CN116063207A - 含n-氧化三级胺基团的双亲性脂质、脂质体递药系统及应用 - Google Patents
含n-氧化三级胺基团的双亲性脂质、脂质体递药系统及应用 Download PDFInfo
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- CN116063207A CN116063207A CN202211658103.8A CN202211658103A CN116063207A CN 116063207 A CN116063207 A CN 116063207A CN 202211658103 A CN202211658103 A CN 202211658103A CN 116063207 A CN116063207 A CN 116063207A
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- tertiary amine
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- oxide
- liposome
- amphiphilic lipid
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Abstract
Description
技术领域
本发明涉及医药技术领域,特别涉及一种含N-氧化三级胺基团的双亲性脂质、脂质体递药系统及应用。
背景技术
脂质体是一种磷脂双层囊泡,由一个或多个同心磷脂双层包裹亲水核构成(Riley等,Nature Reviews Drug Discovery,2019,18,175-196)。脂质体结构多样、生物相容性好,无毒且非免疫原性,是优良的药物递送载体(Shah等,Advanced Drug DeliveryReviews,2020,156,4-22)。脂质体纳米药物广泛应用于多种疾病的治疗,如Doxil(脂质体阿霉素)和Onivyde(脂质体伊利替康)。尽管脂质体制剂可以防止药物泄露和快速清除,但越来越多的证据表明,由传统磷脂制得的脂质体在靶组织的蓄积不足,渗透性较差,因而治疗效果受限(Zhou等,Biomaterials,2020,240,119902)。设计优化脂质体制剂以克服人体内复杂的生理或病理屏障,特别是药物输送过程中限制靶组织蓄积或渗透的步骤,仍然是一个巨大的挑战。
“主动跨细胞转运型”纳米药物能够利用细胞自身的转胞运机制,让细胞在不断吞噬药物的同时将其中一部分吐出来,使药物能够从血管传递出去,到达每个靶细胞,显著提高了药物在靶组织的蓄积和渗透(Zhou等,Nature Nanotechnology,2019,14,799)。设计“主动跨细胞转运型”脂质体递药系统,改善传统脂质体制剂在靶组织的蓄积和渗透,对于提升脂质体递药系统的疗效具有重要的意义。
近期研究表明,N-氧化叔胺基团衍生的纳米药物能够有效诱导肿瘤内皮细胞和肿瘤细胞的主动跨细胞转运,这是因为这类材料与细胞膜上的磷脂具有良好的亲和力,很容易地被吸附到细胞表面继而被内吞,且能够靶向细胞的高尔基体从而被细胞打包外送出去(Chen等,Nature Biomedical Engineering,2021,5,1019)。此外,N-氧化叔胺基团的结构简单、多样,通过对结构的调节可以获得各种疾病治疗所需的含N-氧化叔胺基团的脂质。因此,开发含N-氧化叔胺基团的脂质并将其应用于脂质体递药系统具有很大的临床转化潜力。
发明内容
本发明的目的在于提供一种含N-氧化三级胺基团的双亲性脂质、脂质体递药系统及应用,该类双亲性脂质能够代替全部或部分传统脂质体制剂中的磷脂成分,基于它的脂质体递药系统显著延长药物的血液循环时间,增加药物在靶组织中的蓄积和渗透,因而具有显著提升的疗效。
本发明解决其技术问题所采用的技术方案是:
一种含N-氧化三级胺基团的双亲性脂质,所述双亲性脂质为式Ⅰ所示的化合物,
其中,R、R′各独立的选自C1-C4烷基,X为疏水单元。
