CN116082184A - 基于环己二胺的可电离脂质、脂质纳米颗粒及其制备方法与应用 - Google Patents
基于环己二胺的可电离脂质、脂质纳米颗粒及其制备方法与应用 Download PDFInfo
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- CN116082184A CN116082184A CN202310385922.8A CN202310385922A CN116082184A CN 116082184 A CN116082184 A CN 116082184A CN 202310385922 A CN202310385922 A CN 202310385922A CN 116082184 A CN116082184 A CN 116082184A
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Abstract
本发明属于生物医药技术领域，涉及药物递送技术，具体涉及基于环己二胺的可电离脂质、脂质纳米颗粒及其制备方法与应用。其为式(a)所示化合物；
其中，n独立地选自0~8的自然数；R1、R2、R3、R4独立地选自C8‑C24烷基、取代基团取代的C8‑C24烷基、C8‑C24烯基、取代基团取代的C8‑C24烯基、C8‑C24炔基、取代基团取代的C8‑C24炔基。本发明提供的基于环己二胺的可电离脂质形成脂质纳米颗粒具有可生物降解性及高效的体内外转染效率等优点，临床应用前景良好。
Description
技术领域
本发明属于生物医药技术领域，涉及药物递送技术，具体涉及基于环己二胺的可电离脂质、脂质纳米颗粒及其制备方法与应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
脂质纳米颗粒（LNP）递送技术可实现核酸药物的高效递送，LNP通常由可电离脂质、辅助磷脂、胆固醇和PEG脂质四种成分组成。其中，可电离脂质材料作为关键组分，有利于保护核酸并促进其在体内的运输。基因治疗存在核酸药物容易被血浆和组织中的核酸酶降解、造成免疫原性、难以跨膜进入胞内的问题。因而需要开发高效、安全的核酸药物递送系统对基因疾病及无特效药的蛋白过表达/缺失疾病，包括预防性疾病、遗传性疾病和肿瘤等疾病的治疗具有重要意义。
发明内容
为了解决现有技术的不足，本发明的目的是提供基于环己二胺的可电离脂质、脂质纳米颗粒及其制备方法与应用，本发明提供的基于环己二胺的可电离脂质形成脂质纳米颗粒具有可生物降解性及高效的体内外转染效率等优点，临床应用前景良好。
为了实现上述目的，本发明的技术方案为：
一方面，一种基于环己二胺的可电离脂质，其为式(a)所示化合物、式(a)所示化合物的药学上可接受的盐、式(a)所示化合物的立体异构体、式(a)所示化合物互变异构体、式(a)所示化合物的溶剂化物、式(a)所示化合物的螯合物、式(a)所示化合物的非共价复合物或式(a)所示化合物的前体药物；
其中，n独立地选自0~8的自然数；
R1、R2、R3、R4独立地选自C8-C24烷基、取代基团取代的C8-C24烷基、C8-C24烯基、取代基团取代的C8-C24烯基、C8-C24炔基、取代基团取代的C8-C24炔基。
另一方面，一种上述基于环己二胺的可电离脂质的制备方法，包括按照如下反应式获得式(a)所示化合物的步骤；
其中，n独立地选自0~8的自然数；
R1、R2、R3、R4独立地选自C8-C24烷基、取代基团取代的C8-C24烷基、C8-C24烯基、取代基团取代的C8-C24烯基、C8-C24炔基、取代基团取代的C8-C24炔基。
第三方面，一种脂质纳米颗粒，由上述基于环己二胺的可电离脂质、辅助脂质、固醇和PEG脂质组成。
第四方面，一种药物组合物，包括上述基于环己二胺的可电离脂质或脂质纳米颗粒和活性成分，所述活性成分为核酸药物。
第五方面，一种上述脂质纳米颗粒或药物组合物在制备药物中的应用。
本发明的有益效果为：
1. 本发明通过引入环己二胺及立体异构，改进可电离脂质分子的结构，得到一种新型的可电离脂质化合物，该类化合物的六元环结构有利于核酸药物顺利进入细胞，结构中的酰胺键可在体内可快速被酶水解，易于代谢清除，具有优良的生物可降解性和生物相容性和可降解性。该化合物在酸性条件下可以获得氢质子，具有正电性，可与带负电的核酸分子通过静电相互作用相结合，增加核酸药物的稳定性并延长其在体内的循环时间、改善药物动力学特征，无明显毒副作用，具有良好的临床应用前景。
