CN117567301A - 一种阳离子类脂分子及其用于脂质纳米粒体系的制备 - Google Patents
一种阳离子类脂分子及其用于脂质纳米粒体系的制备 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
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Abstract
本发明公开了一种阳离子类脂分子及其用于脂质纳米粒体系的制备,本发明提供了式I化合物或其药学上可接受的盐
Description
技术领域
本发明涉及医药技术领域,特别涉及一种阳离子类脂分子及其用于脂质纳米粒体系的制备。
背景技术
mRNA药物现已被应用于许多领域,例如传染病治疗、癌症治疗等等,但由于体内外环境中大量RNA酶的存在,裸露的mRNA面临着被降解的问题,因此mRNA药物需要有效的递送载体。
现阶段,mRNA药物最常用的递送系统是脂质纳米粒(lipid nanoparticle,LNP)。目前已实现商业化的LNP系统包括用于冠状病毒疫苗的LNP系统,包括阳离子脂质化合物、胆固醇、聚乙二醇脂质及辅助型脂质四个组份,其中占比最高的为阳离子脂质化合物,其表面带正电荷,在包裹过程中与带负电荷的mRNA以正负电荷作用结合,在LNP的几个组分中起着重要作用。一些LNP系统组成包括SM-102、胆固醇、DMG-PEG-2000、DSPC;也有的LNP系统中的组成分别为ALC-0315、胆固醇、ALC-0159、DSPC。
发明内容
本发明旨在至少解决现有技术中存在的上述技术问题之一。为此,本发明的目的在于提供一种阳离子类脂分子及其用于脂质纳米粒体系的制备。
为了实现上述目的,本发明所采取的技术方案是:
本发明的第一个方面,提供了式I化合物或其药学上可接受的盐:
其中,R1选自氘、H、R2选自/> L选自C1~C10亚烷基、取代C1~C10亚烷基;G1选自1~8个羟基取代的C1~C6直链或支链亚烷基;G2选自-C(O)O-、-OC(O)-、-C(O)O-取代的C1~C6直链或支链、-OC(O)-取代的C1~C6直链或支链;X1、X2分别独立选自C1~C60直链或支链烷基;n选自1~6的自然数;m、p分别独立选自1~20的自然数。
在本发明的一些实施方式中,m、p分别独立选自1~10的自然数。
在本发明的一些实施方式中,L选自C1~C4亚烷基、取代C1~C4亚烷基;G1选自1~3个羟基取代的C1~C3直链或支链亚烷基;G2选自-C(O)O-、-OC(O)-、-C(O)O-取代的C1~C3直链或支链、-OC(O)-取代的C1~C3直链或支链;X1、X2分别独立选自C1~C40直链或支链烷基;n选自1~4的自然数;m、p分别独立选自1~8的自然数。
在本发明的一些实施方式中,L选自亚甲基、取代亚甲基;G1选自羟基取代的亚甲基或亚乙基;G2选自-C(O)O-、-OC(O)-、-C(O)O-取代的亚甲基或亚乙基、-OC(O)-取代的亚甲基或亚乙基;X1、X2分别独立选自C1~C40直链或支链烷基;n为2;m、p分别独立选自1或2。
在本发明的一些实施方式中,式I化合物中,R1选自氘、H、
R2选自/>
L选自C1~C10亚烷基、取代C1~C10亚烷基;n选自1~6的自然数;t1~t6分别独立选自1~20的自然数。
在本发明的一些实施方式中,R1选自氘、H、
在本发明的一些实施方式中,R2选自
在本发明的一些实施方式中,R1选自氘、H、
在本发明的一些实施方式中,R2选自
在本发明的一些实施方式中,取代C1~C10亚烷基包括被氘、羟基、酯基取代的C1~C10亚烷基。
在本发明的一些实施方式中,n选自1~4的自然数;t1~t6分别独立选自1~10的自然数。
在本发明的一些实施方式中,式I化合物为且苯环上取代基的位置关系为邻位、间位或对位。
在本发明的一些实施方式中,式I化合物选自
式I-A化合物~式I-D化合物中,L、t1~t4的定义如前所述。
在本发明的一些实施方式中,式I化合物选自下列化合物:
本发明的第二个方面,提供了化合物的制备方法,包括以下步骤:
i)将式II化合物与式III化合物/>反应制得式I-A化合物或式I-B化合物;或
ii)将式II化合物与式IV化合物/>反应制得式I-C化合物或式I-D化合物。
在本发明的一些实施方式中,式II化合物与式III化合物的摩尔比为1:(2~5)。
在本发明的一些实施方式中,式II化合物与式IV化合物的摩尔比为1:(2~5)。
在本发明的一些实施方式中,式III化合物包括1,2-环氧癸烷、1,2-环氧十二烷、1,2-环氧十四烷、1,2-环氧十六烷、1,2-环氧十八烷的至少一种。
在本发明的一些实施方式中,式IV化合物包括丙烯酸癸酯、丙烯酸十二酯、丙烯酸十四酯、丙烯酸十六酯、丙烯酸十八酯、丙烯酸二十二酯的至少一种。
在本发明的一些实施方式中,所述反应的溶剂为低级醇溶液;优选为乙醇、丙醇、异丙醇;进一步优选为90%~99%的乙醇溶液。
在本发明的一些实施方式中,所述反应的温度为70℃~100℃,时间为12h~72h,优选为80℃~90℃,时间为24h~60h。
在本发明的一些实施方式中,i)中所述反应的溶剂为乙醇;优选为90%~99%的乙醇溶液。
在本发明的一些实施方式中,ii)中所述反应的溶剂为丙醇;优选为异丙醇。
本发明的第三个方面,提供了一种药物组合物,包括载体,所述载体包括阳离子脂质,所述阳离子脂质包括所述的式I化合物或其药学上可接受的盐。
在本发明的一些实施方式中,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10nm~300nm,优选为90nm~280nm;所述纳米颗粒制剂的多分散系数≤50%,优选≤40%,更优选≤30%。
在本发明的一些实施方式中,所述阳离子脂质占载体的摩尔比为10%~75%,例如10%、20%、30%、40%、49%、55%、60%、65%、70%、75%。
该载体可用于递送活性成分例如治疗剂和/或预防剂。活性成分可包封在载体内或者与载体结合。
例如,所述治疗剂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。所述核酸包括但不限于单链DNA、双链DNA和RNA。适宜的RNA包括但不限于小干扰RNA(siRNA)、不对称干扰RNA(aiRNA)、微RNA(miRNA)、Dicer-底物RNA(dsRNA)、小发夹RNA(shRNA)、信使RNA(mRNA)以及其混合物。
该载体可用于递送用于光热疗法的光敏剂和/或光热剂,光敏剂和/或光热剂可包封在载体内或者与载体结合,如应用于脑胶质瘤的光疗法。
在本发明的一些实施方式中,所述光敏剂和/或光热剂包括如Fs、Fc、Fo、Ce6、ICG等的至少一种。
中性脂质
载体可包含中性脂质。中性脂质在本发明中是指在选定的pH值不带电荷或者以两性离子形式存在的起辅助作用的脂质。该中性脂质可能通过促进脂质相变来调节纳米颗粒流动性成脂质双层结构并提高效率,同时还可能影响靶器官的特异性。
在本发明的一些实施方式中,所述阳离子脂质与所述中性脂质的摩尔比为约1:1~15:1,例如约14:1、13:1、12:1、11:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1和2:1。在一种优选的实施方案中,所述阳离子脂质与所述中性脂质的摩尔比为约1.5:1。在另一种优选的实施方案中,所述阳离子脂质与所述中性脂质的摩尔比为约4.9:1。
例如,中性脂质可包括磷脂酰胆碱、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。
包含阳离子脂质的组合物的载体组分可以包括一种或多种中性脂质-磷脂,如一种或多种(多)不饱和脂质。磷脂可以组装成一个或多个脂质双层。一般来说,磷脂可以包括磷脂部分和一个或多个脂肪酸部分。