作为优选,疏水单元X为一条疏水脂肪链时,所述双亲性脂质为式Ⅱ或式Ⅲ所示的化合物:
其中,R1为C5-32烷基、胆固醇、胆酸中的一种或几种;Y为酯基、碳酸酯基、酰胺基、胺基甲酸酯、脲基、醚基、砜基、亚砜基、芳香基中的一种或几种。C5-32烷基如戊基、辛基、癸基、十二烷基、十八烷基等。
作为优选,含一条疏水脂肪链的双亲性脂质包括以下所示化合物:
作为优选,疏水单元X含两条疏水链。
进一步地,含两条疏水链的双亲性脂质为式Ⅳ、式Ⅴ、式Ⅵ或式Ⅶ所示的化合物:
其中,R1为C5-32烷基、胆固醇、胆酸中的一种或几种;R2为C5-32烷基、胆固醇、胆酸中的一种或几种;Y为酯基、碳酸酯基、酰胺基、胺基甲酸酯、脲基、醚基、砜基、亚砜基、芳香基中的一种或几种;Z为N-氧化叔胺结构单元。
作为优选,所述N-氧化叔胺结构单元选自以下之一:
其中,R3和R4分别独立的选自C1-C4烷基、取代烷基、芳香基、取代芳香基中的一种或几种;R5选自C1-C4烷基、取代烷基、芳香基、取代芳香基、杂原子基团中的一种或几种;所述杂原子基团包括卤素、羟基、氰基。
本发明中,取代烷基包括羟烷基、卤代烷基、硝基烷基、氰基烷基、烷基苯等;芳香基包括苯、萘、蒽、芴、吡啶、苯并噻吩、苯并呋喃、吲哚、喹啉等;取代芳香基的取代基包括羟基、卤素、硝基、氰基、萘基等。
作为优选,所述N-氧化叔胺结构单元上的取代基为二甲基或二乙基,由此制备的脂质体具有较小的粒径。
进一步优选的,所述双亲性脂质是以2,2-二羟甲基丙酸为连接单元合成的N-氧化-N,N-二甲基或N-氧化-N,N-二乙基的双亲性脂质,具有合成可控且简便且能够降解,其结构式为:
其中,R1为C5-32烷基(脂肪酸链)。
进一步优选的,所述R1为C18烷基,所述双亲性脂质结构式为:
一种由含N-氧化三级胺基团的双亲性脂质制备的脂质体,所述脂质体由含N-氧化三级胺基团的双亲性脂质中的一种或多种制成;
或由含N-氧化三级胺基团的双亲性脂质中的一种或多种与不含N-氧化三级胺基团的脂质制成。
含N-氧化三级胺基团的双亲性脂质与不含N-氧化三级胺基团的脂质的质量比为1:0-10。
含N-氧化三级胺基团的双亲性脂质可代替传统脂质体制剂中的磷脂成分,基于它的脂质体显著延长药物的血液循环时间,增加药物在靶组织中的蓄积和瘤内渗透。
进一步优选的,不含N-氧化三级胺基团的脂质选自胆固醇、磷脂、维生素E聚乙二醇琥珀酸酯、含阳离子脂质中的一种或多种。含阳离子脂质包括DOTAP(溴化三甲基-2,3-二油酰氧基丙基铵)、DOTMA(氯化三甲基-2,3-二油烯氧基丙基铵)、DC-Chol(3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇)中的一种或多种。
一种脂质体递药系统,包括所述的脂质体和药物,所述脂质体作为载体包载药物。
作为优选,所述药物与脂质体的质量比为0.01-0.5:1,所述药物包括但不限于抗肿瘤药物。
所述抗肿瘤药物为阿霉素、表阿霉素、喜树碱、7-乙基-10-羟基喜树碱、伊利替康、紫杉醇、奥沙利铂、吉西他滨、姜黄素中的一种或多种。
含N-氧化三级胺基团的双亲性脂质在制备脂质体递药系统中的应用。
本发明提供了含N-氧化三级胺基团的双亲性脂质制备的脂质体的制备方法,包括以下步骤:
第一步:脂质体膜的制备:将双亲性脂质,胆固醇和/或维生素E聚乙二醇琥珀酸酯溶于溶剂中,30~45℃浓缩成膜;
第二步:水化:在制得的脂质体膜中加入PBS缓冲液,4~50℃水化12~48h;
载药:对于疏水性药物,在第一步中将药物与脂质一起溶于溶剂中制备脂质体膜;对于亲水性药物,在第二步中将药物溶解在PBS缓冲液中,一起加入制得的脂质体膜中即可。
所述组分中胆固醇与双亲性脂质的质量比为0-1:1,维生素E聚乙二醇琥珀酸酯与双亲性脂质的质量比为0-1:1。
所用溶剂为二氯甲烷、三氯甲烷、四氢呋喃、甲醇、乙醇中的一种或多种。
本发明的有益效果是:
本发明将含N-氧化三级胺基团的双亲性脂质应用于药物输送领域,可为该领域提供一类优良的候选材料。不同于本领域内已有的脂质体只能发挥延长的其血液循环时间的功能,本发明含N-氧化三级胺基团的双亲性脂质中,N-氧化三级胺基团的超亲水的特性显著延长血液循环时间的同时,能够与靶组织的血管内皮细胞和靶细胞的磷脂相互作用,有效诱导它们的跨细胞转运,从而有效地从病灶血管渗出进入靶组织,并在靶细胞间通过转胞运进行在组织内主动传递,从而显著增强疗效。
进一步地,不同于本领域中的传统脂质体,N-氧化三级胺基脂质体进入细胞的途径不同,并在进入细胞后高度选择性地在细胞的内质网或高尔基体富集,避免溶酶体对药物的破坏,提高细胞对药物的利用率。
本发明的N-氧化三级胺基脂质体包载药物的方法简单高效,采用本领域常用的方法即可。
含N-氧化三级胺基团的双亲性脂质结构清晰,合成方法操作简单,采用酰化、酯化、氧化共三步简单的化学反应即可制备得到。通过调节疏水端脂肪链与亲水端N-氧化三级胺的结构,可以获得适用于各种生理疾病治疗所需的脂质分子。
附图说明
图1为实施例1中18-BHP-ODMA的合成反应;
图2为实施例1中18-BHP-ODMA和18-BHP-ODEA的核磁氢谱表征;
图3为实施例1中18-BHP-ODMA的MALDI-TOF-MS质谱;
图4为实施例1中18-BHP-ODEA的MALDI-TOF-MS质谱;
图5为实施例2中脂质体的粒径分布图谱;
图6为测试例1中脂质体在不同介质中孵育24小时后的粒径;
图7为测试例1中脂质体在4℃冰箱中储存不同天数后的粒径变化;
图8为测试例2中脂质体制剂的细胞毒性试验结果;
图9为测试例3中DiIODML和DiIODEL与内质网染料在HepG2细胞系中的对比图;
图10为测试例3中DiIODML和DiIODEL与高尔基体染料在HepG2细胞系中的对比图;
图11为测试例4中DiIODML和DiIODEL的跨细胞转运实验结果;
图12为测试例5中DiRODML或DiRODEL注射48小时候后,小鼠血液的活体成像照片;
图13为测试例5中DiRODML或DiRODEL注射48小时候后,小鼠主要组织的活体成像照片;
图14为测试例6中脂质体制剂对HepG2荷瘤小鼠肿瘤模型的抑瘤曲线;
图15为测试例6中HepG2荷瘤小鼠的体重变化曲线。
具体实施方式
下面通过具体实施例,对本发明的技术方案作进一步的具体说明。
本发明中,若非特指,所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法,如无特别说明,均为本领域的常规方法。本发明化合物可以通过本领域技术人员熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其它化合物合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式,也可以可经市售获得。优选的实施方式包括但不限于本发明的实施例。对本领域技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进是显而易见的。
实施例1:18-BHP-ODMA和18-BHP-ODEA的合成(图1)
1.1:18-BHP的合成
2,2-二羟甲基丙酸(BHP,10.05g,75mmol),4-二甲氨基吡啶(DMAP,0.3g,2.5mmol)和三乙胺(23.6mL,170mmol)加入到盛有200mL无水四氢呋喃(THF)圆底烧瓶中。随后在冰浴条件下,缓慢滴加硬酯酰氯(49.98g,165mmol),滴加完毕后恢复至室温并继续搅拌24小时。待反应完全后,旋蒸除去体系内的THF,加入250mL二氯甲烷溶解残余物,并用1M稀盐酸(80mL×2),去离子水(80mL×3),饱和食盐水(80mL×3)洗涤,用无水硫酸镁干燥,旋蒸除去所有溶剂,以丙酮为溶剂重结晶得白色固体,置于真空箱中过夜,得到白色固体即为产物18-BHP(49.64g,产率89.7%)。
1.2:18-BHP-DMA的合成