2.本发明所提供的可电离脂质通过简单的迈克尔加成合成及缩合反应制备而来，合成具有不同支链长度的可电离脂质。原料成本较低，合成步骤简单，产物分离便捷，易于储存。
3. 本发明所提供的可电离脂质与辅助磷脂、胆固醇和PEG脂质制成的LNP，具有更加优异的核酸载体性能，可有效递送siRNA、mRNA、pDNA等核酸药物进入细胞内发挥作用。
4. 本发明的脂质纳米颗粒的制备方法方便快捷，设备要求较低，工艺可靠。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为本发明实施例中不同可电离脂质所制备mRNA-LNP的粒径表征图；
图2为本发明实施例中不同可电离脂质所制备mRNA-LNP的电位表征图；
图3为本发明实施例中不同可电离脂质所制备mRNA-LNP的包封率表征图；
图4为本发明实施例中不同可电离脂质所制备mRNA-LNP的转染效率表征图。
具体实施方式
应该指出，以下详细说明都是示例性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
本发明术语“核酸”涉及脱氧核糖核苷酸(DNA)、核糖核苷酸(RNA)及其修饰的形式的聚合物，所述聚合物呈单独的片段或作为较大构建体的组分、直链或支链的、单链、双链、三链或其杂合体的形式。该术语还包括RNA/DNA杂合体。
本发明术语“脂质”是指一组有机化合物，其包括但不限于脂肪酸的酯，并且通常以难溶于水但可溶于许多有机溶剂为特征。
本发明术语“脂质纳米颗粒”是指具有至少一个纳米量级尺寸的颗粒，其包含至少一种脂质。
本发明术语“递送系统”是指调控生物活性成分在空间、时间及剂量在生物体内分布的制剂或组合物。
本发明术语“环己二胺”，是指2个氢原子被氨基取代的含6个碳原子的环烷烃。
本发明术语“烷基”指饱和的脂族烃基团，包括直链和支链烷基基团。C8-24烷基的取代基团为一个或更多个卤素、羟基、氨基、烷氧基羰基、酰氨基、烷基酰氨基、二烷基酰氨基、硝基、烷基氨基、二烷基氨基、羧基、硫代烷基、杂原子取代基团（氧代、硫代）。
本发明术语“烯基”指不饱和的脂族烃基团，包括直链和支链烯基基团。C8-24烯基的取代基团为一个或更多个选自卤素、羟基、氨基、烷氧基羰基、酰氨基、烷基酰氨基、二烷基酰氨基、硝基、烷基氨基、二烷基氨基、羧基、硫代烷基、杂原子取代基团（氧代、硫代）。
本发明术语“炔基”指不饱和的脂族烃基团，包括直链和支链炔基基团。C8-24炔基的取代基团为一个或更多个选自卤素、羟基、氨基、烷氧基羰基、酰氨基、烷基酰氨基、二烷基酰氨基、硝基、烷基氨基、二烷基氨基、羧基、硫代烷基、杂原子取代基团（氧代、硫代）。
本发明术语“取代的”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基团取代。
本发明术语“药用辅料”指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，在安全性方面已进行了合理的评估，且包含在药物制剂中的物质。药用辅料可以是阿拉伯胶、糖浆、羊毛脂、淀粉、氯化镁、环糊精、癸二酸、糊精、药用硫酸钙、甘油、甘露醇、山梨醇、肌醇、硫醇、氨丁三醇、苯酚、间甲酚、苯甲醇、对羟基苯甲酸酯、对羟基苯甲酸甲酯、叔丁醇、苯扎氯铵、氯丁醇、硫柳汞等。
本发明术语“立体异构体” 指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。立体异构体可以是烯烃的双键，也有C=N双键，N=N双键及环状等化合物的异构。
本发明术语“互变异构体”，指分子中某一原子在两个位置迅速移动而产生的一种特殊的官能团异构体，通常以比较稳定的一种异构体为其主要的存在形式。互变异构体可以是烯醇式和酮式互变异构、酰胺和亚胺酸互变异构、内酰胺和内酰亚胺互变异构、杂环中的酰胺和亚胺酸互变异构、烯胺和亚胺烯胺互变异构、质子转移互变异构、环内互变异构、环-链互变异构、价互变异构。
本发明术语“螯合物” 指具有环状结构的配合物，通过两个或多个配位体与同一金属离子形成螯合环的螯合作用得到，稳定性与芳香环相似。螯合物可以是氨羧络合剂(包括氨基三乙酸即NTA、乙二胺四乙酸即EDTA等)、双硫腙、8-羟基喹啉、邻菲咯啉(C12H8N2)、酒石酸钾钠、柠檬酸铵、多磷酸盐等。