中性脂质部分可以选自由以下组成的非限制性组:磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸、2-溶血磷脂酰胆碱和鞘磷脂。脂肪酸部分可以选自由以下组成的非限制性组:月桂酸、肉豆蔻酸、肉豆蔻烯酸、棕榈酸、棕榈油酸、硬脂酸、油酸、亚油酸、α-亚麻酸、芥酸、植烷酸、花生酸、花生四烯酸、二十碳五烯酸、山萮酸、二十二碳五烯酸和二十二碳六烯酸。还涵盖包括带有修饰和取代的天然物种的非天然物种,所述修饰和取代包括分支、氧化、环化和炔烃。例如,磷脂可以用一种或多种炔烃(例如一个或多个双键被三键置换的烯基)官能化或与该一种或多种炔烃交联。在适当反应条件下,炔基在暴露于叠氮化物时可能经历铜催化的环加成反应。这些反应可用于使组合物的脂质双层官能化以促进膜渗透或细胞识别,或将组合物与有用组分如靶向或成像部分(例如染料)偶联。
可用于这些组合物中的中性脂质可以选自由以下组成的非限制性组:1,2-二亚油酰基-sn-甘油-3-磷酸胆碱(DLPC)、1,2-二肉豆蔻酰基-sn-甘油-磷酸胆碱(DMPC)、1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1,2-双十一烷酰基-sn-甘油-磷酸胆碱(DUPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1,2-二-O-十八碳烯基-sn-甘油-3-磷酸胆碱(18:0Diether PC)、1-油酰基-2-胆固醇基半琥珀酰基-sn-甘油-3-磷酸胆碱(OChemsPC)、1-十六烷基-sn-甘油-3-磷酸胆碱(C16 Lyso PC)、1,2-二亚麻酰基-sn-甘油-3-磷酸胆碱、1,2-二花生四烯酰基-sn-甘油-3-磷酸胆碱、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸胆碱、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、1,2-二植烷酰基-sn-甘油-3-磷酸乙醇胺(ME 16.0PE)、1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚油酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚麻酰基-sn-甘油-3-磷酸乙醇胺、1,2-二花生四烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-二油酰基-sn-甘油-3-磷酸-rac-(1-甘油)钠盐(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、棕榈酰基油酰基磷脂酰乙醇胺(POPE)、二硬脂酰基-磷脂酰-乙醇胺(DSPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、1-硬脂酰基-2-油酰基-硬脂酰乙醇胺(SOPE)、1-硬脂酰基-2-油酰基-磷脂酰胆碱(SOPC)、鞘磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸、棕榈酰基油酰基磷脂酰胆碱、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺(LPE)以及其混合物。
在本发明的一些实施方式中,中性脂质包括DSPC。在本发明的一些实施方式中,中性脂质包括DOPE。在本发明的一些实施方式中,中性脂质包括DSPC和DOPE两种。
结构性脂质
包含阳离子脂质的组合物的载体还可以包括一种或多种结构性脂质。结构性脂质在本发明中是指通过填充脂质之间的间隙来增强纳米颗粒的稳定性的脂质。
在本发明的一些实施方式中,所述阳离子脂质与所述结构性脂质的摩尔比为约0.6:1~3:1,例如,约1.0:1、1.1:1、1.2:1、1.3:1、1.4:1、1.5:1、1.6:1、1.7:1、1.8:1、1.9:1、2.0:1。
结构性脂质可以选自但不限于由以下组成的组: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、皮质类固醇以及其混合物。在本发明的一些实施方式中,结构性脂质是胆固醇。在本发明的一些实施方式中,结构性脂质包括胆固醇和皮质类固醇(如泼尼松龙(prednisolone)、地塞米松、泼尼松(prednisone)和氢化可的松(hydrocortisone))或其组合。
