CN114890907B - 一种阳离子脂质化合物及其制备方法和应用 - Google Patents
一种阳离子脂质化合物及其制备方法和应用 Download PDFInfo
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- CN114890907B CN114890907B CN202210344395.1A CN202210344395A CN114890907B CN 114890907 B CN114890907 B CN 114890907B CN 202210344395 A CN202210344395 A CN 202210344395A CN 114890907 B CN114890907 B CN 114890907B
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Classifications
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- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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Abstract
本发明公开了一种阳离子脂质化合物及其制备方法及其应用,阳离子脂质化合物在头部引入羟基,同时整体结构类似于锥形,头部小,尾部大;通过结构改进的配合,使得阳离子脂质化合物制备得到的脂质纳米粒均具有更好的生物相容性以及更高的体内mRNA转染效率,具有意想不到的技术效果;本发明阳离子脂质化合物的合成路线简单易行,原料廉价易得,有利于工业化生产;通过本发明的阳离子脂质化合物制成的脂质纳米粒具有稳定的纳米结构,可在低温储存较长时间,延长药品保质期的同时降低药品的运输条件。
Description
技术领域
本发明涉及生物医药领域,特别是一种阳离子脂质化合物及其制备方法和应用。
背景技术
基因治疗(gene therapy)是通过将外源基因导入靶细胞,以纠正或补偿缺陷、异常基因引起的疾病,达到治疗目的的一种治疗方法。核酸疫苗(nucleic acid vaccine),也称基因疫苗(genetic vaccine),是指将含编码免疫原蛋白或多肽的核酸序列(如DNA、mRNA等)导入宿主体内,通过宿主细胞表达免疫原蛋白或多肽,诱导宿主细胞产生对该免疫原的免疫应答,以达到预防和治疗疾病的目的。其中,确保外源基因的顺利导入是基因治疗过程和基因疫苗免疫极为重要的一环。在众多基因导入的方法中,开发合适的脂质纳米粒(Lipid Nanoparticle,LNP)包裹核酸,使其靶向至目标细胞,并将特定基因的核酸递送至细胞内的方法逐渐为科学家所使用。
核酸药物与普通化学药物的一个明显区别是核酸带有数量庞大的磷酸根,因而呈负电,且分子量大。为了使其能够被脂质纳米粒更好地包裹,人们开发了阳离子脂质等多种脂质化合物。
LNP是使用脂质化合物形成纳米粒的一种,具有双层或多层膜结构。外层膜主要是PEG脂质,也有中性脂质,内层膜主要是中性脂质,中间有些胆固醇作为结构脂质。纳米粒中分布有中性可离子脂质、阳离子脂质化合物及其包裹着的核酸。“脂质纳米粒”指使用阳离子脂质化合物等将需要递送的核酸等药物封装或缔合后形成的纳米囊泡体。脂质纳米粒和其组合物可以用于各种目的,包括在体外和体内将封装的或缔合的(例如,复合的)诸如核酸等治疗剂递送至细胞,从而诱导目标蛋白质的表达或者抑制靶基因的表达。
“阳离子脂质化合物”指能够带正电的脂质。示例性的阳离子脂质包括一种或多种带有正电荷的胺基团。优选的阳离子脂质是可电离的,可以根据pH值以带正电的形式或中性形式存在。阳离子脂质的电离影响脂质纳米粒在不同pH条件下的表面电荷。这种电荷状态可以影响其在血液中的免疫识别、血液清除和组织分布,以及其在细胞内的内含体逃逸的能力,对于核酸的细胞内递送是至关重要的。
递送核酸为了在生物系统中产生所期望的治疗效果和/或引发所期望的免疫应答,还存在着诸多挑战:第一,核酸分子易被体、外核酸酶降解;第二,核酸分子进入细胞、与目标细胞器相互作用、调节目标基因表达或目标蛋白表达的能力有限。由阳离子脂质与其他脂质组分(如助脂质、胆固醇和PEG化的脂质)和核酸形成的脂质纳米粒可以用于保护核酸不被降解并促进核酸的细胞摄取。市场需要一种生物相容性好、体内mRNA转染效率高、稳定性高、生物安全性高的mRNA-LNP,从而能够针对不同疾病(如代谢疾病、呼吸道疾病、心脑血管疾病、肿瘤等)、不同给药方式(肌肉注射、皮下注射、静脉注射、局部注射、吸入给药、经皮给药等)、不同的应用场景和目的(细胞治疗、基因编辑、靶向技术等)、及各种目前尚未满足的临床需求等,提供安全有效的核酸药物或疫苗的递送载体的选择。
发明内容
为解决现有技术的不足,本发明的目的在于提供一种阳离子脂质化合物及其制备方法和应用,通过本发明全新结构的阳离子脂质化合物制备得到的mRNA-LNP的生物相容性好、体内mRNA转染效率高、稳定性高、生物安全性高。
为了实现上述目标,本发明采用如下的技术方案:
一种阳离子脂质化合物,为如下结构的化合物:
R1为
R2为
R3为
R4为
R5为
R6为
R7为
R8为
R9为
R10为
R11为
M0、M1为:
M2、M3为:本发明的结构在头部引入羟基,同时整体结构类似于锥形,头小,尾部大。头部小,尾部大的具体意思为:以N原子为中心,带羟基的头部的分子结构空间占位比以烷烃链为结尾的尾部的分子结构空间占位小。通过结构改进的配合;使得阳离子脂质化合物均取得了更好的生物相容性以及更高的体内mRNA转染效率。
前述的一种阳离子脂质化合物,作为一种优选,M0、M1、M2、M3至少有两个为酯键,在脂质分子的疏水尾部引入可降解的酯键,可以改变脂质分子在体内的代谢行为,进而提高mRNA-LNP的生物安全性。前述的一种阳离子脂质化合物,作为一种实施例,
前述的一种阳离子脂质化合物,作为一种实施例,为如下的化合物:
前述的一种阳离子脂质化合物,作为一种实施例,为如下的化合物:
前述的一种阳离子脂质化合物,作为一种实施例,为如下的化合物:
前述的一种阳离子脂质化合物,作为一种实施例,为如下的化合物:
前述的一种阳离子脂质化合物,作为一种实施例,为如下的化合物:
前述的一种阳离子脂质化合物,作为一种实施例,为如下的化合物:
前述的一种阳离子脂质化合物,为如下的化合物:
前述的H-1、H-3-H-16,H-18-H-20结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:将长链烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与端烯长链烷基醇发生酯化反应合成,得到第一中间产物;
第二中间产物的合成:由间氯过氧苯甲酸将双键氧化生成环氧,得到第二中间产物;
阳离子脂质化合物的合成:加热条件下由胺与环氧发生开环反应,将阳离子的亲水头部与疏水尾部连接生成阳离子脂质化合物。