本发明术语“前体药物” 也称前药、药物前体、前驱药物等，指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。可以提高药物生物利用度，增加药物稳定性，减小毒副作用，促使药物长效化等。
为了开发高效、安全的核酸药物递送系统，本发明提出了基于环己二胺的可电离脂质、脂质纳米颗粒及其制备方法与应用。
本发明的一种典型实施方式，提供了一种基于环己二胺的可电离脂质，其为式(a)所示化合物、式(a)所示化合物的药学上可接受的盐、式(a)所示化合物的立体异构体、式(a)所示化合物互变异构体、式(a)所示化合物的溶剂化物、式(a)所示化合物的螯合物、式(a)所示化合物的非共价复合物或式(a)所示化合物的前体药物；
其中，n独立地选自0~8的自然数；
R1、R2、R3、R4独立地选自C8-C24烷基、取代基团取代的C8-C24烷基、C8-C24烯基、取代基团取代的C8-C24烯基、C8-C24炔基、取代基团取代的C8-C24炔基；
本发明中式(a)化学结构中的键“
”表示未指定构型，即如果化学结构中存在立体异构体，键“
”可以为“
”或“
”或者同时包含“
”和“
”两种构型。本公开所述化合物的化学结构中，键“
”并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
在一些实施例中， n独立地选自0或1。
在一些实施例中，包括以下化合物：
（TN-2-10）
；
（TN-2-18-12）
；
（CN-2-10）
；
（CN-2-12）
。
本发明的另一种实施方式，提供了一种上述基于环己二胺的可电离脂质的制备方法，包括按照如下反应式获得式(a)所示化合物的步骤；
其中，n独立地选自0~8的自然数；
R1、R2、R3、R4独立地选自C8-C24烷基、取代基团取代的C8-C24烷基、C8-C24烯基、取代基团取代的C8-C24烯基、C8-C24炔基、取代基团取代的C8-C24炔基。
在一些实施例中，制备中间产物A的过程中，在冰浴条件下添加物料，然后在室温条件下进行反应。
在一些实施例中，中间产物A制备式(a)所示化合物的过程中，反应温度为70~85℃。优选为75~80 ℃。反应时间为4~24 h，优选为5~15 h。
在一些实施例中，反应的溶剂体系包括但不限于甲醇、乙醇、异丙醇、苯、甲苯、二甲苯、戊烷、己烷、辛烷、环己二胺、环己酮、甲苯环己酮、氯苯、二氯苯、二氯甲烷、乙醚、环氧丙烷、丙酮、甲基丁酮、甲基异丁酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙腈、吡啶、苯酚、苯乙烯和三乙醇胺。优选地，所述反应的溶剂为二氯甲烷、甲醇、N,N-二甲基甲酰胺。
本发明的第三种实施方式，提供了一种脂质纳米颗粒，由上述基于环己二胺的可电离脂质、辅助脂质、固醇和PEG脂质组成。
在一些实施例中，辅助磷脂二硬脂酰基-sn-甘油-磷酸乙醇胺、二硬脂酰基磷脂酰胆碱(DSPC)、二油酰基磷脂酰胆碱(DOPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二油酰基磷脂酰甘油(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、二油酰基-磷脂酰乙醇胺(DOPE)、棕榈酰基油酰基磷脂酰胆碱(POPC)、棕榈酰基油酰基磷脂酰乙醇胺(POPE)、二油酰基-磷脂酰乙醇胺4-(N-马来酰亚胺甲基)-环己二胺-1-羧酸酯(DOPE-mal)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二肉豆蔻酰基磷脂酰乙醇胺(DMPE)、二硬脂酰基-磷脂酰-乙醇胺(DSPE)、单甲基-磷脂酰乙醇胺(例如16-O-单甲基PE)、二甲基-磷脂酰乙醇胺(例如16-O-二甲基PE)、18-1-反式PE、1-硬脂酰基-2-油酰基-磷脂酰乙醇胺(SOPE)、氢化大豆磷脂酰胆碱(HSPC)、卵磷脂酰胆碱(EPC)、二油酰基磷脂酰丝氨酸(DOPS)、鞘磷脂(SM)、二肉豆蔻酰基磷脂酰胆碱(DMPC)、二肉豆蔻酰基磷脂酰甘油(DMPG)、二硬脂酰基磷脂酰甘油(DSPG)、二芥子酰基磷脂酰胆碱(DEPC)、棕榈酰基油酰磷脂酰甘油(POPG)、二反式油酰基-磷脂酰乙醇胺(DEPE)、1,2-二月桂酰基-sn-甘油-3-磷酸乙醇胺(DLPE)、1,2-二植烷酰基-sn-甘油-3-磷酸乙醇胺(DPHyPE)、卵磷脂、磷脂酰乙醇胺、溶血卵磷脂、溶血磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、鞘磷脂、卵鞘磷脂(ESM)、脑磷脂、心磷脂、磷脂酸、脑苷脂、二十六烷基磷酸酯、溶血磷脂酰胆碱、二亚油酰基磷脂酰胆碱或它们的混合物。