在本发明的组合物/载体的一种实施方案中,载体包括阳离子脂质、中性脂质、结构脂质;所述阳离子脂质、所述中性脂质、所述结构脂质的摩尔比为(10~70):(5~60):(5~50);例如(20~60):(20~50):(10~30)、(30~60):(25~40):(15~28)、(40~55):(25~35):(18~25)、47.4:31.6:21.1、49.4:30.6:20.1、51.4:29.6:19.1。
聚合物共轭脂质
包含阳离子脂质的组合物的载体还可以包括一种或多种聚合物共轭脂质。聚合物共轭脂质主要是指聚乙二醇(PEG)修饰的脂质。亲水性PEG稳定LNP,通过限制脂质融合来调节纳米颗粒大小,并通过减少与巨噬细胞的非特异性相互作用来增加纳米颗粒的半衰期。
在一种实施方案中,所述聚合物共轭脂质选自以下中的一种或多种: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、PEG修饰的二烷基甘油。PEG修饰的PEG分子量通常为350-5000Da。
例如,所述聚合物共轭脂质选自以下中的一种或多种:二硬脂酰基磷脂酰乙醇胺聚乙二醇2000(DSPE-PEG2000),二肉豆蔻酰甘油-3-甲氧基聚乙二醇2000(DMG-PEG2000)和甲氧基聚乙二醇双十四烷基乙酰胺(ALC-0159)。
在本发明的组合物/载体的一种实施方案中,所述聚合物共轭脂质是DMG-PEG2000和/或ALC-0159。
在本发明的组合物/载体的一种实施方案中,载体包括阳离子脂质、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(25~75):(5~25):(15~65):(0.5~10),例如(45~55):(7.5~15):(35~55):(1~5)、48:10:50.5:1.5或55:10:43.5:1.5或50:10:38.5:1.5。
治疗剂和/或预防剂
组合物可以包括一种或多种治疗剂和/或预防剂。在一种实施方案中,载体与所述治疗剂或预防剂的质量比为1:10~30:1,例如12:1、13:1、14:1、15:1、16:1、17:1、18:1、19:1、20:1、21:1、22:1、23:1、24:1、25:1。
在一种实施方案中,载体与所述治疗剂或预防剂的质量比为12.5:1~20:1,优选为15:1。
氮磷比(N:P)指阳离子类脂上所含氮元素与治疗剂或预防剂中RNA中所含的磷元素的摩尔比。
在本发明的组合物/载体的一种实施方案中,组合物中氮磷比(N:P)为0.375-36。
在一种实施方案中,包含治疗剂或预防剂组合物的制备方法包括以下步骤:
乙醇相制备:将载体溶解在乙醇相中;
水相制备:将治疗剂或预防剂溶解在缓冲液中;
将所述乙醇相加入所述水相,混匀,制得所述组合物。
所述治疗剂或预防剂包括但不限于核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。
例如,所述治疗剂或预防剂是能够引起免疫响应的疫苗或化合物。
本发明的载体可将治疗剂和/或预防剂递送至哺乳动物细胞或器官,因此本发明还提供治疗有需要哺乳动物的疾病或病症的方法,这些方法包括向哺乳动物施用包括治疗剂和/或预防剂的组合物和/或使哺乳动物细胞与该组合物接触。
治疗剂和/或预防剂包括生物活性物质并且替代地称为“活性剂”。治疗剂和/或预防剂可以是在递送至细胞或器官后在该细胞或器官中或者其它身体组织或系统中引起所希望的变化的物质。此类物种可用于治疗一种或多种疾病、病症或病况。在一些实施方案中,治疗剂和/或预防剂是可用于治疗特定疾病、病症或病况的小分子药物。