CN116554125B - 一种阳离子脂质类似物、其组合物及应用 - Google Patents
一种阳离子脂质类似物、其组合物及应用 Download PDFInfo
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- CN116554125B CN116554125B CN202210101998.9A CN202210101998A CN116554125B CN 116554125 B CN116554125 B CN 116554125B CN 202210101998 A CN202210101998 A CN 202210101998A CN 116554125 B CN116554125 B CN 116554125B
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- cationic lipid
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Classifications
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
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Abstract
本发明属于生物医药技术领域,公开了一种阳离子脂质类似物、其组合物及应用。本发明采用醛类化合物、胺类化合物、羧酸类化合物和异腈化合物为原料,通过Ugi反应合成阳离子脂质类似物;得到的阳离子脂质类似物与固醇、辅助脂质和聚乙二醇脂质衍生物形成脂质纳米颗粒样组合物,该组合物可用于药物输送,包括小分子药物,mRNA、DNA、siRNA等核酸药物,蛋白/多肽类药物,以及mRNA/sgRNA,Cas9/sgRNA等基因编辑复合物;通过不同给药方式实现在动物体内不同器官的mRNA表达,可满足mRNA核酸疗法、核酸疫苗以及基因编辑等的应用需求。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种阳离子脂质类似物、其组合物及应用。
背景技术
脂质体是由磷脂等类脂形成的双分子层的完全封闭的多层囊泡,可包封水溶性和脂溶性两种物质,具有靶向高效、缓释可控和安全无毒的特点。近年来通过利用脂质体以及其类似物递送分子药物的技术越来越成熟,越来越多的研究表明了各种脂质纳米粒在分子药物治疗中的潜力。
按电荷性质,脂质体可分为阳离子脂质体、中性脂质体和阴离子脂质体。其中,阳离子脂质体具有可自然降解、无毒无免疫原性、可重复转染等优点。阳离子脂质体通常是用作基因载体,与DNA或RNA复合,保护其不被灭活或被核酸酶降解,携带基因可转运至特定部位,并且要保证转染过程方便易行,重现性好。通过高基因递送效率的脂质体递送系统可以实现特定基因在生物体内的特定器官适当表达,以实现治疗应用,现有技术中已经开发的基因治疗应用包括核酸治疗、核酸疫苗、蛋白替代治疗、基因编辑等等。特别的,随着核酸疫苗在近年来的快速发展,信使RNA疫苗凭借其制备简易型,高效性与稳定性而更加受到重视。
目前,阳离子脂质颗粒的研究已经多有报道,并且也有商品化的阳离子脂质材料可供选择,如阳离子磷脂DOTAP、可电离的阳离子脂质DLin-MC3,但仍存在体内递送效率不高,阳离子对于生物机体有毒性,体内递送靶向性不强等问题。
鉴于阳离子脂质类似物结构的细微差别就会导致其生物性能发生重大改变,因此,对于体内高转染效率、低毒性和特异靶向性的新型阳离子脂质类似物结构的开发至关重要。
发明内容
本发明的目的在于克服现有技术的不足之处而提供一种阳离子脂质类似物、其组合物及应用。
为实现上述目的,本发明采取的技术方案如下:
第一方面,本发明制备了一种阳离子脂质类似物,其具有如式(I)~式(Ⅴ)任一种所示结构:
式中,m1为独立地选自氢原子、直链烷基、支链烷基、直链烯基、支链烯基、取代炔基、环烷基、苯基、含杂原子芳香基中的至少一种基团;
m2为独立地选自直链烷基、直链烯基、含杂原子直链烷基、含杂原子直链亚烷基、含杂原子支链烷基、含杂原子支链亚烷基、含杂原子环的烷基、含杂原子环的亚烷基、含酯基的烷基、含醚基的烷基中的至少一种基团;