前述的H21、H23结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:将长链烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与长链烷基醇化合物发生酯化反应合成,得到第一中间产物;
阳离子脂质化合物的合成:将第一中间产物长链烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与三乙醇胺发生酯化反应合成。
前述的H22、H24结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:将长链烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与三乙醇胺发生酯化反应合成;
第二中间产物的合成:将长链烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与长链烷基醇化合物发生酯化反应合成,得到第二中间产物;
阳离子脂质化合物的合成:将第二中间产物溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与第一中间产物发生酯化反应合成。
前述的H25、H26、H27结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:碱性条件下长链烷基胺与二硫化碳反应后,在4-二甲氨基吡啶以及二碳酸二叔丁酯的催化下,生成相应的异硫氰酸酯;
第二中间产物的合成:在溶剂中,异硫氰酸酯与胺发生亲核取代反应,生成相应的硫脲;
第三中间产物的合成:将长链烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与长链烷基醇化合物发生酯化反应合成;阳离子脂质化合物的合成:将第三中间产物溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与第二中间产物发生酯化反应合成。
前述的H28、H29结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:碱性条件下,胺与三光气反应生成异氰酸酯,异氰酸酯与胺反应生成相应的含脲结构的第一中间产物;
第二中间产物的合成:将长链烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与长链烷基醇化合物发生酯化反应合成;
阳离子脂质化合物的合成:将第二中间产物溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与第一中间产物发生酯化反应合成。
前述的H17结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:亚油醇与溴代酰氯化合物在碱性条件下发生酯化反应得到溴代的长链烷烃;
第二中间产物的合成:由间氯过氧苯甲酸将双键氧化生成环氧;
第三中间产物的合成:碱性条件下由第一中间产物溴代的长链烷烃与胺发生亲核取代反应制得;
阳离子脂质化合物的合成:加热条件下由第二中间产物的环氧和第三中间产物的胺发生开环反应制得。
前述的H2结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:将长链烷基羧酸化合物溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与二元醇发生酯化反应合成;
第二中间产物的合成:将第一中间产物使用戴斯马丁氧化剂将长链烷基醇氧化成长链烷基醛制得;
阳离子脂质化合物的合成:使用胺和第二中间产物的醛基发生还原胺化反应制得。
前述的H30、H31结构的阳离子脂质化合物的制备方法,包括如下步骤:
第一中间产物的合成:由间氯过氧苯甲酸将双键氧化生成环氧,得到第一中间产物;
第二中间产物的合成:将长链环氧烷基羧酸溶于二氯甲烷后,在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺活化下与端烯长链烷基醇发生酯化反应合成,得到第二中间产物;
阳离子脂质化合物的合成:加热条件下由胺与环氧发生开环反应,将阳离子的亲水头部与疏水尾部连接生成阳离子脂质化合物。
前述的一种阳离子脂质化合物的应用,应用于包含阳离子脂质化合物的组合物、其立体异构体、其互变异构体或其在药学上可接受的盐。
前述的一种阳离子脂质化合物的应用,包含阳离子脂质化合物的组合物包括:载体,所载的药物试剂,药物辅助剂。
前述的一种阳离子脂质化合物的应用,载体为脂质纳米粒LNP,脂质纳米粒的平均尺寸为30-200nm,脂质纳米粒的制剂的多分散指数≤0.5。
前述的一种阳离子脂质化合物的应用,载体包括:一种或多种可电离的脂质化合物。
前述的一种阳离子脂质化合物的应用,载体还包括:助脂质,阳离子脂质化合物与助脂质的摩尔比为0.5:1-10:1;这样的摩尔比是一种优选,只要是采用本发明结构的阳离子脂质化合物的组合物均在本发明的保护范围内,均受本发明启示;助脂质包括:磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、甾醇及其衍生物、神经酰胺、带电脂质中的一种或几种的组合。
前述的一种阳离子脂质化合物的应用,载体还包括:结构脂质或聚合物缀合脂质。
前述的一种阳离子脂质化合物的应用,载体还包括:结构脂质,阳离子脂质化合物与结构脂质的摩尔比为0.5:1-5:1;这样的摩尔比是一种优选,只要是采用本发明结构的阳离子脂质化合物的组合物均在本发明的保护范围内,均受本发明启示。
前述的一种阳离子脂质化合物的应用,载体还包括:聚合物缀合脂质,阳离子脂质化合物与聚合物缀合脂质的摩尔比为20:1-250:1;聚合物缀合脂质为聚乙二醇化脂质。
前述的一种阳离子脂质化合物的应用,所载的药物试剂包括:核酸分子,小分子化合物,多肽或蛋白质中的一种或多种;药物试剂的选择和复配不受限制,只要是采用了本发明结构的阳离子脂质化合物均在本发明的保护范围内,且均受本发明的启示。
前述的一种阳离子脂质化合物的应用,药物辅助剂包括:稀释剂,稳定剂,防腐剂或冻干保护剂中的一种或多种;药物辅助剂的选择和复配不受限制,只要是采用了本发明结构的阳离子脂质化合物均在本发明的保护范围内,且均受本发明的启示。
本发明的有益之处在于:
本发明的阳离子脂质化合物在头部引入羟基增加了化合物头部的亲水性,以及促进了纳米粒与细胞膜的融合,同时整体结构类似于锥形,头部(含氮原子的部分)小,尾部(疏水部分的长链烷烃)大;通过结构改进的配合,使得阳离子脂质化合物制备得到的脂质纳米粒均取得了更好的生物相容性以及更高的体内mRNA转染效率,具有意想不到的技术效果;
本发明的阳离子脂质化合物中间的胺电离后可以与核酸结合,利于包封;
本发明在阳离子脂质化合物的疏水尾部引入可降解的酯键,可在人体内酯分解酶的作用下迅速降解,酯键的引入可以改变脂质分子在人体内的代谢行为,进而提高mRNA-LNP的生物安全性;
本发明阳离子脂质化合物制备得到的脂质纳米粒都能形成稳定的纳米结构,尺寸分布较窄,尺寸随不同的脂质化合物结构的不同而有所变化,在30-200nm范围内;
