CN116332776A - 一种阳离子脂质化合物及其组合物和应用 - Google Patents
一种阳离子脂质化合物及其组合物和应用 Download PDFInfo
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- CN116332776A CN116332776A CN202310263478.2A CN202310263478A CN116332776A CN 116332776 A CN116332776 A CN 116332776A CN 202310263478 A CN202310263478 A CN 202310263478A CN 116332776 A CN116332776 A CN 116332776A
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- lipid
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Abstract
Description
技术领域
本发明具体涉及一种阳离子脂质化合物及其组合物和应用。
背景技术
治疗性核酸具有彻底改变疫苗接种、基因疗法、蛋白质替代疗法和其他遗传疾病疗法的潜力。自21世纪初开始基于Zamecnik和Stephenson的最早发现,对治疗性核酸的首次临床研究以来,核酸分子的设计及其递送方法的研究已经取得了重大进展。核酸药物通过将外源基因导入靶细胞或组织,替代、补偿、阻断或修正特定基因,以达到治疗和预防疾病的目的。其优势包括生产工艺相对简单、研发周期短、临床开发成功率高等。
然而,核酸治疗剂仍面临若干挑战,包括带负电的核酸难以跨膜进入胞内和对某些核酸分子暴露在血液中容易被血浆和组织中的核酸酶降解而且会造成免疫原性等。因此,提高核酸药物的体内递送效率是提高该类产品有效性的重要措施之一。则需要开发更多的能够递送治疗或预防剂,尤其是用于递送核酸治疗剂的脂质化合物以及相关的方法和组合物,以促进各类治疗或预防剂在胞外或胞内的递送以用于治疗和/或预防的目的。
发明内容
本发明的目的在于在于提供一种阳离子脂质化合物,丰富了阳离子脂质化合物种类,为核酸药物、基因疫苗、小分子药物、多肽及蛋白质药物等的递送提供更多的选择,对核酸预防剂及治疗剂的发展和应用具有重要的意义。
本发明的另一目的在于提供一种组合物,克服现有技术中存在的上述技术问题。
本发明的另一目的在于提供一种阳离子脂质化合物或其药物可用的盐,或组合物在制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物中的应用。
为此,本发明提供的技术方案如下:
阳离子脂质化合物双(癸酰氧基乙氧基乙基)甲胺,结构式如下:
一种组合物,包括治疗或预防剂和用于递送所述治疗或预防剂的载体,所述载体包括阳离子脂质,所述阳离子脂质包括阳离子脂质化合物双(癸酰氧基乙氧基乙基)甲胺或其药物可用的盐中的一种或多种。
所述其药物可用的盐是指与酸成盐或与碱成盐;有效成分被包封在载体内或与载体缔合。
所述酸包括但不限于盐酸、硫酸、硝酸、磷酸、乙酸、己二酸、海藻酸、苯磺酸、苯甲酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、十二烷基硫酸、乙烷磺酸、甲酸、半乳糖酸、戊二酸、α-酮戊二酸、乙醇酸、水杨酸、3-氨基-2-羟基苯甲酸、琥珀酸、酒石酸、氢溴酸、2,2-二氯乙酸、抗坏血酸、天冬氨酸、4-乙酰氨基苯甲酸、樟脑酸、环酰胺酸、1,2-乙二磺酸、2-羟基乙磺酸、富马酸、龙胆酸、葡庚酸、葡糖酸、葡糖醛酸、谷氨酸、甘油磷酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、β-萘磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、棕榈酸、丙酸、焦谷氨酸、丙酮酸、癸二酸、硬脂酸、十一碳烯酸、硫氰酸、对甲苯磺酸、三氟乙酸。