m3为独立地选自直链烷基、直链烯基、环烷基、含杂原子直链烷基、含杂原子支链烷基、含杂原子支链亚烷基、含杂原子环的烷基、含杂原子和芳香环的烷基、含羟基的烷基、含酯基的烷基、含醚基的烷基、含磺酸酯基的烷基中的至少一种基团;
m4为独立地选自直链烷基、支链烷基、直链烯基、支链烯基、直链炔基、含杂原子直链烷基、含杂原子支链烷基、含杂原子环的烷基中的至少一种基团。
本发明采用醛类化合物、胺类化合物、羧酸类化合物和异腈化合物为原料,通过Ugi反应合成阳离子脂质类似物;阳离子脂质类似物体内转染效率高,具有低毒性和特异靶向性,可通过不同给药方式实现在动物体内不同器官的mRNA表达,可满足mRNA核酸疗法、核酸疫苗以及基因编辑等的应用需求。
作为本发明所述的阳离子脂质类似物的优选实施方式,式中,m1为独立地选自 和/或m2为独立地选自/> 和/或m3为独立地选自/> 和/或
m4为独立地选自
优选地,所述m1为 和/或
所述m2为、 和/或
所述m3为 和/或
所述m4为
第二方面,本发明提供了一种所述的阳离子脂质类似物的制备方法,将醛类化合物和胺类化合物加入到有机溶液中,反应10~120min后依次加入羧酸类化合物和异腈化合物,再于4~60℃反应6~72h,分离提纯产物,即成。
优选地,所述醛类化合物、胺类化合物、羧酸类化合物和异腈化合物的摩尔比为(0.1~1.5):(0.1~1.5):(0.1~1.5):(0.1~1.5);进一步地,摩尔比为1:(0.33~1):1:(0.33~1)。
本发明阳离子脂质类似物的反应条件温和,合成工艺简单、稳定性好。
作为本发明所述的阳离子脂质类似物的制备方法的优选实施方式,所述异腈化合物为单官能团异腈化合物、双官能团异腈化合物、三官能团异腈化合物中的一种。
优选地,所述异腈化合物为如下化合物I3~I38中的任一种:
作为本发明所述的阳离子脂质类似物的制备方法的优选实施方式,所述醛类化合物为单官能团醛类化合物中的一种。
优选地,所述醛类化合物为如下化合物A1~A35中的任一种:
作为本发明所述的阳离子脂质类似物的制备方法的优选实施方式,所述胺类化合物为单官能团胺类化合物、双官能团胺类化合物、三官能团胺类化合物中的一种。
作为本发明所述的阳离子脂质类似物的制备方法的优选实施方式,所述胺类化合物为如下化合物R1~R53中的任一种:
作为本发明所述的阳离子脂质类似物的制备方法的优选实施方式,羧酸类化合物为如下化合物C8~C30或S11~S19中的任一种:
第三方面,本发明提供了一种所述的阳离子脂质类似物的组合物,包括所述阳离子脂质类似物和固醇、辅助脂质、聚乙二醇脂质衍生物中的至少一种。
作为本发明所述阳离子脂质类似物的组合物的优选实施方式,所述固醇包括胆固醇、谷固醇(谷甾醇)、豆甾醇(豆固醇)、胆固醇衍生物中的至少一种;所述辅助脂质为非阳离子脂质,更优选地,所述辅助脂质为中性磷脂,进一步地,所述辅助脂质为磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、神经酰胺中的至少一种。
作为本发明所述阳离子脂质类似物的组合物的优选实施方式,所述阳离子脂质类似物、胆固醇、辅助脂质、聚乙二醇脂质衍生物的摩尔比为(20~70):(20~50):(2~30):(0.1~20);优选地,摩尔比为(40~60):(25~45):(5~15):(0.5~5)。
第四方面,本发明提供一种载药纳米颗粒,包括所述的阳离子脂质类似物的组合物和药物。
作为本发明所述载药纳米颗粒的优选实施方式,所述药物包括小分子化合物,核酸分子,蛋白或多肽类分子,基因编辑复合物中的至少一种。
优选地,所述核酸分子为信使RNA(mRNA)、转移RNA(tRNA)、dsRNA、shRNA、DNA、质粒DNA、siRNA、反义寡核苷酸、aiRNA、miRNA中的至少一种;所述基因编辑复合物为mRNA/sgRNA或Cas9/sgRNA。
优选地,所述阳离子脂质类似物和核酸分子的质量比为阳离子脂质类似物:核酸分子=(2~50):1;优选地,阳离子脂质类似物:核酸分子=(5~20):1。
第五方面,本发明提供一种所述的载药纳米颗粒的制备方法,包括以下步骤:
(1)将所述阳离子脂质类似物的组合物溶于有机溶液,得有机相;
(2)将所述核酸分子溶于缓冲液,得水相;所述水相体积:所述有机相体积=(2~5):1;
(3)将所述水相快速加入有机相(或将有机相快速加入所述水相),混合均匀,透析,即得。
第六方面,本发明将所述的阳离子脂质类似物、所述的阳离子脂质类似物的组合物、所述的载药纳米颗粒在制备、传递或输送分子药物或核酸疫苗中的应用。