可用于组合物的药物的实例包括但不限于抗赘生剂(例如长春新碱(vincristine)、多柔比星(doxorubicin)、米托蒽醌(mitoxantrone)、喜树碱(camptothecin)、顺铂(cisplatin)、博莱霉素(bleomycin)、环磷酰胺(cyclophosphamide)、甲氨蝶呤和链脲佐菌素(streptozotocin))、抗肿瘤剂(例如放线菌素D(actinomycin D)、长春新碱、长春碱(vinblastine)、胞嘧啶阿拉伯糖苷(cytosine arabinoside)、蒽环霉素(anthracycline)、烷化剂、铂类化合物、抗代谢物以及核苷类似物,如甲氨蝶呤以及嘌呤和嘧啶类似物)、抗感染剂、局部麻醉剂(例如地布卡因(dibucaine)和氯丙嗪(chlorpromazine))、β-肾上腺素能阻断剂(例如普萘洛尔(propranolol)、第莫洛(timolol)和拉贝洛尔(labetalol))、抗高血压剂(例如可乐定(clonidine)和肼酞嗪(hydralazine))、抗抑郁剂(例如丙咪嗪(imipramine)、阿米替林(amitriptyline)和多虑平(doxepin))、抗痉挛剂(例如苯妥英(phenytoin))、抗组胺(例如苯海拉明(diphenhydramine)、氯苯那敏(chlorpheniramine)和异丙嗪(promethazine))、抗生素/抗细菌剂(例如庆大霉素(gentamycin)、环丙沙星(ciprofloxacin)和头孢西丁(cefoxitin))、抗真菌剂(例如咪康唑(miconazole)、特康唑(terconazole)、益康唑(econazole)、异康唑(isoconazole)、布康唑(butaconazole)、克霉唑(clotrimazole)、伊曲康唑(itraconazole)、制霉菌素(nystatin)、奈替芬(naftifine)和两性霉素B(amphotericin B))、抗寄生虫剂、激素、激素拮抗剂、免疫调节剂、神经递质拮抗剂、抗青光眼药、维生素、镇静剂以及成像剂。
在一些实施方案中,治疗剂和/或预防剂是细胞毒素、放射性离子、化学治疗剂、疫苗、引起免疫响应的化合物和/或另一治疗剂和/或预防剂。细胞毒素或细胞毒性剂包括对细胞有害的任何试剂。实例包括但不限于紫杉酚(taxol)、细胞松弛素B(cytochalasin B)、短杆菌肽D(gramicidin D)、溴化乙锭(ethidium bromide)、依米丁(emetine)、丝裂霉素(mitomycin)、依托泊苷(etoposide)、替尼泊苷(teniposide)、长春新碱、长春碱、秋水仙碱(colchicine)、多柔比星、柔红霉素(daunorubicin)、二羟基蒽二酮(dihydroxy anthracindione)、米托蒽醌、光辉霉素(mithramycin)、放线菌素D、1-去氢睾酮、糖皮质激素、普鲁卡因(procaine)、丁卡因(tetracaine)、利多卡因(lidocaine)、普萘洛尔、嘌呤霉素、类美登素(maytansinoid)如美登醇(maytansinol)、拉奇霉素(rachelmycin)(CC-1065),以及其类似物或同系物。放射性离子包括但不限于碘(例如碘125或碘131)、锶89、磷、钯、铯、铱、磷酸根、钴、钇90、钐153和镨。疫苗包括能够提供针对与感染性疾病如流感、麻疹、人乳头瘤病毒(HPV)、狂犬病、脑膜炎、百日咳、破伤风、瘟疫、肝炎和肺结核相关的一种或多种病况的免疫性的化合物和制剂并且可以包括编码感染性疾病源性抗原和/或表位的mRNA。疫苗还可以包括引导针对癌细胞的免疫响应的化合物和制剂并且可以包括编码肿瘤细胞源性抗原、表位和/或新表位的mRNA。引起免疫响应的化合物可以包括疫苗、皮质类固醇(例如地塞米松)和其它物种。在一些实施方案中,通过包括根据式(I)、(IA)、(IB)、(II)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(III)的化合物(例如化合物3、18、20、25、26、29、30、60、108-112或122)的组合物肌肉内施用能够引起免疫响应的疫苗和/或化合物。