所述碱加成盐指通过将碱加成至游离碱化合物而制备的盐。所述碱包括但不限于氨、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、组氨酸、赖氨酸、精氨酸、肼苯胺、胆碱、乙二胺、可可碱、三乙醇胺、异丙胺、N-苄基-2-苯乙酰胺、葡糖胺、甲基葡糖胺、嘌呤、哌嗪、哌啶。优选地,碱是二乙胺、乙醇胺、三甲胺、三乙胺。
所述载体与治疗或预防剂的质量比进一步优选为10∶1~35∶1,更优选为15∶1~30∶1。
所述治疗或预防剂包括核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。治疗或预防剂包含至少一种编码抗原的mRNA或其片段或表位。
其中,核酸分子包括但不限于单链DNA、双链DNA、短异构体、反义寡核苷酸(ASON)、小干扰RNA(siRNA)、微小RNA(miRNA)、dicer底物RNA(dsRNA)、小发夹RNA(shRNA)、转移RNA(tRNA)、信使RNA(mRNA)和本领域已知的其他形式的RNA分子或核酸模拟物。
mRNA是单顺反子mRNA或多顺反子mRNA。mRNA包含一种或多种功能性核苷酸类似物,所述功能性核苷酸类似物包括但不限于假尿嘧啶核苷、1-甲基-假尿嘧啶核苷和5-甲基胞嘧啶、5-甲氧基-尿嘧啶核苷中的一种或多种。
抗原是病原性抗原。
小分子化合物包括但不限于治疗和/或预防剂的有效成分,所述治疗和/或预防剂为现有已知的药物,例如抗肿瘤药、抗感染药、抗生素/抗菌剂、抗真菌药、局部麻醉药、抗抑郁药、抗惊厥药、抗寄生虫药或免疫调节剂。
所述阳离子脂质还包括一种或多种其他可电离的脂质化合物。
其他可电离的脂质化合物指已公开的或未公开的其他带电脂质化合物。带电脂质化合物指在选定pH或范围内以带正电或带负电形式存在的任何脂质分子。选定的pH或范围对应于脂质的预期使用环境的pH条件,例如生理pH。
更具体地,所述带电脂质化合物包括但不限于:DLinDMA、DLin-K-DMA、DLin-MC3-DMA、DLin-KC2-DMA、DODMA、KL10、KL22、KL25、辛基-CLinDMA;
或,DOTMA、DOTAP、DOEPC、DMEPC、DLEPC、MVL5、DOGS、DC-CHOL、DDAB、DORI、DORIE、DILA2、DODAC、MOEPC、POEPC;
或具有在生理学pH带电的头部基团,如伯胺和胍盐头部基团的阳离子脂质。在某些实施方式中,所述阳离子脂质是特定对映异构体,并且包括如上的阳离子脂质的多种盐形式;
或DOTAP-Cl、DOTAP-硫酸盐、DLinDMA、DLin-KC2-DMA、DLin-MC3-DMA、DDAB、DODMA、DODAP、Mo-CHOL。
药物组合物为纳米颗粒制剂,所述纳米颗粒制剂的平均尺寸为20nm~200nm,优选为30nm~150nm,进一步优选为35nm~120nm,更优选为40nm~80nm。针对不同的细胞或动物进行转染或递送则优选相应合适的纳米颗粒制剂尺寸。
进一步优选地,所述纳米颗粒制剂的多分散指数(PDI)≤0.5,进一步优选≤0.3,更优选≤0.1。
所述载体还包括中性脂质,所述阳离子脂质与所述中性脂质的摩尔比为1~10∶1,进一步优选为2~8∶1,更优选为3~7∶1。
中性脂质化合物为已公开的或未公开的在选定的pH值或范围内以不带电荷形式或中性两性离子形式存在的任何脂质分子。选定的有用的pH值或范围对应于脂质的预期使用的环境的pH条件,例如生理pH。
更具体地,所述中性脂质包括磷脂酰胆碱(PC)、磷脂酰乙醇胺(PE)、鞘磷脂(SM)、神经酰胺(Cer)、甾醇及其衍生物中的一种或多种。更具体地,所述中性脂质包括但不限于DSPC、DPPC、DMPC、POPC、DOPC、DOPE、DOCP、DGTS、SM、Cer、甾醇及其衍生物。
所述载体还包括结构脂质,所述阳离子脂质与所述结构脂质的摩尔比为1~5∶1,进一步优选为1~3∶1,更优选为1~2∶1。
结构脂质可以稳定载体的两亲结构。具体地,所述结构脂质包括但不限于胆固醇、非甾醇、谷固醇、麦角固醇、豆甾醇、番茄碱、皮质类固醇、菜油甾醇、芸苔甾醇、熊果酸中的一种或多种。