与现有技术相比,本发明的有益效果为:
本发明采用醛类化合物、胺类化合物、羧酸类化合物和异腈化合物为原料,通过Ugi反应合成阳离子脂质类似物;本发明阳离子脂质类似物的反应条件温和,合成工艺简单、稳定性好;合成得到的阳离子脂质类似物与固醇、辅助脂质、聚乙二醇脂质衍生物形成脂质纳米颗粒样组合物,该组合物可用于药物输送,包括小分子化合物,mRNA,DNA,siRNA等核酸分子,蛋白/多肽类分子,以及mRNA/sgRNA,Cas9/sgRNA等基因编辑复合物;通过不同给药方式实现在动物体内不同器官的mRNA表达,可满足mRNA核酸疗法、核酸疫苗以及基因编辑等的应用需求。
附图说明
图1为实施例1中A4I18R3C18-2的核磁共振氢谱图。
图2为实施例1中A4I18R3C18-2的质谱图。
图3为实施例2中A1I4R22C18-2的核磁共振氢谱图。
图4为实施例2中A1I4R22C18-2的质谱图。
图5为实施例3中A1I5R22S15的核磁共振氢谱图。
图6为实施例3中A1I5R22S15的质谱图。
图7为实施例4中A1I32R46C18-2的核磁共振氢谱图。
图8为实施例4中A1I32R46C18-2的质谱图。
图9为实施例5中A1I32R47C18-2的核磁共振氢谱图。
图10为实施例5中A1I32R47C18-2的质谱图。
图11为实施例1的化合物制备OVA-mRNA载药纳米颗粒免疫后抗体滴度统计图。
图12为实施例2的化合物制备OVA-mRNA载药纳米颗粒免疫后抗体滴度统计图。
具体实施方式
为更好地说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。本领域技术人员应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
实施例中所用的试验方法如无特殊说明,均为常规方法;所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1:一种阳离子脂质类似物
以化学反应通式(I)合成阳离子脂质类似物,产物的结构通式为:
具体制备方法为:
室温下分别将1.0mmol的醛类化合物和1.0mmol的胺类化合物加入到0.5mL甲醇溶液中,室温反应60min后加入1.0mmol羧酸类化合物,室温反应60min后加入1.0mmol异腈化合物,40℃反应24h,反应结束后经层析色谱柱分离提纯产物,其中,流动相采用甲醇和二氯甲烷的混液。
式(I)的合成通式为:
其中,醛类化合物为A1,A4,A23中任意一种;异腈类化合物为I18;胺类化合物为R1,R2,R3中任意一种;羧酸类化合物为C18,C18-1,C18-2,C18-3,C23中任意一种。
通过上述优选化合物合成的阳离子脂质类似物为如下45种:
A1I18R1C18、A1I18R1C18-1、A1I18R1C18-2、A1I18R1C18-3、A1I18R1C23、A1I18R2C18、A1I18R2C18-1、A1I18R2C18-2、A1I18R2C18-3、A1I18R2C23、A1I18R3C18、A1I18R3C18-1、A1I18R3C18-2、A1I18R3C18-3、A1I18R3C23、A4I18R1C18、A4I18R1C18-1、A4I18R1C18-2、A4I18R1C18-3、A4I18R1C23、A4I18R2C18、A4I18R2C18-1、A4I18R2C18-2、A4I18R2C18-3、A4I18R2C23、A4I18R3C18、A4I18R3C18-1、A4I18R3C18-2、A4I18R3C18-3、A4I18R3C23、A23I18R1C18、A23I18R1C18-1、A23I18R1C18-2、A23I18R1C18-3、A23I18R1C23、A23I18R2C18、A23I18R2C18-1、A23I18R2C18-2、A23I18R2C18-3、A23I18R2C23、A23I18R3C18、A23I18R3C18-1、A23I18R3C18-2、A23I18R3C18-3、A23I18R3C23。
醛类化合物为A1,A4,A23中任意一种;异腈类化合物为I18;胺类化合物为R5,R12中任意一种;羧酸类化合物为C18,C18-2中任意一种。
通过上述优选化合物合成的阳离子脂质类似物为如下12种:
A1I18R5C18、A1I18R5C18-2、A1I18R12C18、A1I18R12C18-2、A4I18R5C18、A4I18R5C18-2、A4I18R12C18、A4I18R12C18-2、A23I18R5C18、A23I18R5C18-2、A23I18R12C18、A23I18R12C18-2、
醛类化合物为A4或A5;异腈类化合物为I10,I14或I18;胺类化合物为R4,R6,R7,R8,R9,R10或R11;羧酸类化合物为C18或C18-2。
通过上述优选化合物合成的阳离子脂质类似物为如下10种:
A5I18R2C18-2、A4I10R2C18-2、A4I14R2C18-2、A4I18R4C18-2、A4I18R6C18-2、A4I18R7C18-2、A4I18R8C18-2、A4I18R9C18-2、A4I18R10C18-2、A4I18R11C18-2。
其中,A4I18R3C18-2的核磁共振氢谱与质谱图如图1和图2所示。
实施例2:一种阳离子脂质类似物
以化学反应通式(II)合成阳离子脂质类似物,产物的结构通式为:
具体制备方法为:
室温下分别将1.0mmol的醛类化合物和1.0mmol的胺类化合物加入到0.5mL甲醇溶液中,室温反应60min后加入1.0mmol羧酸类化合物,室温反应60min后加入0.5mmol异腈化合物,40℃反应24h,反应结束后经层析色谱柱分离提纯产物,其中,流动相采用甲醇和二氯甲烷的混液。
式(II)的合成通式为:
其中,醛类化合物为A1,A4,A21,A23中任意一种;异腈类化合物为I4;胺类化合物为R2,R13,R21,R22,R23中任意一种;羧酸类化合物为C18,C18-1,C18-2中任意一种。
采用上述化合物合成的阳离子脂质类似物为如下60种:
A1I4R2C18、A1I4R2C18-1、A1I4R2C18-2、A1I4R13C18、A1I4R13C18-1、A1I4R13C18-2、A1I4R21C18、A1I4R21C18-1、A1I4R21C18-2、A1I4R22C18、A1I4R22C18-1、A1I4R22C18-2、A1I4R23C18、A1I4R23C18-1、A1I4R23C18-2、A4I4R2C18、A4I4R2C18-1、A4I4R2C18-2、A4I4R13C18、A4I4R13C18-1、A4I4R13C18-2、A4I4R21C18、A4I4R21C18-1、A4I4R21C18-2、A4I4R22C18、A4I4R22C18-1、A4I4R22C18-2、A4I4R23C18、A4I4R23C18-1、A4I4R23C18-2、A21I4R2C18、A21I4R2C18-1、A21I4R2C18-2、A21I4R13C18、A21I4R13C18-1、A21I4R13C18-2、A21I4R21C18、A21I4R21C18-1、A21I4R21C18-2、A21I4R22C18、A21I4R22C18-1、A21I4R22C18-2、A21I4R23C18、A21I4R23C18-1、A21I4R23C18-2、A23I4R2C18、A23I4R2C18-1、A23I4R2C18-2、A23I4R13C18、A23I4R13C18-1、A23I4R13C18-2、A23I4R21C18、A23I4R21C18-1、A23I4R21C18-2、A23I4R22C18、A23I4R22C18-1、A23I4R22C18-2、A23I4R23C18、A23I4R23C18-1、A23I4R23C18-2。
醛类化合物为A1;异腈类化合物为I4;胺类化合物为R27,R28,R29,R30,R31,R32,R33,R34,R35,R36,R42,R43,R48中任意一种;羧酸类化合物为C18-2。
采用上述化合物合成的阳离子脂质类似物为如下13种:
A1I4R27C18-2、A1I4R28C18-2、A1I4R29C18-2、A1I4R30C18-2、A1I4R31C18-2、A1I4R32C18-2、A1I4R33C18-2、A1I4R34C18-2、A1I4R35C18-2、A1I4R36C18-2、A1I4R42C18-2、A1I4R43C18-2、A1I4R48C18-2。
醛类化合物为A1中任意一种;异腈类化合物为I4;胺类化合物为R22;羧酸类化合物为C12,C14,C16,S11,S13,S15,S17,S19中任意一种。