根据一些实施方案，所述非阳离子脂质选自由二油酰基磷脂酰胆碱(DOPC)、二硬脂酰基磷脂酰胆碱(DSPC)和二油酰基-磷脂酰乙醇胺(DOPE) 中的一种或其任意组合。
在一些实施例中，所述固醇包括但不限于：胆固醇（Cholesterol）、20α-羟基胆固醇（20a Cholesterol）和β-谷固醇中的一种或其任意组合。优选地，所述固醇为Cholesterol和/或20a Cholesterol。
PEG脂质为PEG及其改性的脂质。在一些实施例中，PEG脂质包括但不限于：聚乙二醇 (PEG)， 1-(单甲氧基-聚乙二醇)-2,3-二肉豆蔻酰基甘油(PEG-DMG或DMG-PEG)、二硬脂酰基磷脂酰乙醇胺-聚乙二醇（DSPE-PEG）、二棕榈酰磷脂酰乙醇胺-甲氧基聚乙二醇（DPPE-PEG）、二甲基丙烯酸酯-聚乙二醇（PEG-DMA）、1,2-二硬脂基氧基丙基-3-胺-N-[甲氧基(聚乙二醇)](PEG-DSA)。优选地，所述PEG脂质选自DMG-PEG2000。
在一些实施例中，还包括阳离子脂质。所述阳离子脂质包括但不限于：氯化三甲基-2,3-二油烯氧基丙基铵（DOTMA）、溴化三甲基-2,3-二油酰氧基丙基铵（DOTAP）、4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯（MC3）、三氟乙酸二甲基-2, 3 -二油烯氧基丙基-2-(2-精胺甲酰氨基)乙基铵（DOSPA）、溴化三甲基十二烷基铵（DTAB）、溴化三甲基十四烷基铵（TTAB）、溴化二甲基-2-羟乙基-2,3-双十四烷氧基丙基铵（DMRIE）、N-(2-精胺甲酰基)-N’,N’-双十八烷基甘氨酰胺（DOGS）、1,2-二油酰-3-琥珀酰-sn-甘油胆碱酯（DOSC）、3β-[N-(N’,N’-二甲基胺乙基)胺基甲酰基]胆固醇（DC-Chol）中的一种或其任意组合。
在一些实施例中，基于环己二胺的可电离脂质的摩尔百分比为0.1~100%。优选为30~50%。
在一些实施例中，辅助脂质的摩尔百分比为0~99.9%。优选为10~20％。
在一些实施例中，固醇的摩尔百分比为0~99.9%。优选为20~50％。
在一些实施例中，PEG脂质固醇的摩尔百分比为0~99.9%。优选为2~5％。
本发明的第四种实施方式，提供了一种药物组合物，包括上述基于环己二胺的可电离脂质或脂质纳米颗粒和活性成分，所述活性成分为核酸药物。
在一些实施例中，所述核酸药物包括但不限于siRNA、mRNA、microRNA、环状mRNA、snRNA、snoRNA、tRNA、rRNA、gRNA、shRNA、piRNA、rasiRNA、hnRNA、long non-coding RNA、plasmid DNA、ceDNA、mini circle DNA、反义寡核苷酸（ASOs）、DNA病毒载体、病毒RNA载体、非病毒载体中一种或几种的组合。
在一些实施例中，所述核酸药物还可以为化学修饰改性的多核苷酸，化学修饰包括但不限于核酸骨架上的化学修饰、碱基上的化学修饰、核糖上的化学修饰。
具体地，核酸骨架上的化学修饰包括硫代磷酸二酯键、吗啉环取代、二甲氨基代磷酸二酯键、肽核酸、磷硫酰化等中的一种或其任意组合。
具体地，碱基上的化学修饰包括m6A、N6、m5C、hm5C、Ψ、Nm、m3C、m7G、Cm、Gm、m5U、Um等中的一种或其任意组合。
具体地，核糖上的化学修饰包括2'-OMe、2'-MOE、2'-F、2'-O-AP、2'-O-m6Am、2'-O-m3Um、PMO等中的一种或其任意组合。
在一些实施例中，所述核酸药物包括含有立体结构的多核苷酸。含有立体结构的多核苷酸包括但不限于锁核酸（LNA）、三环DNA（tcDNA）、甘油核酸（GNA）、解锁核酸（UNA）、苏糖核酸(TNA)等中的一种或其任意组合。