所述载体还包括聚合物共轭脂质,所述阳离子脂质与所述聚合物共轭脂质的摩尔比为10~90∶1,进一步优选为10~60∶1,再进一步优选为15~50∶1,更优选为20~35∶1。
聚合物共轭脂质主要包括已公开的或未公开的PEG修饰的脂质化合物,可以改善脂质体的稳定性并减少脂质体的蛋白质吸收,例如聚乙二醇-磷酸乙醇胺(PEG-PE)、聚乙二醇-磷脂酸(PEG-PA)、聚乙二醇-神经酰胺(PEG-Cer)、聚乙二醇-二肉豆蔻酰甘油(PEG-DMG)、聚乙二醇-二烷基胺、聚乙二醇-二酰基甘油、聚乙二醇-二烷基甘油中的一种或多种。
更具体地,所述聚合物共轭脂质可以是PEG-DMG、PEG-DAG、PEG-DLPE、PEG-DMPE、PEG-DSPE、PEG-DPPC、PEG-c-DOMG、Cer-PEG2000、Chol-PEG2000、PEG-PE、PEG-S-DMG、PEG-Cer、DMG-PEG-NH2、DMG-PEG-MAL、DMG-PEG-COOH、DMG-PEG-SH、DMG-PEG-OH、DMG-PEG-FA、DMG-PEG-Biotin、DSPE-PEG-SH、DSPE-PEG-NH2、DSPE-PEG-Biotin、DSPE-PEG-Silane、DSPE-PEG-MAL、DSPE-PEG-COOH、DSPE-PEG-OH、DSPE-PEG-SP94、DSPE-PEG-Mannose、DSPE-PEG-NBD。
根据一些具体且优选地实施方式,所述聚合物共轭脂质为DMG-PEG2000或者DMPE-PEG2000。
所述载体为阳离子脂质中性脂质、结构脂质和聚合物共轭脂质的混合物时,所述阳离子脂质、中性脂质、结构脂质和聚合物共轭脂质的摩尔比为(10~40)∶(1~10)∶(5~35)∶1,进一步优选为(15~35)∶(2~10)∶(10~30)∶1,更优选为(20~35)∶(3~10)∶(20~30)∶1。。
组合物中还包括药物可用的赋形剂或稀释剂中的一种或多种。
一种阳离子脂质化合物或其药物可用的盐,或其组合物在制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物中的应用。
本发明的有益效果是:
本发明提供了一种新的阳离子脂质化合物,丰富了阳离子脂质化合物种类,为核酸药物、基因疫苗、小分子药物、多肽及蛋白质药物等的递送提供更多的选择,对核酸预防剂及治疗剂的发展和应用具有重要的意义。
使用本发明的阳离子脂质化合物制备的载体对核酸分子的包封效率高,可将核酸分子成功转运至细胞中并进行表达。
附图说明
图1为阳离子脂质化合物双(癸酰氧基乙氧基乙基)甲胺的氢谱图;
图2为阳离子脂质化合物双(癸酰氧基乙氧基乙基)甲胺的质谱图;
图3为本发明设计的阳离子脂质化合物组成的GFP-mRNA-LNP制剂转染人原代DC细胞GFP的表达结果;
图4为本发明设计的阳离子脂质化合物组成的GFP-mRNA-LNP制剂转染人原代T细胞GFP的表达;
图5为本发明设计的阳离子脂质化合物组成的HPV16-E7-mRNA-LNP制剂转染的DC细胞刺激TCR-T分泌细胞免疫因子图;
图6为本发明设计的阳离子脂质化合物组成的Luciferase-mRNA-LNP制剂小鼠体内Luc递送成像结果。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式,本领域技术人员可由本说明书所揭示的内容轻易地了解本发明的其他优点及功效。
现参考附图介绍本发明的示例性实施方式,然而,本发明可以用许多不同的形式来实施,并且不局限于此处描述的实施例,提供这些实施例是为了详尽地且完全地公开本发明,并且向所属技术领域的技术人员充分传达本发明的范围。对于表示在附图中的示例性实施方式中的术语并不是对本发明的限定。
除非另有说明,此处使用的术语(包括科技术语)对所属技术领域的技术人员具有通常的理解含义。另外,可以理解的是,以通常使用的词典限定的术语,应当被理解为与其相关领域的语境具有一致的含义,而不应该被理解为理想化的或过于正式的意义。
实施例1
本实施例提供了一种阳离子脂质化合物,结构式如下:
该阳离子脂质化合物的化学名称是双(癸酰氧基乙氧基乙基)甲胺,合成路线如下:
制备过程如下:
步骤1:中间产物(1)的合成
在100mL耐压烧瓶中投入2-氯乙氧基乙醇(7.5g)和一甲胺(21.5g),然后密封加热,温度从55℃逐步到90℃反应5h;然后反应混合物在95-100℃反应3h,之后在减压下除去过量的一甲胺,并用过量的浓氢氧化钠水溶调pH至14,混合液用氯仿萃取,萃取液干燥浓缩,浓缩浆状物减压蒸馏得到所需的目标化合物约500mg(I)(b.p.126℃/2毫米Hg柱)。
步骤2:双(癸酰氧基乙氧基乙基)甲胺的合成
在25mL圆底烧瓶中投入中间产物(1)310mg(0.1mmol),加入CH2Cl2(15mL),三乙胺1mL,冰浴条件下,向溶液中滴加葵酰氯试剂(0.15mmol),TLC点板监测,反应完成后。减压蒸除溶剂,拌样。使用DCM-MeOH(10:1)作为洗脱剂,快速柱色谱纯化得双(癸酰氧基乙氧基乙基)甲胺(169mg,54.5%产率)。双(癸酰氧基乙氧基乙基)甲胺的氢谱图具体见附图1,质谱图具体见附图2。
实施例2
本实施例提供了一种组合物,具体为GFP-mRNA-LNP制剂。
制备过程:
将实施例1的阳离子脂质化合物双(癸酰氧基乙氧基乙基)甲胺与中性脂质DSPC二硬脂酰磷脂酰胆碱、结构脂质胆固醇和聚合物共轭脂质DMG-PEG2000(1,2-二肉豆蔻酰-rac-甘油-3-甲氧基聚乙二醇2000)以50∶10∶37.5∶2.5的摩尔比溶于乙醇制备乙醇脂质溶液,并将绿色荧光蛋白(GFP)mRNA在10至100mM柠檬酸盐缓冲液(pH=4)中稀释得到mRNA水溶液。通过使用微流控装置以1∶4的体积比混合乙醇脂质溶液和mRNA水溶液,以总脂质(载体)与mRNA的质量比为15~30∶1制备纳米脂质体。经4℃静置透析12-24h(截留分子量:100KDa)除去乙醇并使用1×PBS代替。随后超滤浓缩至理想浓度。最后,脂质纳米颗粒通过0.22μm无菌过滤器过滤,得到使用阳离子脂质双(癸酰氧基乙氧基乙基)甲胺/DSPC/胆固醇/DMG-PEG2000(50/10/37.5/2.5mol%)包封绿色荧光蛋白(GFP)mRNA的LNP制剂,编号为1。
其中,DSPC、胆固醇和DMG-PEG2000均购自厦门赛诺邦格生物科技股份有限公司。
在氮原子上,使用商业软件ACD/Labs(Advanced Chemistry Development,Inc.)在水介质中理论上估算pKa,阳离子脂质化合物的pKa理论计算如表1所示。
通过TNS染料结合分析测定,LNP制剂中阳离子脂质化合物的pKa如表1所示。pKa从理论值下降到TNS值的2-3个点是由于脂相中质子的溶剂化能高得多。
使用Malvern Zetasizer Nano ZS(Malvern UK),反向散射检测模式通过动态光散射测定脂质纳米颗粒的大小(Size)及多分散指数(PDI),测定结果如表1所示。
表1包封率
GFP-mRNA-LNP制剂细胞学研究
将实施例2包封的绿色荧光蛋白(GFP)mRNA的LNP制剂转染人外周血单核细胞衍生的原代树突状细胞(dendritic cell,DC)。原代DC细胞在Medium for human lymphocyteand tissue culture(TaKaRa)培养基中以1.0×10^5的密度接种在24孔板中,用1.0μg/mL的GFP-mRNA-LNP制剂转染DC细胞。在37℃5%CO2培养箱DC细胞与GFP-mRNA-LNP制剂共培养24h后,通过流式细胞仪测定GFP表达。图3是检测的GFP-mRNA-LNP制剂转染人原代DC细胞24h的GFP表达情况。
将实施例2包封的绿色荧光蛋白(GFP)mRNA的LNP制剂转染原代人T细胞。从人外周血分离外周血单核细胞(PBMC),在含有10%FBS的RPMI 1640培养基中将细胞悬浮至1.0×10^6个/mL,并通过每mL每1.0×10^6细胞添加10μL的T Cell TransActTM(MiltenyiBiotec)人CD3/CD28偶联磁珠活化T细胞4天。活化的T细胞以5.0×10^5的密度接种在24孔板中,用2.0μg/mL的GFP-mRNA-LNP制剂转染T细胞24h,对照组不进行转染。通过流式细胞仪测定人T细胞上GFP表达。图4是GFP-mRNA-LNP制剂转染人原代T细胞24h的GFP表达情况。