采用上述化合物合成的阳离子脂质类似物为如下8种:
A1I4R22C12、A1I4R22C14、A1I4R22C16、A1I4R22S11、A1I4R22S13、A1I4R22S15、A1I4R22S17、A1I4R22S19。
其中,A1I4R22C18-2的核磁共振氢谱与质谱图如图3和图4所示。
实施例3:一种阳离子脂质类似物
以化学反应通式(III)合成阳离子脂质类似物,产物的结构通式为:
具体制备方法为:
室温下分别将1.0mmol的醛类化合物和1.0mmol的胺类化合物加入到0.5mL甲醇溶液中,室温反应60min后加入1.0mmol羧酸类化合物,室温反应60min后加入0.33mmol异腈化合物,40℃反应24h,反应结束后经层析色谱柱分离提纯产物,其中,流动相采用甲醇和二氯甲烷的混液。
式(III)的合成通式为:
其中,醛类化合物为A1;异腈化合物为I5;胺类化合物为R2,R13,R21,R22,R23,R26,R27,R28,R29,R30,R31,R32,R33,R34,R35,R36,R37,R38,R39,R40,R41或R50;羧酸类化合物为C8,C10,C12,C14,C16,C18,C18-2,C21,S11,S13,S15,S17或S19。
采用上述化合物合成的阳离子脂质类似物为如下29种:
A1I5R22C8、A1I5R22C10、A1I5R22C12、A1I5R22C14、A1I5R22C16、A1I5R22C18、A1I5R22C18-2、A1I5R22S11、A1I5R22S13、A1I5R22S15、A1I5R22S17、A1I5R22S19、A1I5R26S15、A1I5R27S15、A1I5R28S15、A1I5R29S15、A1I5R30S15、A1I5R31S15、A1I5R32S15、A1I5R33S15、A1I5R34S15、A1I5R35S15、A1I5R36S15、A1I5R37S15、A1I5R38S15、A1I5R39S15、A1I5R40S15、A1I5R41S15、A1I5R50C21。
其中,A1I5R22S15的核磁共振氢谱与质谱图如图5和图6所示。
实施例4:一种阳离子脂质类似物
以化学反应通式(IV)合成阳离子脂质类似物,产物的结构通式为:
具体制备方法为:
室温下分别将1.0mmol的醛类化合物和0.5mmol的胺类化合物加入到0.5mL甲醇溶液中,室温反应60min后加入1.0mmol羧酸类化合物,室温反应60min后加入1.0mmol异腈化合物,40℃反应24h,反应结束后经层析色谱柱分离提纯产物,其中,流动相采用甲醇和二氯甲烷的混液。
式(IV)的合成通式为:
其中,醛类化合物为A1;异腈类化合物为I10、I12、I31或I32;胺类化合物为R46或R51;羧酸类化合物为C8或C18-2。
采用上述化合物合成的阳离子脂质类似物为如下4种:
A1I12R51C8、A1I10R51C18-2、A1I31R46C18-2、A1I32R46C18-2。
其中,A1I32R46C18-2的核磁共振氢谱与质谱图如图7和图8所示。
实施例5:一种阳离子脂质类似物
以化学反应通式(V)合成阳离子脂质类似物,产物的结构通式为:
具体制备方法为:
室温下分别将1.0mmol的醛类化合物和0.33mmol的胺类化合物加入到0.5mL甲醇溶液中,室温反应60min后加入1.0mmol羧酸类化合物,室温反应60min后加入1.0mmol异腈化合物,40℃反应24h,反应结束后经层析色谱柱分离提纯产物,其中,流动相采用甲醇和二氯甲烷的混液。
式(V)的合成通式为:
其中,醛类化合物为A1;异腈类化合物为I12、I31或I32;胺类化合物为R47;羧酸类化合物为C21或C18-2。
采用上述化合物合成的阳离子脂质类似物为如下3种:
A1I12R47C21、A1I31R47C18-2、A1I32R47C18-2。
其中,A1I32R47C18-2的核磁共振氢谱与质谱图如图9和图10所示。
实施例6:一种载药纳米颗粒
该载药纳米颗粒包括阳离子脂质类似物、胆固醇、二硬脂酰磷脂酰胆碱(DSPC)、1,2-二肉豆蔻酰-rac-甘油-3-甲氧基聚乙二醇(DMG-PEG)。
其中,采用摩尔比计,阳离子脂质类似物:胆固醇:DSPC:DMG-PEG=50:38.5:10:1.5。