本发明的脂质纳米粒的纳米结构稳定,可在低温储存120天-150天;
本发明相比现有技术普遍使用的阳离子脂质化合物(如MC3)的合成,合成路线简单易行,原料廉价易得,有利于工业化生产;
由本发明的阳离子脂质化合物制备得到的mRNA-LNP,能够针对不同疾病(如代谢疾病、呼吸道疾病、心脑血管疾病、肿瘤等)、不同给药方式(肌肉注射、皮下注射、静脉注射、局部注射、吸入给药、经皮给药等)、不同的应用场景和目的(细胞治疗、基因编辑、靶向技术等)、及各种目前尚未满足的临床需求,提供安全有效的核酸药物或疫苗的递送载体的选择。
附图说明
图1是本发明的H1的氢谱图;
图2是本发明的H2的氢谱图;
图3是本发明的H3的氢谱图;
图4是本发明的H4的氢谱图;
图5是本发明的H5的氢谱图;
图6是本发明的H6的氢谱图;
图7是本发明的H7的氢谱图;
图8是本发明的H8的氢谱图;
图9是本发明的H9的氢谱图;
图10是本发明的H10的氢谱图;
图11是本发明的H11的氢谱图;
图12是本发明的H12的氢谱图;
图13是本发明的H13的氢谱图;
图14是本发明的H14的氢谱图;
图15是本发明的H15的氢谱图;
图16是本发明的H16的氢谱图;
图17是本发明的H17的氢谱图;
图18是本发明的H18的氢谱图;
图19是本发明的H19的氢谱图;
图20是本发明的H20的氢谱图;
图21是本发明的H21的氢谱图;
图22是本发明的H22的氢谱图;
图23是本发明的H23的氢谱图;
图24是本发明的H24的氢谱图;
图25是本发明的H25的氢谱图;
图26是本发明的H26的氢谱图;
图27是本发明的H27的氢谱图;
图28是本发明的H28的氢谱图;
图29是本发明的H29的氢谱图;
图30是本发明实验三阳离子脂质化合物H-1形成的脂质纳米粒的透射电镜图。
术语、英文缩写解释说明:
核酸是脱氧核糖核酸(DNA)和核糖核酸(RNA)的总称,是由多个核苷酸单体组成的生物大分子;核酸由核苷酸组成,核苷酸单体由五碳糖、磷酸基、含氮碱基、或任何修饰基团组成。如果五碳糖是核糖,则形成的聚合物是RNA;如果五碳糖是脱氧核糖,则形成的聚合物是DNA。
核酸分子包括单链DNA、双链DNA、短异构体、mRNA、tRNA、rRNA、长链非编码RNA(lncRNA)、微小非编码RNA(miRNA和siRNA)、端粒酶RNA(Telomerase RNA Component)、小分子RNA(snRNA和scRNA)、环状RNA(circRNA)、合成miRNA(miRNA mimics、miRNA agomir、miRNAantagomir)、反义DNA、反义RNA、核酶(ribozyme)、不对称干扰RNA(aiRNA)、Dicer-substrate RNA(dsRNA)、小发夹RNA(shRNA)、转移RNA(tRNA)、信使RNA(mRNA)、gRNA、sgRNA、crRNA或tracrRNA、锁核酸(LNA)、肽核酸(PNA)、吗啉反义寡核苷酸、吗啉代寡核苷酸或生物定制寡核苷酸等。这里的举例也并非穷举,只要是由核苷酸单体聚合成的都可以应用于本发明。
药物可用的盐是指酸加成盐或碱加成盐。
其中酸加成盐的酸包括但不限于:盐酸、氢溴酸、硫酸、硝酸、磷酸、酸式磷酸盐、乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸,柠檬酸、环酰胺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚酸、葡糖酸、葡聚糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代戊二酸、甘油磷酸、乙醇酸、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、萘-1,5二甲酸、萘-2-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、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、季铵酸以及十一碳烯酸。
其中碱加成盐举例包括但不限于:钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐,锌盐、铜盐、锰盐、以及铝盐;有机碱包括但不限于氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、脱醇、2-二甲基氨基乙醇、2-二乙基氨基乙醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、肼苯胺、胆碱、甜菜碱、苯那敏(benethamine)、苄星青霉素(benzathine)、乙二胺、葡糖胺、甲基葡糖胺、可可碱、三乙醇胺、嘌呤、哌嗪、哌啶、N-乙基哌啶、以及聚胺树脂;优选地,有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
带电脂质是指一类脂质化合物以带正电荷或带负电荷的形式存在;其所带电荷不依赖于生理学范围内的pH,例如pH 3~9,不受pH的影响。带电脂质可以是合成的或天然来源的。带电脂质的实例包括但不限于DOTAP、DOTMA、18PA。
mRNA,信使RNA,中文译名:信使核糖核酸,是由DNA的一条链作为模板转录而来的、携带遗传信息能指导蛋白质合成的一类单链核糖核酸。mRNA可以是单顺反子mRNA也可以是多顺反子mRNA。mRNA也可以包含一种或多种功能性核苷酸类似物,功能性核苷酸类似物举例包括:假尿嘧啶核苷、1-甲基-假尿嘧啶核苷或5-甲基胞嘧啶等。这里的举例也并非穷举,任何修饰的mRNA或其衍生物都可以应用于本发明。
小分子化合物可以是用于治疗或预防的试剂中的有效成分,例如:抗肿瘤药、抗感染药、局部麻醉药、抗抑郁药、抗惊厥药、抗生素/抗菌剂、抗真菌药、抗寄生虫药、激素、激素拮抗剂、免疫调节剂、神经递质拮抗剂、抗青光眼剂、麻醉剂、或成像剂等,这里并非穷举。
多肽是α-氨基酸以肽键连接在一起而形成的化合物,是蛋白质水解的中间产物。
蛋白质是由氨基酸以“脱水缩合”的方式组成的多肽链经过盘曲折叠形成的具有一定空间结构的物质;蛋白质可以是干扰素、蛋白质激素、细胞因子、趋化因子或者酶类等。
稀释剂是本领域技术人员可知的任意可以药用的水溶性辅料,包括:氨基酸、单糖、二糖、三糖、四糖、五糖、其它寡聚糖、甘露醇、右旋糖苷、氯化钠、山梨醇、聚乙二醇、磷酸盐,或其衍生物等。
稳定剂可以是本领域技术人员可知的任意可以药用的辅料:吐温-80,十二烷基硫酸钠,油酸钠,甘露醇,甘露糖或海藻酸钠等。
防腐剂可以是本领域技术人员可知的任意可以药用的防腐剂,比如:硫柳汞等。
冻干保护剂可以是领域技术人员可知的任意可以药用的冻干保护剂,比如:葡萄糖、甘露醇、蔗糖、乳糖,海藻糖,麦芽糖等。
DSPC:英文名称:Distearoyl Phosphatidylcholine,1,2-distearoyl-sn-glycero-3-phosphocholine;中文名称:二硬脂酰基卵磷脂,CAS号:816-94-4。