其它治疗剂和/或预防剂包括但不限于抗代谢物(例如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷和5-氟尿嘧啶达卡巴嗪(dacarbazine))、烷化剂(例如氮芥(mechlorethamine)、噻替哌(thiotepa)、苯丁酸氮芥(chlorambucil)、拉奇霉素(CC-1065)、美法兰(melphalan)、卡莫司汀(carmustine,BSNU)、罗莫司丁(lomustine,CCNU)、环磷酰胺、白消安(busulfan)、二溴甘露醇、链脲佐菌素、丝裂霉素C和顺二氯二胺络铂(II)(DDP)、顺铂)、蒽环霉素(例如柔红霉素(以前称为道诺霉素(daunomycin))和多柔比星)、抗生素(例如更生霉素(dactinomycin)(以前称为放线菌素)、博莱霉素、光辉霉素(mithramycin)和安曲霉素(anthramycin,AMC))以及抗有丝分裂剂(例如长春新碱、长春碱、紫杉酚和类美登素)。
在其它实施方案中,治疗剂和/或预防剂是蛋白质。可用于本发明中的纳米粒子中的治疗性蛋白质包括但不限于庆大霉素、阿米卡星(amikacin)、胰岛素、促红细胞生成素(EPO)、粒细胞集落刺激因子(G-CSF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、因子VIR、黄体激素释放激素(LHRH)类似物、干扰素、肝素、乙型肝炎表面抗原、伤寒疫苗和霍乱疫苗。
在一些实施方案中,治疗剂是多核苷酸或核酸(例如核糖核酸或脱氧核糖核酸)。术语“多核苷酸”的最广泛含义包括呈寡核苷酸链或可以并入寡核苷酸链中的任何化合物和/或物质。根据本发明使用的示例性多核苷酸包括但不限于以下一种或多种:脱氧核糖核酸(DNA);核糖核酸(RNA),包括信使mRNA(mRNA)、其杂交体;RNAi诱导因子;RNAi因子;siRNA;shRNA;miRNA;反义RNA;核糖酶;催化性DNA;诱导三股螺旋形成的RNA;适体等。在一些实施方案中,治疗剂和/或预防剂是RNA。可用于本文所描述的组合物和方法中的RNA可以选自由但不限于以下组成的组:shortmer、antagomir、反义RNA、核糖酶、小干扰RNA(siRNA)、不对称干扰RNA(aiRNA)、微RNA(miRNA)、Dicer-底物RNA(dsRNA)、小发夹RNA(shRNA)、转运RNA(tRNA)、信使RNA(mRNA)及其混合物。在某些实施方案中,RNA是mRNA。
在某些实施方案中,治疗剂和/或预防剂是mRNA。mRNA可以编码任何所关注多肽,包括任何天然或非天然存在或以其它方式修饰的多肽。由mRNA编码的多肽可以具有任何大小并且可以具有任何二级结构或活性。在一些实施方案中,由mRNA编码的多肽当在细胞中表达时可以具有治疗作用。
在某些实施方案中,所述mRNA包括乳腺癌疫苗抗原mRNA、结直肠癌乳腺癌疫苗抗原mRNA、脑胶质瘤疫苗抗原mRNA、黑色素瘤疫苗抗原mRNA、前列腺癌疫苗抗原mRNA、淋巴癌乳腺癌疫苗抗原mRNA、血液肿瘤疫苗抗原mRNA等肿瘤抗原mRNA的至少一种。
在其它实施方案中,治疗剂和/或预防剂是siRNA。siRNA能够选择性降低所关注基因的表达或下调该基因的表达。例如,siRNA的选择可以使得在将包括该siRNA的组合物施用给有需要受试者后使与特定疾病、病症或病况有关的基因沉默。siRNA可以包含与编码所关注基因或蛋白质的mRNA序列互补的序列。在一些实施方案中,siRNA可以是免疫调节性siRNA。
在某些实施方案中,治疗剂和/或预防剂是sgRNA和/或cas9 mRNA。sgRNA和/或cas9 mRNA可以用作基因编辑工具。例如,sgRNA-cas9复合物可以影响细胞基因的mRNA翻译。
在一些实施方案中,治疗剂和/或预防剂是shRNA或者其编码载体或质粒。shRNA可以在将适当构建体递送至核中后在目标细胞内部产生。与shRNA相关的构建体和机制是相关领域中众所周知的。
疾病或病症