在一些实施例中，所述核酸药物中的化学改性还包括但不限于以下任意一种或其任意组合的靶向基团修饰：GalNac、甘露糖、半乳糖、RGD、PLGA、PEI、CPP、RVG等。
本发明的第五种实施方式，提供了一种上述脂质纳米颗粒或药物组合物在制备药物中的应用。
在一些实施例中，所述药物用于治疗的病症包括但不限于：癌症、感染、内分泌系统疾病、自身免疫疾病、呼吸系统疾病、神经退行性疾病、炎症和基因疾病。优选为基因疾病。
具体地，所述基因疾病包括但不限于：镰状细胞性贫血，黑色素瘤，血友病A(凝血因子VIII(FVIII)缺乏症)和血友病B(凝血因子IX(FIX)缺乏症)，囊性纤维化(CFTR)，家族性高胆固醇血症(LDL受体缺陷)，肝母细胞瘤，威尔逊病，遗传性肝代谢疾病，LeschNyhan综合征，地中海贫血，色素性干皮病，范可尼贫血，色素性视网膜炎，共济失调毛细血管扩张症，布鲁姆综合征，视网膜母细胞瘤，粘多糖贮积病(例如，Hurler综合征(MPS-IH型)，Scheie综合征(MPS-IS型)，Hurler-Scheie综合征(MPS-IH/S型)，亨特综合征(MPS-II型)，SanfilippoA、B、C和D型(MPS-IIIA、B、C和D型)，MorquioA和B型(MPS-IVA和MPS-IVB)，Maroteaux-Lamy综合征(MPS-VI型)，Sly综合征(MPS-VII型)，透明质酸酶缺乏症(MPS-IX型))，Niemann-Pick病A/B、C1和C2型，法布里病，Schindler病，GM2-神经节苷脂沉积症II型(Sandhoff病)，Tay-Sachs病，异染性脑白质营养不良，Krabbe病，粘脂沉积症I、II/III和IV型，唾液酸贮积症I和II型，糖原贮积病I和II型(庞贝病)，戈谢病I、II和III型，法布里病，胱氨酸病，巴顿病，天冬氨酰氨基葡萄糖尿症，Salla病，达农病(LAMP-2缺乏症)，溶酶体酸性脂肪酶(LAL)缺乏症，神经元蜡样脂褐质沉积症(CLN1-8、INCL和LINCL)，鞘脂症，半乳糖唾液酸中毒，帕金森病，阿尔茨海默病，亨廷顿病，脊髓小脑共济失调，脊髓性肌萎缩症，弗里德赖希共济失调，杜氏肌营养不良症(DMD)，贝克尔肌营养不良症(BMD)，营养不良性大疱性表皮松解症(DEB)，外核苷酸焦磷酸酶1缺乏症，婴儿全身性动脉钙化(GACI) ,利伯先天性黑矇，Stargardt黄斑营养不良(ABCA4)，鸟氨酸转氨甲酰酶(OTC)缺乏症，Usher综合征，α-1抗胰蛋白酶缺乏症，进行性家族性肝内胆汁淤积症(PFIC)I型(ATP8B1缺乏症)、II型(ABCB11)、III型(ABCB4)或IV型(TJP2)和组织蛋白酶A缺乏症。
在一些实施例中，所述药物的给药方式为全身给药或局部给药。包括但不限于以下任意一种或其任意组合：口服给药、舌下给药、直肠给药、阴道给药、静脉注射、肌肉注射、皮下注射、腹腔注射、骨髓注射、吸入给药、鼻内给药、颊部给药、经皮给药、黏膜给药、眼内给药、耳内给药等。
本发明第六种实施方式，提供了一种可电离脂质或其盐的药物组合递送至细胞的方法，将上述药物组合物配制成特异性地靶向和/或转染一种或多种靶细胞、组织和器官的任意形式。
促进靶细胞转染的机制例如：靶细胞的脂质双层膜的膜融合基的释放和/或质子海绵效应介导的破裂。
在一些实施例中，所述靶细胞包括但不限于以下的一种或多种细胞：肝细胞、造血细胞、上皮细胞、内皮细胞、肺细胞、骨细胞、干细胞、间充质细胞、神经细胞、心脏细胞、脂肪细胞、血管平滑肌细胞、心肌细胞、骨骼肌细胞、细胞、垂体细胞、滑膜衬里细胞、卵巢细胞、睾丸细胞、成纤维细胞、B细胞、T细胞、网状细胞、巨噬细胞、中性粒细胞、嗜酸粒细胞和嗜碱粒细胞、肿瘤细胞。其中靶细胞为原核细胞或真核细胞。
本发明的第七种实施方式，提供了一种治疗受试者病症的方法，向所述受试者施用有效量的上述药物组合物。
在一些实施例中，所述受试者是动物和/或人类。
在一些实施例中，所述病症包括但不限于：癌症、感染、内分泌系统疾病、自身免疫疾病、呼吸系统疾病、神经退行性疾病、炎症和基因疾病。优选为基因疾病。