18-BHP(3g,4mmol),DMAP(49mg,0.4mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC,1.53g,8mmol)置于圆底烧瓶中,加入50mL二氯甲烷搅拌15min后,加入N,N-二甲基乙醇胺(357mg,4mmol)并继续搅拌过夜。待反应完全后,将反应液用去离子水(50mL×2),饱和食盐水(50mL×2)洗涤,用无水硫酸镁干燥,旋蒸浓缩后使用硅胶进行柱层析分离,洗脱流动相为含有50%乙酸乙酯的正己烷溶液,所得洗脱液旋干浓缩,置于真空箱中过夜,得到白色固体即为产物18-BHP-DMA(1.93g,产率58.1%)。
1.3:18-BHP-DEA的合成
18-BHP(3g,4mmol),DMAP(49mg,0.4mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC,1.53g,8mmol)置于圆底烧瓶中,加入50mL二氯甲烷搅拌15min后,加入N,N-二乙基乙醇胺(468mg,4mmol)并继续搅拌过夜。待反应完全后,将反应液用去离子水(50mL×2),饱和食盐水(50mL×2)洗涤,用无水硫酸镁干燥,旋蒸浓缩后使用硅胶进行柱层析分离,洗脱流动相为含有30%乙酸乙酯的正己烷溶液,所得洗脱液旋干浓缩,置于真空箱中过夜,得到白色固体即为产物18-BHP-DEA(2.11g,产率61.5%)。
1.4:18-BHP-ODMA或18-BHP-ODEA的合成。
将18-BHP-DMA(1.11g,1.5mmol)或18-BHP-DEA(1.15g,1.5mmol)加入盛有5mL二氯甲烷的圆底烧瓶中,随后将间氯过氧苯甲酸(0.31g,1.8mmol)溶于5mL二氯甲烷,于冰浴条件下缓慢滴加至上述溶液,滴加完毕后撤去冰浴并继续反应3h。待反应完全后,将反应液用碱性氧化铝进行柱层析分离,洗脱流动相为含有10%甲醇的二氯甲烷溶液,所得洗脱液旋干浓缩,置于真空箱中过夜,得到白色固体即为产物18-BHP-ODMA(1.04g,92.0%)或18-BHP-ODEA(1.12g,95.1%)。
18-BHP直接与2-(N-氧化-N,N-二甲基)乙醇或2-(N-氧化-N,N-二乙基)乙醇2-反应,也可以制备18-BHP-ODMA或18-BHP-ODEA。18-BHP-ODMA或18-BHP-ODEA的核磁氢谱或MALDI-TOF-MS质谱如图2-4所示。
将1.1中的硬酯酰氯替换为相同摩尔量的棕榈酰氯、肉豆蔻酰氯或月桂酰氯可得到碳链长度为16,14,或12的中间体X-BHP(X代表碳链长度);接着按照1.2或1.3的步骤,将18-BHP替换为相同摩尔量的X-BHP,和/或将1.2或1.3中的乙醇胺替换为相同摩尔量的N,N-二丁基乙醇胺(DBU)或4-(2-羟乙基)吡啶(PY),最后按照1.4的步骤氧化,可得到不同碳链长度,不同N-氧化叔胺基团的脂质X-BHP-ODMA,X-BHP-ODEA,X-BHP-ODBU或X-BHP-OPY。
实施例2:N-氧化叔胺基脂质体的制备(由含N-氧化三级胺基团的双亲性脂质制备的脂质体)
称取10mg18-BHP-ODMA或18-BHP-ODEA,2.5mg胆固醇和/或2.5mg维生素E聚乙二醇琥珀酸酯置于烧瓶,加入9mL三氯甲烷和1mL甲醇,超声溶解后进行减压旋蒸,在烧瓶壁上形成脂质干膜。之后加入5mL PBS缓冲液,室温下水化1h。最后将溶液过滤膜(200nm)即得空白的N-氧化叔胺基脂质体,命名为ODML或ODEL。
将18-BHP-ODMA或18-BHP-ODEA替换为实施例1中其它含N-氧化叔胺基团脂质(相同摩尔量),可得到其它的N-氧化叔胺基脂质体。
实施例3:荧光标记N-氧化叔胺基脂质体的制备
称取10mg18-BHP-ODMA或18-BHP-ODEA,2.5mg胆固醇和/或2.5mg维生素E聚乙二醇琥珀酸酯、100μg DiI或DiR置于烧瓶,加入9mL三氯甲烷和1mL甲醇,超声溶解后进行减压旋蒸,在烧瓶壁上形成脂质干膜。之后加入0.5mL制备好的7-乙基-10-羟基喜树碱/伊利替康纳米粒与4.5mL PBS缓冲液,室温下水化1h,通过葡聚糖凝胶柱分离除去游离的荧光分子,即得DiI或DiR标记的氮氧化物脂质体DiIODML,DiIODEL,DiRODML或DiRODEL。