该载药米粒颗粒中,阳离子脂质类似物和mRNA或siRNA等核酸药物质量比为阳离子脂质类似物:核酸药物=11:1。
以负载mRNA的该载药纳米颗粒的制备方法为例:
将阳离子脂质类似物、胆固醇、DSPC、DMG-PEG溶于乙醇溶液,按上述摩尔比混合得有机相;将对应质量比的mRNA核酸药物溶于醋酸钠缓冲溶液(25mM,pH=3.0)得水相,使水相体积:有机相体积=3:1;将水相快速加入有机相中混合均匀,静置10分钟后装入1000Da透析袋中,在4℃1×PBS溶液中透析2小时,即得到可直接用于注射的纳米颗粒。
表1使用实施例6制备脂质纳米颗粒表征数据
实施例 | 阳离子脂质类似物名称 | 粒径(nm) | PDI | Zeta电位(mV) | 包封率 |
1 | A4I18R3C18-2 | 83±9 | 0.12 | -3.2 | 75.3% |
2 | A1I4R22C18-2 | 133±6 | 0.17 | -5.5 | 62.1% |
3 | A1I5R22S15 | 144±7 | 0.22 | -7.2 | 65.4% |
4 | A1I32R46C18-2 | 110±11 | 0.20 | -2.5 | 67.2% |
5 | A1I32R47C18-2 | 150±9 | 0.21 | -3.1 | 60.5% |
实施例7:一种载药纳米颗粒
该载药纳米颗粒包括阳离子脂质类似物、β-谷固醇、二油酰磷脂酰乙醇胺(DOPE)、1,2-二肉豆蔻酰-rac-甘油-3-甲氧基聚乙二醇(DMG-PEG)。
其中,采用摩尔比计,阳离子脂质类似物:β-谷固醇:DOPE:DMG-PEG=35:25:5:2。该载药纳米颗粒中,阳离子脂质类似物和mRNA或siRNA等核酸药物质量比为阳离子脂质类似物:核酸药物=5:1。
实施例8:一种载药纳米颗粒
该载药纳米颗粒包括阳离子脂质类似物、豆甾醇、神经酰胺磷酸胆碱、1,2-二肉豆蔻酰-rac-甘油-3-甲氧基聚乙二醇(DMG-PEG)。
其中,采用摩尔比计,阳离子脂质类似物:豆甾醇:神经酰胺磷酸胆碱:DMG-PEG=55:40:12:2.5。
该载药米粒颗粒中,阳离子脂质类似物和mRNA或siRNA等核酸药物质量比为阳离子脂质类似物:核酸药物=15:1。
实施例9:一种载药纳米颗粒
该载药纳米颗粒包括阳离子脂质类似物、胆固醇琥珀酸单酯(胆固醇衍生物)、鞘磷脂、1,2-二肉豆蔻酰-rac-甘油-3-甲氧基聚乙二醇(DMG-PEG)。
其中,采用摩尔比计,阳离子脂质类似物:胆固醇琥珀酸单酯:鞘磷脂:DMG-PEG=60:45:15:3.5。
该载药纳米颗粒中,阳离子脂质类似物和mRNA或siRNA等核酸药物质量比为阳离子脂质类似物:核酸药物=18:1。
实施例10:动物实验检测静脉注射mRNA体内递送表达水平
以Luciferase-mRNA作为模型mRNA;以实施例1~5的阳离子脂质类似物按照实施例6的方法制备载药纳米颗粒。
具体操作方法如下:
向6~8周龄的C57BL/6小鼠尾静脉注射200μL含5μg Luciferase-mRNA的纳米颗粒或上述制备的载药纳米颗粒,6小时后向小鼠腹腔注射200μL含3mg D-Luciferinpotassium salt的1×PBS溶液,等待10min后通过生物发光成像来评价体内mRNA表达情况。
载药纳米颗粒的体内表达情况如表2至表6所示:
表2实施例1的化合物制备mRNA载药纳米颗粒静脉注射的体内表达情况
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表3实施例2的化合物制备mRNA载药纳米颗粒静脉注射的体内表达情况
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表4实施例3的化合物制备mRNA载药纳米颗粒静脉注射的体内表达情况
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表5实施例4的化合物制备mRNA载药纳米颗粒静脉注射的体内表达情况
表6实施例5的化合物制备mRNA载药纳米颗粒静脉注射的体内表达情况
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实施例11:动物实验检测肌肉注射mRNA体内递送表达水平