具体地，所述基因疾病包括但不限于：镰状细胞性贫血，黑色素瘤，血友病A(凝血因子VIII(FVIII)缺乏症)和血友病B(凝血因子IX(FIX)缺乏症)，囊性纤维化(CFTR)，家族性高胆固醇血症(LDL受体缺陷)，肝母细胞瘤，威尔逊病，遗传性肝代谢疾病，LeschNyhan综合征，地中海贫血，色素性干皮病，范可尼贫血，色素性视网膜炎，共济失调毛细血管扩张症，布鲁姆综合征，视网膜母细胞瘤，粘多糖贮积病(例如，Hurler综合征(MPS-IH型)，Scheie综合征(MPS-IS型)，Hurler-Scheie综合征(MPS-IH/S型)，亨特综合征(MPS-II型)，SanfilippoA、B、C和D型(MPS-IIIA、B、C和D型)，MorquioA和B型(MPS-IVA和MPS-IVB)，Maroteaux-Lamy综合征(MPS-VI型)，Sly综合征(MPS-VII型)，透明质酸酶缺乏症(MPS-IX型))，Niemann-Pick病A/B、C1和C2型，法布里病，Schindler病，GM2-神经节苷脂沉积症II型(Sandhoff病)，Tay-Sachs病，异染性脑白质营养不良，Krabbe病，粘脂沉积症I、II/III和IV型，唾液酸贮积症I和II型，糖原贮积病I和II型(庞贝病)，戈谢病I、II和III型，法布里病，胱氨酸病，巴顿病，天冬氨酰氨基葡萄糖尿症，Salla病，达农病(LAMP-2缺乏症)，溶酶体酸性脂肪酶(LAL)缺乏症，神经元蜡样脂褐质沉积症(CLN1-8、INCL和LINCL)，鞘脂症，半乳糖唾液酸中毒，帕金森病，阿尔茨海默病，亨廷顿病，脊髓小脑共济失调，脊髓性肌萎缩症，弗里德赖希共济失调，杜氏肌营养不良症(DMD)，贝克尔肌营养不良症(BMD)，营养不良性大疱性表皮松解症(DEB)，外核苷酸焦磷酸酶1缺乏症，婴儿全身性动脉钙化(GACI) ,利伯先天性黑矇，Stargardt黄斑营养不良(ABCA4)，鸟氨酸转氨甲酰酶(OTC)缺乏症，Usher综合征，α-1抗胰蛋白酶缺乏症，进行性家族性肝内胆汁淤积症(PFIC)I型(ATP8B1缺乏症)、II型(ABCB11)、III型(ABCB4)或IV型(TJP2)和组织蛋白酶A缺乏症。
在一些实施例中，所述药物的给药方式为全身给药或局部给药。包括但不限于以下任意一种或其任意组合：口服给药、舌下给药、直肠给药、阴道给药、静脉注射、肌肉注射、皮下注射、腹腔注射、骨髓注射、吸入给药、鼻内给药、颊部给药、经皮给药、黏膜给药、眼内给药、耳内给药等。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
本发明中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1：可电离脂质化合物 TN系列的制备
1）将5.0mmol 反式1,4-环己二胺、11mmol三乙胺和25mL无水二氯甲烷依次加入装有磁子的100mL反应瓶中，在冰浴条件下预冷，缓慢滴加11mmol丙烯酰氯，待丙烯酰氯滴加完毕，移走冰浴，反应在室温搅拌4h。使用旋转蒸发仪除去溶剂，加入饱和碳酸氢钠溶液搅拌、抽滤，得到中间产物A，收率达95%。
2）将0.20mmol中间产物A、0.44mmol有机胺和0.50mL甲醇加入到装有磁子的4mL反应瓶中，反应在75℃条件下搅拌过夜。使用旋转蒸发仪除去溶剂，产物通过薄层色谱柱分离（二氯甲烷：甲醇体积比=10:1），得到下列目标产物。
采用反式1,4-环己二胺制备中间产物A，有机胺为二癸胺，产物为TN-2-10（收率40%），结构表征：1H NMR（400 MHz, CDCl3）δ 8.64 (s, 2H), 3.70 (s, 2H), 2.61 (t,J=5.5 Hz, 4H), 2.47-2.35 (m, 8H), 2.35-2.26 (m, 4H), 1.95 (d,J=6.2 Hz, 4H),1.25 (s, 68H), 0.86 (t,J= 6.7 Hz, 12H)。
采用反式1,4-环己二胺制备中间产物A，有机胺为N-9-十八烯-1-十二胺，产物为TN-2-18-12（收率35%），结构表征：1H NMR (400 MHz, CDCl3) δ 8.57 (s, 2H), 5.44-5.15(m, 4H), 3.66 (s, 2H), 2.56 (t,J= 5.9 Hz, 4H), 2.34 (t,J= 7.6 Hz, 8H), 2.26(t,J= 5.8 Hz, 4H), 1.93 (dt,J= 22.5, 7.1 Hz, 12H), 1.37 (s, 4H), 1.19 (s,88H), 0.81 (t,J= 6.6 Hz, 12H)。
