,CH2),4.08(m,2H,CH2),1.83(s,1H,CH-CH3),1.86(m,2H,CHCH2),2.08,2.33(m,4H,CH2),2.74(s,1H,CHCOOH),2.91(s,1H,CHCO),3.04,3.29(m,2H,CHCH2),4.42(s,1H,CHNH),4.53(s,1H,CHNH),5.59(m,2H,CH=CH),7.83(d,1H,CH2C=CH),8.18(d,1H,N=CH).
13C-NMR(CDCl3+CD3OD,75MHz,δppm):14.1(CH3),22.5(CH-CH3),22.8(CH2)22.9(CH3),24.3(CH2CH2NH),25.9(CH2),26.0(CH2),27.3(CH2),29.0(CHCH2),29.1(CH2),29.4(CH2),29.7(CH2),31.9(CH2),37.1(CH2NH),39.0(CHCO),40.6(CHCH2),44.9(CHCOOH),50.1(CHNH),54.2(CONH),65.3(CH2-O),126.1(CH=CH),131.7(CH=CH),134.9(CH=NH),158.0(C=NH),171.6(C=O),171.1(C=O),175.1(C=O),178.5(COOH).
实施例9
1,5-十八醇-L-谷氨酸-组氨酸-丁二酸酐寡肽两性脂质体与表面电位的反转
采用薄膜分散法,将大豆磷脂(PC)与SA2-Glu-His-Suc(SHG2C18)分别以质量比5∶1和2∶1溶解在氯仿和甲醇的混合溶液中,40℃旋干成膜,抽真空过夜,加入纯化水,37℃水合30分钟后,探针式超声30min,过0.45和0.22μm滤膜,得SA2-Glu-His-Suc脂质体(SHG2C18-L),质量比5∶1的粒径为114.9nm,质量比2∶1的粒径为140.7nm。在pH7.4、pH6.5、pH5.5和pH4.5缓冲液中的Zeta电位(Brookhaven粒度仪)见表1,结果表明不同质量比的SHG2C18-L能够发生电荷反转,从表面负电荷到正电荷。
表1脂质体SHG2C18-L在不同pH下的表面电位.
实施例10
1,5-十八醇-L-谷氨酸-组氨酸-六氢苯酐寡肽两性脂质体的制备与表面电位的反转
采用薄膜分散法,将大豆磷脂(PC)与SA2-Glu-His-HHPA(HHG2C18)分别以质量比2∶1、3∶1、4∶1和5∶1溶解在氯仿中,40℃旋干成膜,抽真空过夜,加入纯化水,37℃水合30分钟后,探针式超声30min,过0.45和0.22μm滤膜,得SA2-Glu-His-HHPA脂质体(HHG2C18-L)。在pH7.4、pH6.5、pH5.5和pH4.5缓冲液中的粒径和Zeta电位(Brookhaven粒度仪)见表2,结果表明不同质量比的SHG2C18-L能够发生电荷反转,从表面负电荷到正电荷。
表2脂质体HHG2C18-L在不同pH下的粒径与表面电位.
实施例11
1,5-十八醇-L-谷氨酸-组氨酸-柠糠酸酐寡肽两性脂质体的制备与表面电位的反转
采用薄膜分散法,将大豆磷脂(PC)与SA2-Glu-His-CTA(CHG2C18)分别以质量比3∶1溶解在氯仿中,40℃旋干成膜,抽真空过夜,加入纯化水,37℃水合30分钟后,探针式超声30min,过0.45和0.22μm滤膜,得SA2-Glu-His-CTA脂质体(CHG2C18-L),粒径为186.4nm。在pH7.4、pH6.5、pH5.5和pH4.5缓冲液中的粒径和Zeta电位(Brookhaven粒度仪)见表3,结果表面不同质量比的CHG2C18-L能够发生电荷反转,从表面负电荷到正电荷。
表3脂质体CHG2C18-L在不同pH下的电位.