以Luciferase-mRNA作为模型mRNA;以实施例1~5的阳离子脂质类似物按照实施例6的方法制备载药纳米颗粒。
具体操作方法如下:
向6~8周龄的C57BL/6小鼠腿部肌肉注射100μL含5μg Luciferase-mRNA的纳米颗粒或上述制备的载药纳米颗粒,6小时后向小鼠腹腔注射200μL含3mg D-Luciferinpotassium salt的1×PBS溶液,等待10min后通过生物发光成像来评价体内mRNA表达情况。
表7实施例1的化合物制备mRNA载药纳米颗粒肌肉注射的体内表达情况
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表8实施例2的化合物制备mRNA载药纳米颗粒肌肉注射的体内表达情况
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表9实施例3的化合物制备mRNA载药纳米颗粒肌肉注射的体内表达情况
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表10实施例4的化合物制备mRNA载药纳米颗粒肌肉注射的体内表达情况
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表11实施例5的化合物制备mRNA载药纳米颗粒肌肉注射的体内表达情况
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实施例12:动物实验检测腹腔注射mRNA体内递送表达水平
以Luciferase-mRNA作为模型mRNA;以实施例2的阳离子脂质类似物A1I4R22C18-2按照实施例6的方法制备载药纳米颗粒。
具体操作方法如下:
向6~8周龄的C57BL/6小鼠腹腔注射200μL含5μg Luciferase-mRNA的纳米颗粒或上述制备的载药纳米颗粒,6小时后向小鼠腹腔注射200μL含3mg D-Luciferin potassiumsalt的1×PBS溶液,等待10min后通过生物发光成像来评价体内mRNA表达情况。
表12实施例2的化合物制备mRNA载药纳米颗粒腹腔注射的体内表达情况
实施例13:动物实验检测气管注射mRNA体内递送表达水平
以Luciferase-mRNA作为模型mRNA;以实施例2的阳离子脂质类似物A1I4R22C18-2按照实施例6的方法制备载药纳米颗粒。
具体操作方法如下:
向6~8周龄的C57BL/6小鼠气管注射100μL含5μg Luciferase-mRNA的纳米颗粒或上述制备的载药纳米颗粒,6小时后向小鼠腹腔注射200μL含3mg D-Luciferin potassiumsalt的1×PBS溶液,等待10min后通过生物发光成像来评价体内mRNA表达情况。
表13实施例2的化合物制备mRNA载药纳米颗粒气管注射的体内表达情况
实施例14:动物实验评估体内递送mRNA的免疫性能
以OVA-mRNA作为模型mRNA;以实施例1和2的阳离子脂质类似物按照实施例6的方法制备载药纳米颗粒。
具体操作方法如下:
选6~8周龄的C57BL/6小鼠于SPF级动物房实验,每组选取5只小鼠,向每只小鼠腿部肌肉或腹腔注射100μL含5μg OVA-mRNA的纳米颗粒或上述制备的载药纳米颗粒,使用相同剂量再加强一次后,取血通过酶联免疫吸附测定(ELISA)用于抗体滴度分析。
以实施例1中阳离子脂质类似物为例,在第0,14天分别肌肉注射5μg OVA-mRNA的纳米颗粒或上述制备的载药纳米颗粒后,在第21天取血进行抗体滴度分析,结果如图11所示。
以实施例2中阳离子脂质类似物A1I4R22C18-2为例,在第0,7天分别肌肉或腹腔注射5μg OVA-mRNA的纳米颗粒或上述制备的载药纳米颗粒后,在第14天取血进行抗体滴度分析,结果如图12所示。
实施例15:动物实验检测静脉注射siRNA体内递送水平
以Cy5-siRNA作为模型siRNA;以实施例1的阳离子脂质类似物A4I18R2C18-2和A1I4R22C18-2按照实施例6的方法制备载药纳米颗粒。
具体操作方法如下:
向6~8周龄的C57BL/6小鼠腿部静脉注射200μL含10μg Cy5-siRNA的纳米颗粒或上述制备的载药纳米颗粒,1小时后通过生物荧光成像来评价体内siRNA递送情况。
表14实施例1的化合物制备siRNA载药纳米颗粒静脉注射的体内递送情况