实施例2：可电离脂质化合物CN系列的制备
1）将5.0mmol顺式1,4-环己二胺、11mmol三乙胺和25mL无水二氯甲烷依次加入装有磁子的100mL反应瓶中，在冰浴条件下预冷，缓慢滴加11mmol丙烯酰氯，待丙烯酰氯滴加完毕，移走冰浴，反应在室温搅拌4h。使用饱和碳酸氢钠溶液、乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥有机相，通过薄层色谱柱分离（二氯甲烷：甲醇体积比=10:1），得到中间产物A，收率达37%。
2）将0.20mmol中间产物A、0.44mmol有机胺和0.50mL甲醇加入到装有磁子的4mL反应瓶中，反应在75℃条件下搅拌过夜。使用旋转蒸发仪除去溶剂，产物通过薄层色谱柱分离（二氯甲烷：甲醇体积比=10:1），得到下列目标产物。
采用顺式1,4-环己二胺制备中间产物A，有机胺为二癸胺，产物为CN-2-10（收率49%），结构表征：1H NMR (400 MHz, CDCl3) δ 8.29 (s, 2H), 3.88 (s, 2H), 2.75 (s,4H), 2.53 (s, 8H), 2.40 (s, 4H), 1.73 (s, 4H), 1.48 (s, 4H), 1.25 (s, 64H),0.87 (t,J= 6.7 Hz, 12H)。
采用顺式1,4-环己二胺制备中间产物A，有机胺为十二胺，产物为CN-2-12（收率35%），结构表征：1H NMR (400 MHz, CDCl3) δ 8.12 (s, 2H), 3.88 (s, 2H), 2.84 (s,4H), 2.59 (s, 8H), 2.48 (s, 4H), 1.72 (s, 4H), 1.52 (s, 4H), 1.25 (s, 80H),0.87 (s, 12H)。
实施例3：mRNA-LNP的制备
将可电离脂质、胆固醇、PEG、辅助脂质溶于乙醇中，将编码表达EGFP的mRNA（购自载体家的EGFP IVT mRNA，m1Ψ修饰）溶于pH=4.0的柠檬酸盐缓冲液中。将混合脂质溶液和mRNA溶液按照表1中的处方混合得到mRNA-LNP。
表1中，mRNA浓度为1μg/μL，体积为4μL且水相总体积为90μL，可电离脂质浓度为10μg/μL，体积为4μL且有机相总体积为45μL，固醇浓度为5μg/μL，PEG浓度为5μg/μL，辅助脂质浓度为5μg/μL，可电离脂质与mRNA的重量比约为10：1，混合方法为微流控法。
表1
实施例4：mRNA-LNP的粒径与电位表征
使用Malvern Zetasizer Nano ZS，以90°反向散射检测模式，利用动态光散射检测LNP的粒径和电位。结果如图1、图2所示。图1所示LNP粒径范围在70-110 nm，大多集中于80-100 nm，符合纳米药物尺度，说明所制备的LNP可顺利穿过细胞间隙，具有优异的核酸药物递送性能。图2所示ζ电位在-6 ~ 6 mV之间，证明LNP制剂体系稳定，不易聚集或沉降。
实施例5：mRNA-LNP的包封率表征
使用Quant-iT™RiboGreen®RNA试剂及多模式微孔板检测系统Mutimode PlateReader (EnSight)，测定LNP包封率。Quant-iT™RiboGreen®RNA试剂是无法透过LNP，因此只有游离的未被LNP包载的核酸可以被结合。Triton-100作为一种表面活性剂常被用做破乳剂，使用2%的Triton-100处理获得的LNP可以使包载的核酸释放，得到总核酸量。通过计算破乳前后核酸量的差异得到载药量，再除以总核酸量即可得到包封率。测得本系列产品包封率在60%-95%之间，如附图3所示。
实施例6：mRNA-LNP的转染效率表征
取对数生长期的Hep3B细胞接种到6孔细胞板（20万细胞/孔）培养过夜，待细胞密度达到80％以上，弃掉培养基并使用1X PBS洗涤3次，取1 mL 无血清DMEM培养基配制的EGFP mRNA-LNP（1μg/mL）溶液，加入到细胞孔中并设置3个复孔。6小时后弃掉培养基，更换为有血清的正常DMEM培养基继续培养24小时，使用流式细胞仪检测细胞的荧光比例。结果如附图4所示，转染率在10%到90%之间，TN系列具有更高的转染效率，有良好的转染性能。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种基于环己二胺的可电离脂质，其特征是，其为式(a)所示化合物、式(a)所示化合物的药学上可接受的盐、式(a)所示化合物的立体异构体、式(a)所示化合物互变异构体、式(a)所示化合物的溶剂化物、式(a)所示化合物的螯合物、式(a)所示化合物的非共价复合物或式(a)所示化合物的前体药物；