实施例3
本实施例提供了一种组合物,具体为HPV16 E7-mRNA-LNP制剂。
制备过程:
将实施例1的阳离子脂质化合物双(癸酰氧基乙氧基乙基)甲胺分别与DSPC、胆固醇和DMG-PEG2000以50∶10∶37.5∶2.5的摩尔比溶于乙醇制备乙醇脂质溶液,并将人乳头瘤病毒属(HPV)16早期致癌蛋白E7 mRNA在10至100mM柠檬酸盐缓冲液(pH=4)中稀释得到mRNA水溶液。通过使用微流控装置以1∶4的体积比混合乙醇脂质溶液和mRNA水溶液,以总脂质与mRNA的质量比为15~30∶1制备纳米脂质体。经4℃静置透析12-24h(截留分子量:100KDa)除去乙醇并使用1×PBS代替。随后超滤浓缩至理想浓度。最后,脂质纳米颗粒通过0.22μm无菌过滤器过滤,得到使用阳离子脂质双(癸酰氧基乙氧基乙基)甲胺/DSPC/胆固醇/DMG-PEG2000(50/10/37.5/2.5mol%)包封HPV16-E7 mRNA的LNP制剂,编号为2。
同实施例2方法测定HPV16-E7 mRNA脂质纳米颗粒的大小(Size)、多分散指数(PDI)及脂质纳米颗粒的包封效率,结果如表2所示。
表2包封率
HPV16-E7-mRNA-LNP制剂细胞学研究
将实施例3包封的HPV16-E7-mRNA的LNP制剂转染人类白细胞抗原(HLA)-A*02:01的人外周血单核细胞衍生的原代树突状细胞(dendritic cell,DC)。原代DC细胞以1.0×10^5的密度接种在24孔板中,对照组不做LNP制剂的转染,实验组用1.0μg/mL的HPV16-E7-mRNA-LNP制剂转染细胞,在37℃5%CO2培养箱DC细胞与HPV16-E7-mRNA-LNP制剂共培养24h。然后在96孔板将转染的DC细胞与同等数量的HLA-A*02:01限制性的HPV16 E7 T细胞受体(TCR)-T细胞继续培养,并使用Brefeldin A(BFA,作用是使T细胞中的免疫因子置留于细胞内而不被释放出来,以便用FACS进行染色监测)处理,共培养24h后收集细胞,先用抗CD8-APC进行细胞表面染色,然后使用FIX&PERMTM试剂盒(ThermoFisher)按照说明进行细胞内免疫因子染色,染色后的细胞用FACS检测其免疫因子的产生情况如图5所示。图5显示HPV16E7-TCR-T与DC细胞共培养后,HPV16-E7-mRNA-LNP制剂转染的DC细胞可刺激TCR-T分泌IFN-γ,而对照不做LNP制剂转染的DC细胞不能引起TCR-T表达IFN-γ。
实施例4
本实施例提供了一种组合物,具体为荧光素酶-mRNA-LNP制剂。
制备过程:
将实施例1的阳离子脂质化合物双(癸酰氧基乙氧基乙基)甲胺分别与DSPC、胆固醇和DMG-PEG2000以50∶10∶37.5∶2.5的摩尔比溶于乙醇制备乙醇脂质溶液,并将荧光素酶Luciferase mRNA在10至100mM柠檬酸盐缓冲液(pH=4)中稀释得到mRNA水溶液。通过使用微流控装置以1∶4的体积比混合乙醇脂质溶液和mRNA水溶液,以总脂质与mRNA的质量比为15~30∶1制备纳米脂质体。经4℃静置透析12-24h(截留分子量:100KDa)除去乙醇并使用1×PBS代替。随后超滤浓缩至理想浓度。最后,脂质纳米颗粒通过0.22μm无菌过滤器过滤,得到使用阳离子脂质双(癸酰氧基乙氧基乙基)甲胺/DSPC/胆固醇/DMG-PEG2000(50/10/37.5/2.5mol%)包封荧光素酶Luciferase mRNA的LNP制剂,编号为3。
同实施例2方法测定荧光素酶Luciferase mRNA脂质纳米颗粒的大小(Size)、多分散指数(PDI)及脂质纳米颗粒的包封效率,结果如表3所示。
表3包封率
荧光素酶-mRNA-LNP制剂动物学研究