实施例12
将制备的HHG2C18-L溶液,用0.3M的NaOH将pH调至10.0,之后分别用0.05M和0.01M盐酸滴定至pH 3.0,以大豆磷脂脂质体为对照,记录所用盐酸的体积。结果见图1,表明HHG2C18-L由于组氨酸的作用,具有很强的缓冲能力,在酸性的溶酶体环境下能够发生质子海绵作用,达到溶酶体逃逸。
实施例13
寡肽两性离子脂质体包埋抗肾肿瘤药物坦西莫斯的制备
采用薄膜分散法,将3mg药物坦西莫斯、90mg大豆磷脂(PC),30mg 1,5-十八醇-L-谷氨酸-组氨酸-六氢苯酐(SA2-Glu-His-HHPA,HHG2C18)10mg胆固醇溶于氯仿中,40℃旋干成膜,抽真空过夜,加入纯化水,37℃水合30分钟后,探针式超声30min,过0.45和0.22μm滤膜,得坦西莫斯寡肽两性离子脂质体,包封率为92.34%,在在pH7.4、pH6.5、pH5.5和pH4.5缓冲液中的Zeta电位(Brookhaven粒度仪)见表4,结果表明载药HHG2C18脂质体能够发生电荷反转,从表面负电荷到正电荷。以10%(w/v)蔗糖为动感保护剂,将冷冻干燥的脂质体在4℃贮存1个月后,加入5ml注射用水重组得到的坦西莫斯脂质体包封率为91.89%,粒径没有显著性变化,且仍具有电荷反转能力,见表5。以5%葡萄糖或0.9%氯化钠注射液稀释后12小时无沉淀析出。
表4载药脂质体和空白脂质体在不同pH下的表面电位
表5载药脂质体载冻干前后在不同pH下粒径与电位的变化
实施例14
将大豆磷脂、胆固醇和二油酰基-N,N,N-三甲胺丙烷(1,2-dioleoyl-3-trimethylammo-niumpropane,DOTAP)以6∶3∶2(w/w)在氯仿中溶解,旋转蒸发15分钟,使其均匀成膜,加入5ml水,37℃下水合30min;探头超声,过0.22um滤膜。粒径为90nm,表面电位为30mv。
将总脂质浓度6mg/ml的脂质体溶液与10%(寡肽两性离子脂质:脂质体,w/w)的1,5-十八醇-L-谷氨酸-赖氨酸-丁二酸酐溶液以体积比1∶1孵化。50℃下孵化4h后,磷脂与材料的终浓度:2mg/ml。修饰后的粒径为110nm,,表面电位为-12.2mv。
实施例15
细胞毒性试验
由于市售坦西莫斯制剂中含有一定量的表面活性剂聚乙二醇400(PEG-400)和吐温80(Tween80),这些表面活性剂导致了一些不良反应,通过细胞实验比较了脂质体和这些表面活性剂的细胞毒性。配制一系列相同浓度的空白寡肽两性离子脂质体、空白脂质体、聚乙二醇400、吐温80和聚乙二醇400与吐温80(质量比为1∶1)的不完全培养基溶液。将对数生长期L02(人源肝正常细胞)细胞按1×105/mL接种到96孔培养板上,接种后培养24小时后,吸弃培养液,按一定顺序分别向每孔中加入上述各个浓度的上述4种供试液各200μL,放入37℃的5%CO2恒温培养箱中培养24小时后,向每孔中加入20μL的5mg/mL的MTT溶液,放入培养箱中。4小时后,吸弃孔中所有溶液,每孔中加入150μL N,N-二甲基亚砜,于酶联免疫检测仪测定吸收度,测定波长为570nm,求算细胞存活率。
细胞存活率=(1-(A对照-A)/(A对照-A0)×100%
A对照:含细胞孔的空白不完全培养基的吸收值
A:含细胞孔的供试液的吸收值
A0:不含细胞孔的空白不完全培养基的吸收值
Claims (9)
2.一种空白脂质体,含脂质体基质和权利要求1的脂质衍生物。
3.权利要求2的空白脂质体,其中脂质体基质为磷脂。
4.权利要求3的空白脂质体,其中脂质体基质还含胆固醇。
5.一种药物脂质体,含药物、脂质体基质和权利要求1的脂质衍生物。
6.权利要求5的药物脂质体,其中脂质体基质为磷脂。
7.权利要求5的药物脂质体,其中药物为坦西莫斯、喜树碱类、紫杉醇、多西紫杉醇、藤黄酸、环孢素A、足叶乙苷、替尼泊甙、依托泊甙、长春酰胺、尼莫地平、硝苯地平、尼群地平、阿霉素、柔红霉素、丝裂霉素、甲氨喋呤、冬凌草素、藤黄酸、三尖杉酯碱、高三尖杉酯碱、灯盏花素、银杏内酯、水飞蓟素或靛玉红。
8.权利要求5的药物脂质体,其中药物和脂质衍生物的药载质量比为1:40~1:60。
9.权利要求1的脂质衍生物用作脂质体修饰剂的用途。
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