实施例4:装载7-乙基-10-羟基喜树碱/伊利替康纳米粒N-氧化叔胺基脂质体的制备7-乙基-10-羟基喜树碱/伊利替康纳米粒(SC)的制备参照文献(Hu等,Journal ofControlled release,2015,220,175-179)进行。
称取10mg18-BHP-ODMA或18-BHP-ODEA,2.5mg胆固醇和/或2.5mg维生素E聚乙二醇琥珀酸酯置于烧瓶,加入9mL三氯甲烷和1mL甲醇,超声溶解后进行减压旋蒸,在烧瓶壁上形成脂质干膜。之后加入0.5mL制备好的7-乙基-10-羟基喜树碱/伊利替康纳米粒与4.5mLPBS缓冲液,室温下水化1h,通过葡聚糖凝胶柱分离除去未装载的7-乙基-10-羟基喜树碱/伊利替康纳米粒,即得装载7-乙基-10-羟基喜树碱/伊利替康的N-氧化叔胺基脂质体,命名为ODMLSC或ODELSC。
ODML,ODEL,ODMLSC,ODELSC的粒径分布谱图如图5所示。
测试例1:脂质体制剂的稳定性测试
吸取1mL实施例4的脂质体溶液分别至4mL去离子水、PBS缓冲液、HEPES缓冲液,DMEM培养基或胎牛血清(FBS),在37℃下以100rpm的速度振荡培养24h,随后用动态光散射粒度分析仪(DLS)测定脂质体的粒径。而对于长期稳定性的测试,将脂质体储存在4℃冰箱,在设定时间点取样,并通过DLS测定脂质体的粒径。
测试结果如图6-7所示,氮氧化物脂质体在去离子水、PBS缓冲液、HEPES缓冲液,DMEM培养基或FBS等介质中具有良好的稳定性,且在长期储存过程中维持稳定。
测试例2:细胞毒性实验
将细胞以5000个/孔培养在96孔板中,每孔加入100μL培养基,于5% CO2浓度和95%湿度的37℃恒温培养箱中培养24h。向每个孔加入100μL不同浓度的药物,包括SC,ODMLSC或ODELSC,使每个孔中药物分子终浓度为实验设计值,而空白组则加入100μL的新鲜培养基。继续培养48h后,于1100rpm离心6min后弃去每个孔中的培养基,加入100μL的MTT工作液,继续培养3h。其后于3300rpm离心5min,弃尽每孔中的MTT工作液,加入100μL的DMSO,震荡5min,使每孔中的结晶全部溶解。最终用酶标仪测试样品在562nm处的吸光度。每一组数据均为同一种样品三次独立实验的平均值。
测试结果如图8所示,N-氧化叔胺基脂质体本身在细胞水平没有显著毒性,具有良好的生物相容性,适合用作药物输送载体。值得注意的是,ODMLSC或ODELSC的细胞毒性远大于SC本身,其IC50值远小于SC(表1),证明N-氧化叔胺基脂质体能够增加荷载药物对细胞的毒性。
表1:SC,ODMLSC,或ODELSC在不同细胞系的IC50值(单位:微克/毫升)
HepG2 | HCT116 | BxPC3 | |
SC | 0.98±0.27 | 5.76±0.31 | 0.40±0.02 |
ODMLSC | 0.17±0.01 | 0.54±0.08 | 0.09±0.01 |
ODELSC | 0.22±0.03 | 0.74±0.12 | 0.10±0.01 |
。
测试例3:N-氧化叔胺基脂质体的亚细胞分布
在共聚焦培养皿中铺入10万HepG2细胞,过夜贴壁后更换为新鲜培养基,加入0.2μL内质网或高尔基体荧光染料,孵育30min,随后加入细胞核荧光染料Hoechst后继续孵育15min,最后加入DiIODML或DiIODEL,使培养基中DiI的终浓度为0.5μg/mL。孵育60min后,利用激光共聚焦显微镜拍照并利用imageJ计算脂质体与细胞微粒体的重叠率。
测试结果如图9-10所示,在HepG2细胞中,DiIODML或DiIODEL与内质网或高尔基体在细胞内的分布几乎完全一致,共定位程度均高于60%,证明N-氧化叔胺基脂质体能够靶向细胞的内质网或高尔基体。
测试例4:脂质体制剂的跨细胞转运