DPPC:中文名称:二棕榈酸磷脂酰胆碱;英文名称:1,2-DIPALMITOYL-SN-GLYCERO-3-PHOSPHOCHOLINE,CAS号:63-89-8。
DMPC:中文名称:二肉豆蔻酰磷脂酰胆碱;英文名称:1,2-Dimyristoyl-sn-glycero-3-phosphocholine,CAS号:18194-24-6。
DOPC:中文名称:1,2-二油酰基-sn-甘油-3-磷酸胆碱;英文名称:1,2-dioleoyl-sn-glycero-3-phosphocholine,CAS号:4235-95-4。
POPC:中文名称:2-油酰-1-棕榈锡甘油-3-磷酸胆碱;英文名称:2-Oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine,CAS号:26853-31-6。
DOPE:中文名称:1,2-二油酰-SN-甘油-3-磷酰乙醇胺;英文名称:1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE,CAS号:4004-05-1。
DOTAP:中文名称:(1,2-二油氧基丙基)三甲基氯化铵,;英文名称:1,2-dioleoyl-3-trimethylammonium-propane(chloride salt),CAS号:132172-61-3;化学结构式如下所示:
DOTMA:中文名称:N,N,N-三甲基-2,3-双(十八碳-9-烯-1-基氧基)丙-1-铵氯化物,CAS号:1325214-86-5,化学结构式如下所示:
18PA:CAS号:108392-02-5,化学结构式如下所示:
SM:中文名称:鞘磷脂(SM);英文名称:sphingomyelin。
PEG:中文名称:聚乙二醇;英文名称:Polyethylene glycol。
具体实施方式
以下结合附图和具体实施例对本发明作具体的介绍。
本发明的阳离子脂质化合物,为如下结构的化合物:
R1为
R2为
R3为
R4为
R5为
R6为
R7为
R8为
R9为/>
R10为
R11为
M0、M1为:
M2、M3为:
本发明的结构类似于锥形,头部小,尾部大,通过这样的结构和在头部引入羟基配合;使得阳离子脂质化合物均取得了更好的生物相容性以及更高的体内mRNA转染效率,这样意想不到的技术效果。
通过以下实施例1-7的制备方法制备阳离子脂质化合物。
实施例1:
化合物c的合成:将2-己基癸酸(化合物b,9.22g,36mmol)溶于100mL二氯甲烷(DCM)中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,9.2g,36mmol),4-二甲氨基吡啶(DMAP,1.46g,12mmol)以及N,N-二异丙基乙胺(DIPEA,7.74g,60mmol),搅拌10min后,加入5-己烯-1-醇(化合物a,3g,30mmol),室温搅拌过夜。TLC监测反应完全后,旋蒸仪减压蒸馏除去二氯甲烷。加入200mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相经无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去乙酸乙酯,柱分离纯化(硅胶柱,洗脱液为PE:EA=3:1(体积比)),得8.2g无色液体,收率81%。
化合物d的合成:将化合物c(8g,24mmol)溶于100mL DCM中,冰浴条件下加入间氯过氧苯甲酸(m-CPBA,7.2g,36mmol,质量分数85%),搅拌15min后,撤去冰浴,搅拌过夜。TLC监测反应完全后,加入过量的饱和亚硫酸氢钠溶液(10mL)以消耗未反应完的间氯过氧苯甲酸,旋蒸仪减压蒸馏除去二氯甲烷。加入200mL乙酸乙酯,200mL饱和碳酸氢钠溶液洗涤3次,200mL饱和氯化钠溶液洗涤1次,有机相经无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去乙酸乙酯,柱分离纯化(硅胶柱,洗脱液为PE:EA=1:1(体积比)),得6g无色液体,收率72%。
化合物H-15的合成:将二甘醇胺(化合物e,0.6g,6mmol)溶于无水甲醇中,加入化合物d(6g,17mmol),室温搅拌10min后,加热回流反应,反应12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。柱分离纯化(硅胶柱,洗脱液为DCM:MeOH=200:1(体积比)),得3.9g无色液体,收率85%。1H NMR(400MHz,Chloroform-d)δ4.05(t,J=6.5Hz,4H),3.86–3.74(m,2H),3.68–3.57(m,2H),2.80–2.53(m,5H),2.43(d,J=14.3Hz,1H),2.28(td,J=8.9,5.2Hz,2H),1.74–1.49(m,14H),1.48–1.34(m,10H),1.17–1.29(m,40H),0.85(t,J=6.6Hz,12H).MS m/z(ESI):814.72[M+H]+
采用实施例1的方法,制备得到化合物H-1,H-3,H-4,H-5,H-6,H-7,H-8,H-9,H-10,H-11,H-12,H-13,H-14,H-15,H-16,H-18,H-19,H-20。氢谱图见图1、3-16、18-20。
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需要说明的是:以上18个化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内。头部小,尾部大的具体意思为:以N原子为中心,带羟基的头部的分子结构空间占位比以烷烃链为结尾的尾部的分子结构空间占位小。
实施例2:
化合物c的合成:将辛二酸(化合物b,1.52g,8.71mmol)溶于50mL二氯甲烷中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,3.34g,17.4mmol),4-二甲氨基吡啶(DMAP,0.3g,2.4mmol)以及N,N-二异丙基乙胺(DIPEA,1.5g,11.6mmol),搅拌10min后,加入6-十一烷醇(化合物a,1g,5.8mmol)室温搅拌12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入100mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=20:1(体积比)),得1.2g无色液体,收率63%。