对6-8周龄的BALB/c小鼠以0.5mg/kg的剂量分别通过肌肉注射和尾静脉注射实施例6制备的荧光素酶Luciferase-mRNA-LNP制剂,对照组注射PBS。在给制剂后特定的时间节点小鼠腹腔注射150mg/kg剂量的D-Luciferin Potassium Salt(D-荧光素钾盐),腹腔注射10-15min后进行成像分析,使用小动物活体成像系统进行检测。在ATP和荧光素酶的催化作用下,底物被氧化发光(不同底物光的颜色和波长不同),当底物过量时,产生的光量子数与荧光素酶的浓度呈正相关性。本发明设计的阳离子脂质化合物组成的LNP制剂包裹荧光素酶-mRNA注射后小鼠体内递送水平如图6所示。图6显示了荧光素酶Luciferase-mRNA-LNP肌肉和尾静脉不同的注射方式分别在注射后6h、24h、48h递送至肝脏的表达情况。
实验证明,本发明的阳离子脂质化合物能够递送核酸分子、小分子化合物、多肽或蛋白质等。使用本发明的阳离子脂质化合物制备的载体对核酸分子的包封效率高,可将核酸分子成功转运至细胞中并进行表达。
以上例举仅仅是对本发明的举例说明,并不构成对本发明的保护范围的限制,凡是与本发明相同或相似的设计均属于本发明的保护范围之内。
Claims (15)
2.一种组合物,其特征在于:包括治疗或预防剂和用于递送所述治疗或预防剂的载体,所述载体包括阳离子脂质,所述阳离子脂质包括权利要求1中所示的阳离子脂质化合物、或其药物可用的盐中的一种或多种。
3.根据权利要求2所述的组合物,其特征在于:所述治疗或预防剂包括核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。
4.根据权利要求2或3所述的组合物,其特征在于:所述载体与所述治疗或预防剂的质量比为5∶1~45∶1。
5.根据权利要求2所述的组合物,其特征在于:所述组合物为纳米颗粒制剂,所述纳米颗粒制剂的平均尺寸为20nm~200nm;所述纳米颗粒制剂的多分散指数PDI≤0.5。
6.根据权利要求2所述的组合物,其特征在于:所述阳离子脂质还包括一种或多种其他可电离的脂质化合物。
7.根据权利要求2-5任一项所述的组合物,其特征在于:所述载体还包括中性脂质,所述阳离子脂质与所述中性脂质的摩尔比为1~10∶1。
8.根据权利要求7所述的一种组合物,其特征在于:所述中性脂质包括磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、神经酰胺、甾醇及其衍生物中的一种或多种。
9.根据权利要求2-5任一项所述的组合物,其特征在于:所述载体还包括结构脂质,所述阳离子脂质与所述结构脂质的摩尔比为1~5∶1。
10.一种如权利要求9所述的组合物,其特征在于:所述结构脂质包括胆固醇、非甾醇、谷固醇、麦角固醇、豆甾醇、番茄碱、皮质类固醇、菜油甾醇、芸苔甾醇、熊果酸中的一种或多种。
11.根据权利要求2-5任一项所述的组合物,其特征在于:所述载体还包括聚合物共轭脂质,所述阳离子脂质与所述聚合物共轭脂质的摩尔比为10~90∶1。
12.根据权利要求11所述的组合物,其特征在于:所述聚合物共轭脂质包括聚乙二醇-磷酸乙醇胺(PEG-PE)、聚乙二醇-磷脂酸(PEG-PA)、聚乙二醇-神经酰胺(PEG-Cer)、聚乙二醇-二肉豆蔻酰甘油(PEG-DMG)、聚乙二醇-二烷基胺、聚乙二醇-二酰基甘油、聚乙二醇-二烷基甘油中的一种或多种。
13.根据权利要求2至5中任一项所述的组合物,其特征在于:所述载体还包括中性脂质、结构脂质以及聚合物共轭脂质,所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为(10~40)∶(1~10)∶(5~35)∶1。
14.根据权利要求2所述的组合物,其特征在于:所述组合物还包括药物可用的赋形剂或稀释剂中的一种或多种。
15.一种如权利要求1所述的阳离子脂质化合物或其药物可用的盐,或权利要求2-14任一项所述的组合物在制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物中的应用。
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