本发明的组合物/载体可以向受试者或患者递送治疗剂或预防剂。所述治疗剂或预防剂包括但不限于核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。因此,本发明的组合物可用于制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物。由于上述治疗剂或预防剂的种类广泛,本发明的组合物可用于治疗或预防多种疾病或病症。
在一种实施方案中,所述疾病或病症以功能失常或异常的蛋白质或多肽活性为特征。
例如,所述疾病或病症选自由以下组成的组:感染性疾病、癌症和增生性疾病、遗传性疾病、自体免疫性疾病、糖尿病、神经退化性疾病、心血管和肾血管疾病以及代谢性疾病。
在一种实施方案中,所述感染性疾病选自由冠状病毒,流感病毒,或HIV病毒引起的疾病、小儿肺炎,裂谷热,黄热病,狂犬病,多种疱疹。
其它组分
组合物可以包括一种或多种除前述部分中所描述的那些外的组分。例如,组合物可以包括一个或多个疏水性小分子,如维生素(例如维生素A或维生素E)或固醇。
组合物还可以包括一个或多个渗透性增强分子、碳水化合物、聚合物、表面改变剂或其它组分。渗透性增强分子可以是例如美国专利申请公布第2005/0222064号所描述的分子。碳水化合物可以包括简单糖(例如葡萄糖)和多糖(例如糖原以及其衍生物和类似物)。
表面改变剂可以包括但不限于阴离子性蛋白质(例如牛血清白蛋白)、表面活性剂(例如阳离子性表面活性剂,如二甲基双十八烷基溴化铵)、糖或糖衍生物(例如环糊精)、核酸、聚合物(例如肝素、聚乙二醇和泊洛沙姆)、粘液溶解剂(例如乙酰半胱氨酸、艾蒿、菠萝蛋白酶(bromelain)、木瓜蛋白酶、大青(clerodendrum)、溴己新(bromhexine)、羧甲司坦(carbocisteine)、依普拉酮(eprazinone)、美司钠(mesna)、氨溴索(ambroxol)、索布瑞醇(sobrerol)、多米奥醇(domiodol)、来托司坦(letosteine)、司替罗宁(stepronin)、硫普罗宁(tiopronin)、凝溶胶蛋白(gelsolin)、胸腺肽(thymosin)β4、链球菌DNA酶α(dornasealfa)、奈替克新(neltenexine)和厄多司坦(erdosteine))和DNA酶(例如rhDNA酶)。表面改变剂可以被安置在组合物的纳米粒子内和/或表面上(例如通过涂布、吸附、共价连接或其它方法)。
组合物还可以包含一种或多种官能化脂质。例如,脂质可以用炔基官能化,该炔基当在适当反应条件下暴露于叠氮化物时可能经历环加成反应。确切地说,脂质双层可以通过这一方式,用一个或多个可有效地促进膜渗透、细胞识别或成像的基团官能化。组合物的表面还可以与一种或多种有用抗体偶联。可用于靶向细胞递送、成像和膜渗透的官能团和偶联物是本领域中众所周知的。
除这些组分外,组合物可以包括可用于药物组合物中的任何物质。例如,组合物可以包括一种或多种药学上可接受的赋形剂或辅助成分,如但不限于一种或多种溶剂、分散介质、稀释剂、分散助剂、悬浮助剂、造粒助剂、崩解剂、填充剂、助流剂、液体媒剂、粘合剂、表面活性剂、等渗剂、增稠剂或乳化剂、缓冲剂、润滑剂、油、防腐剂、调味剂、着色剂等。赋形剂例如淀粉、乳糖或糊精。药学上可接受的赋形剂是本领域中众所周知的(参见例如Remington’s The Science and Practice of Pharmacy,第21版,A.R.Gennaro;Lippincott,Williams&Wilkins,Baltimore,MD,2006)。
稀释剂的实例可以包括但不限于碳酸钙、碳酸钠、磷酸钙、磷酸二钙、硫酸钙、磷酸氢钙、磷酸钠、乳糖、蔗糖、纤维素、微晶纤维素、高岭土、甘露糖醇、山梨糖醇、肌醇、氯化钠、干淀粉、玉米淀粉、粉末状糖和/或其组合。
在一些实施方案中,包括一种或多种本文所述的脂质的组合物还可以包括一种或多种佐剂,例如吡喃葡萄糖基脂质佐剂(GLA)、CpG寡聚脱氧核糖核苷酸(例如A类或B类)、多聚(I:C)、氢氧化铝和Pam3CSK4。