化合物H-21的合成:将化合物c(0.88g,2.68mmol)溶于20mL二氯甲烷中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,0.64g,3.35mmol),4-二甲氨基吡啶(DMAP,0.065g,0.54mmol)以及N,N-二异丙基乙胺(DIPEA,0.35g,2.68mmol),搅拌10min后,加入三乙醇胺(0.2g,1.34mmol)室温搅拌12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入50mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=1:1(体积比)),得0.4g无色液体,收率39%。1H NMR(400MHz,Chloroform-d)δ4.84(p,J=6.3Hz,2H),4.15(s,4H),3.55(s,2H),2.85(s,4H),2.76(s,2H),2.28(dt,J=14.1,7.5Hz,8H),1.66–1.57(m,8H),1.53–1.43(m,8H),1.36–1.18(m,32H),0.94–0.78(m,12H).MS m/z(ESI):770.71[M+H]+
采用实施例2的方法,制备得到化合物H-21,H-23:
氢谱图见图21、23。
需要说明的是:以上2个化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内。
实施例3
化合物b的合成:将十四烷酸(化合物a,1.57g,6.48mmol)溶于70mL二氯甲烷中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,1.86g,9.72mmol),4-二甲氨基吡啶(DMAP,0.32g,2.6mmol)以及N,N-二异丙基乙胺(DIPEA,1.67g,12.3mmol),搅拌10min后,加入三乙醇胺(2.9g,19.44mmol)室温搅拌12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入120mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=1:5(体积比)),得1.8g无色液体,收率74%。
化合物c的合成:参考实施例2中化合物c的合成方法。
化合物H-22的合成:将化合物c(0.88g,2.68mmol)溶于30mL二氯甲烷中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,0.51g,2.68mmol),4-二甲氨基吡啶(DMAP,0.13g,1.07mmol)以及N,N-二异丙基乙胺(DIPEA,0.52g,4.02mmol),搅拌10min后,加入化合物b(1g,2.68mmol)室温搅拌12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入70mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=1:1(体积比)),得1.0g无色液体,收率55%。1H NMR(400MHz,Chloroform-d)δ4.85(t,J=6.2Hz,1H),4.16(s,4H),3.56(s,2H),3.04–2.65(m,6H),2.39–2.16(m,6H),1.64–1.57(m,6H),1.51–1.45(m,4H),1.36–1.21(m,38H),0.91–0.80(m,9H).MS m/z(ESI):684.57[M+H]+
采用实施例3的方法,制备得到化合物H-22,H-24。
氢谱图见图22、24。
需要说明的是:以上2个化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内。
实施例4
化合物a的合成:将油胺(2g,7.48mmol)溶于50mL THF中,加入三乙胺(1.13g,11.21mmol),冰浴条件下滴加CS2(0.74g,9.72mmol),室温搅拌反应12h。之后,4-二甲氨基吡啶(DMAP,0.27g,2.24mmol),冰浴条件下加入二碳酸二叔丁酯((Boc)2O,2.12g,9.72mmol)室温搅拌反应3h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入100mL乙酸乙酯,等体积饱和氯化钠溶液洗3次,无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=100:1(体积比)),得1.78g浅黄色液体,收率77%。
化合物b的合成:将化合物a(0.5g,1.62mmol)溶于10mL DMF中,加化合物d(0.24g,1.62mmol),室温搅拌反应12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去大部分溶剂。加入70mL乙酸乙酯,等体积饱和氯化钠溶液洗3次,无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=1:1(体积比)),得0.5g无色液体,收率68%。
化合物c的合成:参考实施例2中化合物c的合成方法。
化合物H-25的合成:将化合物c(0.36g,1.09mmol)溶于20mL二氯甲烷中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,0.32g,1.64mmol),4-二甲氨基吡啶(DMAP,0.05g,0.44mmol)以及N,N-二异丙基乙胺(DIPEA,0.28g,2.81mmol),搅拌10min后,加入化合物b(0.5g,1.09mmol)室温搅拌12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入50mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=5:1(体积比)),得0.5g无色液体,收率60%。1H NMR(400MHz,Chloroform-d)δ7.02(s,1H),5.45–5.24(m,2H),4.85(t,J=6.3Hz,1H),4.30(t,J=6.2Hz,2H),3.97–3.75(m,6H),3.57(q,J=6.9Hz,2H),2.28(dt,J=14.9,7.4Hz,4H),2.04–1.92(m,4H),1.73(s,2H),1.66–1.56(m,6H),1.53–1.45(m,4H),1.41–1.16(m,42H),0.90–0.82(m,9H).MS m/z(ESI):768.62[M+H]+。
采用实施例4的方法,制备得到化合物H-25,H-26,H-27,氢谱图见图25、26、27。
需要说明的是:以上3个化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内;头部小,尾部大的具体意思为:以N原子为中心,带羟基的头部的分子结构空间占位比以烷烃链为结尾的尾部的分子结构空间占位小。
实施例5