在共聚焦培养皿中铺入10万HepG2细胞,过夜贴壁后更换为新鲜培养基,加入DiIODML或DiIODEL,使培养基中DiI的终浓度为0.5μg/mL,培养6h后,用PBS洗涤,并用激光共聚焦显微镜拍照。随后加入0.8mL新鲜培养基培养12h,收集培养基用于培养第二批细胞12h,随后用PBS(含0.5mg/mL肝素)洗涤,并用激光共聚焦显微镜成像,之后将该过程继续重复两次。
测试结果如图11所示,在第一批皿DiIODML或DiIODEL处理的细胞中可以观察到很强的DiI荧光信号,随后部分被细胞吐出,并随后被第二批皿中的细胞吸收,这种转胞运持续到第四批皿中,仍能观察到微弱的荧光信号,证明N-氧化叔胺基脂质体可以有效诱导跨细胞转运。
测试例5:N-氧化叔胺基脂质体制剂的血浆清除及组织分布
将荷有HepG2皮下瘤(~70mm3)的雌性BALB/c裸鼠随机分为三组,每组3只,通过静脉注射DiR,DiRODML或DiRODEL。24小时后通过小鼠眼眶静脉取血,各取500μL于小动物活体成像仪检测血样的荧光强度。之后将小鼠解剖,取出心、肝、脾、肺、肾、肠、肿瘤等组织,用小动物活体成像仪检测各组织的荧光强度。
测试结果如图12-13所示,DiR组的小鼠血液或组织中几乎观察不到荧光信号的存在,而在N-氧化叔胺基脂质体组的小鼠血液或组织中可以观察到强烈的DiR荧光信号。定量统计显示N-氧化叔胺基脂质体组小鼠血液、心、肝、脾、肺、肾、肠、肿瘤中DiR的信号强度远远高于DiR组,证明N-氧化叔胺基脂质体可以延长荷载药物的血液循环时间,增加药物在肿瘤组织的蓄积。
测试例6:抗肿瘤活性实验
Balb/c裸鼠皮下注射2×106个CT26肿瘤细胞,待肿瘤长至约70mm3后将小鼠分组,分别为空白对照组,SC组,ODMLSC组或ODELSC组,开始给药,每隔两天(Day0,Day2,Day4,Day6,Day8)进行尾静脉注射,给药剂量为SN38当量10mg/kg,给药周期结束后继续观察小鼠19天。
结果如图14-15所示,图14显示ODMLSC或ODELSC的抗肿瘤效果明显优于SC本身,该组小鼠肿瘤的体积在观察周期内增长缓慢,而SC组的小鼠肿瘤在停止给药后即进入指数生长期。将试验结束当天解剖下的小鼠肿瘤称重,显示SN38/CPT-11的N-氧化叔胺基脂质体的抑瘤率高达90%,远高于SN38/CPT-11纳米粒本身(抑瘤率10%)。图15显示SN38/CPT-11的N-氧化叔胺基脂质体组小鼠体重没有下降的现象,显示出药物的生物安全性高。
本N-氧化叔胺基脂质体结构清晰,合成步骤简单且高效,基于它的脂质体制剂能够显著增加药物的治疗效果,在本领域处于领先水平,具有良好的应用前景。
以上所述的实施例只是本发明的一种较佳的方案,并非对本发明作任何形式上的限制,在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (15)
4.根据权利要求1所述的含N-氧化三级胺基团的双亲性脂质,其特征在于,疏水单元X含两条疏水链。
7.根据权利要求6所述的含N-氧化三级胺基团的双亲性脂质,其特征在于,所述N-氧化叔胺结构单元上的取代基为二甲基或二乙基。
10.一种由含N-氧化三级胺基团的双亲性脂质制备的脂质体,其特征在于,所述脂质体由含N-氧化三级胺基团的双亲性脂质中的一种或多种制成;
或由含N-氧化三级胺基团的双亲性脂质中的一种或多种与不含N-氧化三级胺基团的脂质制成。
11.根据权利要求10所述的脂质体,其特征在于,不含N-氧化三级胺基团的脂质选自胆固醇、磷脂、维生素E聚乙二醇琥珀酸酯、含阳离子脂质中的一种或多种。
12.一种脂质体递药系统,其特征在于,包括权利要求10所述的脂质体和药物,所述脂质体作为载体包载药物。
13.根据权利要求12所述的一种脂质体递药系统,其特征在于,所述药物与脂质体的质量比为0.01-0.5:1,所述药物包括但不限于抗肿瘤药物。
14.根据权利要求13所述的一种脂质体递药系统,其特征在于,所述抗肿瘤药物为阿霉素、表阿霉素、喜树碱、7-乙基-10-羟基喜树碱、伊利替康、紫杉醇、奥沙利铂、吉西他滨、姜黄素中的一种或多种。