其中，n独立地选自0~8的自然数；
R1、R2、R3、R4独立地选自C8-C24烷基、取代基团取代的C8-C24烷基、C8-C24烯基、取代基团取代的C8-C24烯基、C8-C24炔基、取代基团取代的C8-C24炔基。
2.如权利要求1所述基于环己二胺的可电离脂质，其特征是，n独立地选自0或1。
3.如权利要求1所述基于环己二胺的可电离脂质，其特征是，包括以下化合物：
4.一种权利要求1所述的基于环己二胺的可电离脂质的制备方法，其特征是，包括按照如下反应式获得式(a)所示化合物的步骤；
其中，n独立地选自0~8的自然数；
R1、R2、R3、R4独立地选自C8-C24烷基、取代基团取代的C8-C24烷基、C8-C24烯基、取代基团取代的C8-C24烯基、C8-C24炔基、取代基团取代的C8-C24炔基。
5.如权利要求4所述的基于环己二胺的可电离脂质的制备方法，其特征是，制备中间产物A的过程中，在冰浴条件下添加物料，然后在室温条件下进行反应；
或，中间产物A制备式(a)所示化合物的过程中，反应温度为70~85 ℃。
6.一种脂质纳米颗粒，其特征是，由权利要求1所述的基于环己二胺的可电离脂质、辅助脂质、固醇和PEG脂质组成。
7.如权利要求6所述的脂质纳米颗粒，其特征是，基于环己二胺的可电离脂质的摩尔百分比为30~50%。
8.一种药物组合物，其特征是，包括权利要求1所述的基于环己二胺的可电离脂质或权利要求6或7所述的脂质纳米颗粒和活性成分，所述活性成分为核酸药物。
9.一种权利要求6或7所述的权利要求脂质纳米颗粒或权利要求8所述的药物组合物在制备药物中的应用。
10.如权利要求9所述的应用，其特征是，所述药物用于治疗的病症包括癌症、感染、内分泌系统疾病、自身免疫疾病、呼吸系统疾病、神经退行性疾病、炎症和/或基因疾病。
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| WO2023001323A1 (en) * | 2021-07-19 | 2023-01-26 | Ustav Organicke Chemie A Biochemie AV CR v.v.i. | Cyclohexane lipidoids for nucleic acid transfection and use thereof |
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| US20220378938A1 (en) * | 2021-04-30 | 2022-12-01 | Purecodon (Hong Kong) Biopharma Limited | Lipid compound as well as lipid vector, nucleic acid lipid nanoparticle composition, and pharmaceutical preparation comprising the same |
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| WO2023001323A1 (en) * | 2021-07-19 | 2023-01-26 | Ustav Organicke Chemie A Biochemie AV CR v.v.i. | Cyclohexane lipidoids for nucleic acid transfection and use thereof |
| WO2023036311A1 (zh) * | 2021-09-10 | 2023-03-16 | 浙江吉量科技有限公司 | 可离子化脂质体、其制备及在基因递送中的应用 |
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