化合物b的合成:将油胺(1g,3.74mmol)溶于50mL DCM,加入三乙胺(1.13g,11.21mmol),冰浴条件下滴加三光气(0.44g,1.5mmol),室温搅拌反应3h。TLC监测油胺反应完全后,旋蒸仪减压蒸馏除去溶剂。加入30mL DMF,然后加入化合物a(1.11g,7.48mmol),室温搅拌反应12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去大部分溶剂。加入100mL乙酸乙酯,等体积饱和氯化钠溶液洗3次,无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=1:1(体积比)),得1.0g浅黄色液体,收率61%。
化合物c的合成:参考实施例2中化合物c的合成方法。
化合物H-28的合成:将化合物c(0.5g,1.52mmol)溶于20mL二氯甲烷中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,0.44g,2.28mmol),4-二甲氨基吡啶(DMAP,0.07g,0.61mmol)以及N,N-二异丙基乙胺(DIPEA,0.39g,3.04mmol),搅拌10min后,加入化合物b(0.67g,1.52mmol)室温搅拌12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入100mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=5:1(体积比)),得0.4g无色液体,收率35%。1H NMR(400MHz,Chloroform-d)δ5.40–5.25(m,2H),4.85(dt,J=12.0,6.1Hz,1H),4.18(t,J=6.1Hz,2H),3.78–3.71(m,2H),3.49–3.39(m,4H),3.18(t,J=7.3Hz,2H),2.28(dt,J=14.7,7.4Hz,4H),2.06–1.81(m,8H),1.67–1.55(m,4H),1.54–1.43(m,6H),1.36–1.18(m,38H),0.93–0.79(m,9H).MS m/z(ESI):752.64[M+H]+。
采用实施例5的方法,制备得到化合物H-28,H-29,氢谱图见图28、29。
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需要说明的是:以上2个化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内。
实施例6
化合物b的合成:将亚油醇(1.25g,4.68mmol)溶于50mL DCM中,加入三乙胺(0.62g,6.09mmol),冰浴搅拌10min后,滴加6-溴己酰氯(化合物a,1g,4.68mmol),逐渐恢复室温,室温搅拌反应12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入100mL乙酸乙酯,等体积饱和碳酸氢钠溶液洗3次,等体积饱和氯化钠溶液洗3次,无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=200:1(体积比)),得1.8g无色液体,收率87%。
化合物d的合成:参考化合物H-15合成过程中的化合物d的合成方法。
化合物e的合成:将b(1.5g,3.38mmol)溶于50mL无水乙醇中,加入三乙胺(0.44g,4.4mmol),加化合物c(1.07g,10.25mmol),50℃加热搅拌反应24h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入100mL乙酸乙酯,等体积饱和氯化钠溶液洗3次,无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为DCM:MeOH=20:1(体积比)),得1.1g无色液体,收率70%。
化合物H-17的合成:将化合物e(0.4g,0.85mmol)溶于无10mL水甲醇中,加入化合物d(0.3g,0.85mmol),搅拌10min后,加热回流反应,反应12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=5:1(体积比)),得0.4g无色液体,收率57%。1H NMR(400MHz,Chloroform-d)δ5.41–5.28(m,4H),4.09–3.99(m,4H),3.79–3.50(m,7H),2.76(t,J=6.5Hz,2H),2.64–2.44(m,3H),2.37–2.24(m,4H),2.03(q,J=6.9Hz,4H),1.68–1.19(m,56H),0.86(q,J=6.6Hz,9H).MS m/z(ESI):822.72[M+H]+
采用实施例6的方法,制备得到化合物H-17,氢谱图见图17。
需要说明的是:以上H-17化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内。
实施例7
化合物c的合成:将2-己基癸酸(化合物b,1.6g,5.64mmol)溶于50mL二氯甲烷中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,1.3g,6.77mmol),4-二甲氨基吡啶(DMAP,0.28g,2.26mmol)以及N,N-二异丙基乙胺(DIPEA,1.09g,8.46mmol),搅拌10min后,加入己二醇(化合物a,1g,8.46mmol)室温搅拌12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入100mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=50:1(体积比)),得1.5g无色液体,收率69%。
将化合物d(1.0g,2.6mmol)溶于50mL DCM中,加入NaHCO3(1.75g,20.8mmol),搅拌5min后,加入化合物戴斯-马丁氧化剂(Dess-Martin Periodinane,1.75g,4.16mmol)室温搅拌3h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入石油醚,等体积饱和碳酸氢钠溶液洗3次,等体积饱和食盐水洗1次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=10:1(体积比)),得0.5g无色液体,收率50%。
化合物H-2的合成:将化合物d(0.3g,0.78mmol)溶于10mL DCM中,加入化合物e(0.08g,0.78mmol),搅拌10min后,加三乙酰氧基硼氢化钠(0.22g,1.02mmol)室温搅拌过夜。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。加入50mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相使用无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去溶剂,柱分离纯化(硅胶柱,洗脱液为PE:EA=5:1(体积比)),得0.3g无色液体,收率46%。1H NMR(400MHz,Chloroform-d)δ4.03(t,J=6.7Hz,4H),3.75–3.55(m,6H),2.75–2.39(m,6H),2.27(t,J=7.5Hz,4H),1.77–0.97(m,70H),0.91–0.75(m,12H).MS m/z(ESI):838.79[M+H]+