表15实施例2的化合物制备siRNA载药纳米颗粒静脉注射的体内递送情况
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (21)
1.一种阳离子脂质类似物,其特征在于,其具有如式(I)所示结构:
式中,m1为独立地选自
和/或
m2为独立地选自
和/或
m3为独立地选自
和/或
m4为独立地选自
2.一种阳离子脂质类似物,其特征在于,其具有如式(II)~式(Ⅴ)任一种所示结构:
式中,m1为独立地选自
和/或
m2为独立地选自 和/或m3为独立地选自/>
和/或
m4为独立地选自
3.根据权利要求2所述的阳离子脂质类似物,其特征在于,所述m1为 和/或所述m2为、
和/或
所述m3为
和/或
所述m4为
4.一种权利要求1-3任一项权利要求所述的阳离子脂质类似物的制备方法,其特征在于,将醛类化合物和胺类化合物加入到有机溶液中,反应10~120min后依次加入羧酸类化合物和异腈化合物,再于4~60℃反应6~72h,分离提纯产物,即成。
5.根据权利要求4所述的阳离子脂质类似物的制备方法,其特征在于,所述醛类化合物、胺类化合物、羧酸类化合物和异腈化合物的摩尔比为(0.1~1.5):(0.1~1.5):(0.1~1.5):(0.1~1.5)。
6.根据权利要求4所述的阳离子脂质类似物的制备方法,其特征在于,所述异腈化合物为单官能团异腈化合物、双官能团异腈化合物、三官能团异腈化合物中的一种。
7.根据权利要求5所述的阳离子脂质类似物的制备方法,其特征在于,所述异腈化合物为如下化合物I3~I38中的任一种:
8.根据权利要求4所述的阳离子脂质类似物的制备方法,其特征在于,所述醛类化合物为单官能团醛类化合物中的一种。
9.根据权利要求8所述的阳离子脂质类似物的制备方法,其特征在于,所述醛类化合物为如下化合物A1~A35中的任一种:
10.根据权利要求4所述的阳离子脂质类似物的制备方法,其特征在于,所述胺类化合物为单官能团胺类化合物、双官能团胺类化合物、三官能团胺类化合物中的一种。
11.根据权利要求10所述的阳离子脂质类似物的制备方法,其特征在于,优选地所述胺类化合物为如下化合物R1~R53中的任一种:
12.根据权利要求4所述的阳离子脂质类似物的制备方法,其特征在于,羧酸类化合物为如下化合物C8~C30或S11~S19中的任一种:
13.一种权利要求1-3任一项权利要求所述的阳离子脂质类似物的组合物,其特征在于,包括所述阳离子脂质类似物,以及固醇、辅助脂质和聚乙二醇脂质衍生物中的至少一种。
14.根据权利要求13所述阳离子脂质类似物的组合物,其特征在于,所述固醇为胆固醇、谷固醇、豆甾醇、胆固醇衍生物中的至少一种;所述辅助脂质为中性磷脂。
15.根据权利要求13所述阳离子脂质类似物的组合物,其特征在于,所述阳离子脂质类似物、胆固醇、辅助脂质、聚乙二醇脂质衍生物的摩尔比为(20~70):(20~50):(2~30):(0.1~20)。
16.一种载药纳米颗粒,其特征在于,包括权利要求13所述的阳离子脂质类似物的组合物和药物。
17.根据权利要求16所述的载药纳米颗粒,其特征在于,所述药物为小分子化合物,核酸分子,蛋白或多肽类分子,基因编辑复合物中的至少一种。
18.根据权利要求17所述的载药纳米颗粒,其特征在于,所述核酸分子为信使RNA、转移RNA、dsRNA、shRNA、DNA、质粒DNA、siRNA、反义寡核苷酸、aiRNA、miRNA中的至少一种;所述基因编辑复合物为mRNA/sgRNA或Cas9/sgRNA。
19.根据权利要求17所述的载药纳米颗粒,其特征在于,所述阳离子脂质类似物和核酸分子的质量比为阳离子脂质类似物:核酸分子=(2~50):1。
20.一种权利要求19所述的载药纳米颗粒的制备方法,其特征在于,包括以下步骤:
(1)将所述阳离子脂质类似物的组合物溶于有机溶液,得有机相;
(2)将所述核酸分子溶于缓冲液,得水相;
所述水相体积:所述有机相体积=(2~5):1;
(3)将所述水相与所述有机相快速混合均匀,透析,即得。
21.权利要求1-3任一项权利要求所述的阳离子脂质类似物、权利要求13-15任一项权利要求所述的阳离子脂质类似物的组合物、权利要求16-19任一项权利要求所述的载药纳米颗粒在制备传递或输送类分子药物或核酸疫苗中的应用。
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