15.权利要求1-9任意一项所述的含N-氧化三级胺基团的双亲性脂质在制备脂质体递药系统中的应用。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1096030A (zh) * | 1992-12-09 | 1994-12-07 | 拜尔公司 | 膦酰基羧酸和膦基羧酸的氟化羧酸酯及其用途 |
CN1097762A (zh) * | 1993-01-14 | 1995-01-25 | 拜尔公司 | 含丙烯酸酯和/或甲基丙烯酸酯基团的膦酰基-和膦基羧酸的氟化羧酸酯类及其制备方法和用途 |
CN107519497A (zh) * | 2016-06-21 | 2017-12-29 | 浙江大学 | 含n‑氧化三级胺基团的聚合物作为药物或载体的应用 |
CN109010838A (zh) * | 2017-06-08 | 2018-12-18 | 浙江大学 | 含n-氧化三级胺基团的化合物作为细胞线粒体靶向载体的应用 |
CN109721511A (zh) * | 2019-01-21 | 2019-05-07 | 北京工商大学 | 一种含烷基酯基乙基的双子氧化胺的制备方法 |
CN112851934A (zh) * | 2020-12-29 | 2021-05-28 | 浙江大学杭州国际科创中心 | 一种含N-氧化三级胺基团的聚(β-氨基酯)及其制备方法和应用 |
CN114044741A (zh) * | 2022-01-13 | 2022-02-15 | 北京悦康科创医药科技股份有限公司 | 一种阳离子脂质化合物、包含其的组合物及用途 |
-
2022
- 2022-12-22 CN CN202211658103.8A patent/CN116063207A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1096030A (zh) * | 1992-12-09 | 1994-12-07 | 拜尔公司 | 膦酰基羧酸和膦基羧酸的氟化羧酸酯及其用途 |
CN1097762A (zh) * | 1993-01-14 | 1995-01-25 | 拜尔公司 | 含丙烯酸酯和/或甲基丙烯酸酯基团的膦酰基-和膦基羧酸的氟化羧酸酯类及其制备方法和用途 |
CN107519497A (zh) * | 2016-06-21 | 2017-12-29 | 浙江大学 | 含n‑氧化三级胺基团的聚合物作为药物或载体的应用 |
CN109010838A (zh) * | 2017-06-08 | 2018-12-18 | 浙江大学 | 含n-氧化三级胺基团的化合物作为细胞线粒体靶向载体的应用 |
CN109721511A (zh) * | 2019-01-21 | 2019-05-07 | 北京工商大学 | 一种含烷基酯基乙基的双子氧化胺的制备方法 |
CN112851934A (zh) * | 2020-12-29 | 2021-05-28 | 浙江大学杭州国际科创中心 | 一种含N-氧化三级胺基团的聚(β-氨基酯)及其制备方法和应用 |
CN114044741A (zh) * | 2022-01-13 | 2022-02-15 | 北京悦康科创医药科技股份有限公司 | 一种阳离子脂质化合物、包含其的组合物及用途 |
CN114957027A (zh) * | 2022-01-13 | 2022-08-30 | 北京悦康科创医药科技股份有限公司 | 一种阳离子脂质化合物、包含其的组合物及用途 |
Non-Patent Citations (1)
Title |
---|
XIANG JIAJIA等: ""Multipotent Poly(Tertiary Amine-Oxide) Micelles for Efficient Cancer Drug Delivery"", ADV. SCI., vol. 9, pages 1 - 13 * |
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