采用实施例7的方法,制备得到化合物H-2,氢谱图见图2。
需要说明的是:以上H-2化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内。
实施例8:
化合物b的合成:将化合物a(5g,29mmol)溶于100mL DCM中,冰浴条件下加入间氯过氧苯甲酸(m-CPBA,8.9g,44mmol,质量分数85%),搅拌15min后,撤去冰浴,搅拌过夜。TLC监测反应完全后,加入过量的饱和亚硫酸氢钠溶液(10mL)以消耗未反应完的间氯过氧苯甲酸,旋蒸仪减压蒸馏出去二氯己烷。加入200mL乙酸乙酯,200mL饱和碳酸氢钠溶液洗涤3次,200mL饱和氯化钠溶液洗涤1次,有机相经无水硫酸钠干燥30min,旋蒸仪减压蒸馏出去乙酸乙酯,柱分离纯化(硅胶柱,洗脱液为PE:EA=1:2(体积比)),得4.5g无色液体,收率82%。
化合物d的合成:将化合物b(3.0g,16mmol)溶于50mL二氯甲烷(DCM)中,加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(EDC,4.01g,21mmol),4-二甲氨基吡啶(DMAP,0.79g,6mmol)以及N,N-二异丙基乙胺(DIPEA,3.12g,24mmol),搅拌10min后,加入己-5-烯-2-醇(化合物c,1.94g,19mmol),室温搅拌过夜。TLC监测反应完全后,旋蒸仪减压蒸馏除去二氯甲烷。加入100mL乙酸乙酯,等体积饱和氯化钠溶液洗涤3次,有机相经无水硫酸钠干燥30min,旋蒸仪减压蒸馏除去乙酸乙酯,柱分离纯化(硅胶柱,洗脱液为PE:EA=20:1(体积比)),得3.5g无色液体,收率81%。
化合物H-30的合成:将二甘醇胺(化合物e,0.65g,6mmol)溶于无水甲醇中,加入化合物d(5g,19mmol),室温搅拌10min后,加热回流反应,反应12h。TLC监测反应完全后,旋蒸仪减压蒸馏除去溶剂。柱分离纯化(硅胶柱,洗脱液为DCM:MeOH=100:1(体积比)),得3.0g无色液体,收率75%。MS m/z(ESI):642.47[M+H]+。
采用实施例8的方法,制备得到化合物H-30、H-31;
需要说明的是:以上H-30、H31化合物并非穷举,只要是采用本发明的合成思路,头部带羟基,整体结构头部小,尾部大的阳离子脂质化合物均落在本发明的保护范围内。
作为一种应用,以上化合物可以用于制备医药用途的组合物,组合物包括:载体,所载的药物试剂,药物辅助剂;
载体包括:一种或多种可电离的脂质化合物,助脂质,结构脂质或聚合物缀合脂质。作为一种实施例,载体为脂质纳米粒(LNP),脂质纳米粒的平均尺寸为30-200nm,纳米粒制剂的多分散指数≤0.5。需要说明的是:一种或多种本发明阳离子脂质化合物制备成的任何纳米粒都在本专利范围内,均受本发明的启示;比如:除了脂质纳米粒还可能是一种或多种阳离子脂质化合物与高分子形成的杂化纳米粒,比如:PLGA-PEG,PLA-PEG,PCL等这里不再穷举。
助脂质包括:磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂(SM)、甾醇及其衍生物、神经酰胺、带电脂质中的一种或几种的组合;磷脂酰胆碱作为一种优选包括:DSPC,DPPC,DMPC,DOPC,POPC;磷脂酰乙醇胺作为一种优选为DOPE;甾醇作为一种优选为胆固醇;带电脂质作为一种实施例为DOTAP、DOTMA、18PA;这里并非穷举,只要是采用本发明结构的阳离子脂质化合物的组合物均在本发明的保护范围内,均受本发明启示。这里并非穷举,助脂质的选择不受限制,只要是采用本发明结构的阳离子脂质化合物均在本发明的保护范围内,均受本发明启示。
结构脂质包括:胆固醇、非甾醇、谷固醇、麦角固醇、菜油甾醇、豆甾醇、芸苔甾醇、番茄碱、番茄碱、熊果酸、α-生育酚或皮质类固醇中的一种或几种。这里并非穷举,结构脂质的选择不受限制,只要是采用本发明结构的阳离子脂质化合物均在本发明的保护范围内,均受本发明启示。
聚合物缀合脂质为聚乙二醇化脂质;作为一种实施例,聚乙二醇化脂质包括:PEG修饰的磷脂酰乙醇胺、PEG修饰的磷脂酸、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油或PEG修饰的二烷基甘油中的一种或多种。这里并非穷举,聚合物缀合脂质的选择不受限制,只要是采用本发明结构的阳离子脂质化合物均在本发明的保护范围内,均受本发明启示。
所载的药物试剂包括:核酸分子,小分子化合物,多肽或蛋白质中的一种或多种。这里并非穷举,只要是采用本发明结构的阳离子脂质化合物,无论选用何种药物试剂均可以应用于本发明,均在本发明的保护范围内,均受本发明启示。
药物辅助剂包括:稀释剂,稳定剂,防腐剂或冻干保护剂中的一种或多种。这里并非穷举,只要是采用本发明结构的阳离子脂质化合物,无论选用何种药物辅助剂复配,均在本发明的保护范围内,均受本发明启示。
实验一:脂质纳米粒的制备和检测:
H-1到H-29的化合物制备mRNA-LNP用于以下实验:
将阳离子脂质,DSPC或DOPE(艾维拓(上海)医药科技有限公司),胆固醇(艾维拓(上海)医药科技有限公司),以及PEG-脂质以设计的处方配比(Lipid(阳离子脂质化合物)/DOPC/Cholesterol(胆固醇)/DMG-PEG(缀合脂质)为40/10/50/1.7(摩尔比)),溶于乙醇中(Lipid的浓度20mg/mL),并充分混匀。脂质纳米粒(LNP)与mRNA的质量比为10:1到30:1。使用柠檬酸盐或醋酸钠缓冲液(pH=3或5)将mRNA稀释至0.2mg/mL。将上述阳离子脂质乙醇溶液与mRNA溶液以体积比为1:5到1:1的比例充分混匀。所获纳米粒通过超滤和透析的手段纯化。过滤除菌。使用Malvern Zetasizer Nano ZS,以173反相散射检测模式通过动态光散射表征mRNA-LNP(包载mRNA的脂质纳米粒)的粒径和粒径分布指数(particle dispersionindex,PDI),粒径分布指数体现了粒子粒径均一程度,是粒径表征的一个重要指标。mRNA的包封率均使用Ribogreen RNA定量测定试剂盒(Thermo Fisher)测定。见表1。
表1
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实验二,采用实验一制得的样品进行脂质纳米粒动物试验:
雄性ICR小鼠(6-8week,上海杰思捷实验动物有限公司)饲养在22±2℃以及相对湿度为45–75%的实验条件下,光照/黑暗周期为12h。使用编码荧光素酶的mRNA(luciferase mRNA)作为报道基因。荧光素酶催化荧光素产生生物荧光,通过检测单位时间内生物荧光强度,反映LNP的转染效率。以荧光素酶mRNA(购自ApexBio Technology)为例,将上述获得的mRNA-LNP样品1-29,将现有的商业可得的化合物MC3:作为对比样品,用MC3公知最优PEG-脂质处方配比(Lipid(阳离子脂质)/DSPC/Cholesterol(胆固醇)/DMG-PEG(缀合脂质)为50/10/38.5/1.5(摩尔比))制得的脂质纳米粒作为对比样品进行阳性对照,以150μg/kg mRNA的剂量,通过肌肉注射给药,每组样品一只小鼠,两条腿。取特定的时间点,于小鼠腹腔注射荧光素(20μg/mL),5分钟后,将小鼠置于小动物活体成像仪测定荧光强度,最后的结果以平均荧光强度表示,小鼠腹腔注射给药后荧光强度实验结果如表2所示。
表2
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结果显示,相较于现有的商业可得的阳离子脂质化合物MC3,本发明的阳离子脂质化合物均取得了显著更好的生物相容性以及显著更高的体内mRNA转染效率。
实验三:采用实验一制得的样品进行脂质纳米粒结构稳定性实验:
透射电镜样品的制备及表征(以样品1为例)。在铜网上滴上10μ制备好的样品15L,放置10min后吸干样品并晾干。醋酸双氧铀染色5min,滤纸吸干染液后干燥过夜,利用透射电子显微镜(TEM)观察其形貌。
如图30所示,本发明的脂质纳米粒都能形成稳定的纳米结构,尺寸分布较窄(PDI小),尺寸随不同的脂质纳米粒的结构有所变化,在30-200nm范围内。
实验四:采用实验一制得的样品和实验二的对比样品进行生物相容性验证实验:
使用CCK-8(cell counting kit-8)试剂盒测定细胞活力。将处于指数增长期的Hep3B细胞(100μL,细胞密度为2×104个/ml)悬浮液加入96孔板中,于细胞培养箱中孵育24h,然后从每个孔中除去细胞培养液,并添加100μL含mRNA20μg/mL的LNP的新制细胞培养液,和细胞共孵育4h。随后,除去细胞上清液,加入新鲜细胞培养液,继续孵育20h。然后,除去上清液,加入含CCK-8工作溶液(10μL/mL)的新鲜的细胞培养液100μL,孵育2h,空白孔的设置:加含CCK-8工作溶液的细胞培养液。使用多功能微孔板检测仪检测每孔于450nm处的吸光度(检测过程中孔板中不能出现气泡),将未经LNP处理的细胞作为对照组,将其细胞活力设为100%。
细胞活力(%)=[A1-A0]/[A2-A0]×100。
A1为加药组吸光度,A0为空白组吸光度,A2为对照组吸光度。实验结果如表3所示。
表3
实验结果表明在限定的LNP浓度内,大多数的细胞活力不小于95%,未见明显细胞毒性。
实验五:脂质纳米粒低温储存效果实验:
以样品1为例,将按照配方制作的脂质纳米粒置于4℃条件下低温保存,取不同时间点(0天、6天、10天、15天、30天、45天),使用Malvern Zetasizer Nano ZS表征mRNA-LNP(包载mRNA的脂质纳米粒)的粒径(Size)和PDI,mRNA的包封率均使用Ribogreen RNA定量测定试剂盒(Thermo Fisher)测定。测定结果见表4所示。
表4
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由表4可知:本发明的脂质分子形成的LNP(脂质纳米粒)可在低温储存较长时间,方便产品的运输和保存。
综上所述,本发明在结构上,在阳离子脂质化合物的头部引入羟基,增加脂质化合物头部的亲水性,以及纳米粒与细胞膜的融合,同时整体结构类似于锥形,头部(含氮原子的部分)小,尾部(疏水部分的长链烷烃)大,通过结构改进的配合;使得阳离子脂质化合物制备得到的脂质纳米粒均取得了更好的生物相容性以及更高的体内mRNA转染效率;化合物在疏水尾部引入可降解的酯键,可在人体内酯分解酶的作用下迅速降解,相对于MC3的长链烷烃,酯键的引入可以改变脂质分子在体内的代谢行为,进而提高mRNA-LNP的生物安全性;在合成上,MC3需要五步反应制得,且反应过程中涉及到危险性较高的格氏试剂;本发明相比较MC3的合成路线简单易行,原料廉价易得,有利于其工业化生产。本发明化合物制备得到的LNP(脂质纳米粒)可在低温储存较长时间,方便产品的运输和保存,所以本发明设计的新阳离子脂质化合物具有良好的应用前景。
这里需要说明的是:本发明阳离子脂质化合物是一种药物原料、药物产品,不涉及任何疾病的治疗方法或诊断方法,属于可以授予专利权利的范围。
以上显示和描述了本发明的基本原理、主要特征和优点。本行业的技术人员应该了解,上述实施例不以任何形式限制本发明,凡采用等同替换或等效变换的方式所获得的技术方案,均落在本发明的保护范围内。
Claims (12)
1.一种阳离子脂质化合物,其特征在于,所述的化合物选自下组:
,
,
,
,
,
,
,
。
2.一种阳离子脂质化合物,其特征在于,所述的化合物选自下组:
。
3.根据权利要求1-2任意所述的一种阳离子脂质化合物、其立体异构体、其互变异构体或其在药学上可接受的盐的应用,其特征在于,应用于制备包含所述的阳离子脂质化合物的组合物。
4.根据权利要求3所述的一种阳离子脂质化合物的应用,其特征在于,所述包含阳离子脂质化合物的组合物包括:载体,所载的药物试剂,药物辅助剂。
5.根据权利要求4所述的一种阳离子脂质化合物的应用,其特征在于,所述载体为脂质纳米粒LNP,所述脂质纳米粒的平均尺寸为30-200nm,所述脂质纳米粒的制剂的多分散指数≤0.5。
6.根据权利要求5所述的一种阳离子脂质化合物的应用,其特征在于,所述载体包括:一种或多种可电离脂质化合物。
7.根据权利要求6所述的一种阳离子脂质化合物的应用,其特征在于,所述载体还包括:助脂质;所述阳离子脂质化合物与助脂质的摩尔比为0.5:1-10:1;所述助脂质包括:磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、甾醇及其衍生物、神经酰胺、带电脂质中的一种或几种的组合。
8.权利要求6或7所述的一种阳离子脂质化合物的应用,其特征在于,所述载体还包括:结构脂质或聚合物缀合脂质。
9.根据权利要求8所述的一种阳离子脂质化合物的应用,其特征在于,所述载体还包括:结构脂质;所述阳离子脂质化合物与结构脂质的摩尔比为0.5:1-5:1。
10.根据权利要求7所述的一种阳离子脂质化合物的应用,其特征在于,所述载体还包括:聚合物缀合脂质;所述阳离子脂质化合物与聚合物缀合脂质的摩尔比为20:1-250:1;所述聚合物缀合脂质为聚乙二醇化脂质。
11.根据权利要求3所述的一种阳离子脂质化合物的应用,其特征在于,所述所载的药物试剂包括:核酸分子,小分子化合物,多肽或蛋白质中的一种或多种。
12.根据权利要求3所述的一种阳离子脂质化合物的应用,其特征在于,所述药物辅助剂包括:稀释剂,稳定剂,防腐剂或冻干保护剂中的一种或多种。
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