本发明的组合物可以制成固体、半固体、液体或气体的形式的制剂,例如片剂、胶囊剂、软膏剂、酏剂、糖浆、溶液、乳液、悬浮液、注射剂、气溶胶。本发明的组合物可以通过制药领域熟知的方法来制备。例如,无菌注射溶液可通过将所需量的治疗剂或预防剂与所需的上述各种其它成分掺入适当的溶剂例如无菌蒸馏水中,然后过滤灭菌来制备。还可以加入表面活性剂以促进形成均匀的溶液或悬浮液。
例如,本发明的组合物可以经静脉内、肌肉内、皮内、皮下、鼻内或通过吸入施用。在一种实施方案中,所述组合物是皮下施用的。
本发明的组合物以治疗有效量给药,所述量不仅可以随所选择的特定试剂而变化,还可以随给药途径,所治疗疾病的性质以及患者的年龄和状况而变化,并且最终可以由主治医师或临床医生自行决定。例如,可将约0.001mg/kg至约10mg/kg剂量的所述治疗剂或预防剂施用给哺乳动物(例如人)。
术语“药学上可接受的盐”是指本发明化合物的相对无毒、无机酸或有机酸加成盐。例如,参见S.M.Berge等人“Pharmaceutical Salts”,J.Pharm.Sci.1977,66,1-19。其中,无机酸例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸等;有机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟酸、巴莫酸、果胶酯酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、胺基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对-甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水杨酸等。例如,可使用HCl(或盐酸)、HBr(或氢溴酸溶液)、甲磺酸、硫酸、酒石酸或富马酸与式(I)所示的化合物形成药学上可接受的盐。
术语“烷基”在本发明中是指包括具有规定碳原子数的支链和直链饱和脂族一价烃基。术语“亚烷基”在本发明中是指包括具有规定碳原子数的支链和直链饱和脂族二价烃基。Cn~Cm是指包括具有n至m个碳原子数的基团。例如C2~C5亚烷基包括C2亚烷基、C3亚烷基、C4亚烷基、C5亚烷基。
“治疗有效量”为当给予患者时能改善疾病或症状的治疗剂的量。“预防有效量”为当给予受试者时能预防疾病或症状的预防剂的量。构成“治疗有效量”的治疗剂的量或“预防有效量”的预防剂的量随着治疗剂/预防剂、疾病状态及其严重性、待治疗/预防的患者/受试者的年龄、体重等而变化。本领域普通技术人员可根据其知识以及本发明常规地确定治疗有效量和预防有效量。
本文所用术语阳离子脂质是指在选定的pH值带正电荷的脂质。阳离子脂质体易于与带负电荷的核酸结合,即通过静电力与核酸中存在的带负电的磷酸基团相互作用,形成脂质纳米颗粒(LNP)。LNP是目前主流的递送载体之一。
本发明的有益效果是:
本发明中三组分LNP组成中不含PEG脂质成分,避免了由于PEG脂质成分造成的生物毒性,提高了安全性;对四组分LNP进行了简化,提高了转染效率。
附图说明
图1为本发明AO12的核磁图谱。
图2为本发明AM12的核磁图谱。
图3为本发明AP12的核磁图谱。
图4为本发明CO14的核磁图谱。
图5为本发明CM14的核磁图谱。
图6为本发明CP14的核磁图谱。
图7为本发明试验例2阳离子类脂质分子递送性能测试结果。
具体实施方式
以下通过具体的实施例对本发明的内容作进一步详细的说明。实施例和对比例中所用的原料、试剂或装置如无特殊说明,均可从常规商业途径得到,或者可以通过现有技术方法得到。除非特别说明,试验或测试方法均为本领域的常规方法。
实施例1:阳离子脂质化合物的合成
AO10、AO12、AO14、AO16、AO18的合成,合成路线示意图如下:
分别将1,2-苯二甲胺与1,2-环氧癸烷或1,2-环氧十二烷或1,2-环氧十四烷或1,2-环氧十六烷或1,2-环氧十八烷以摩尔比为1:2.2于95%乙醇中85℃反应48小时,依次对应制得AO10、AO12、AO14、AO16、AO18。
其中,AO12的核磁图谱如图1所示。
实施例2:阳离子脂质化合物的合成
AM10、AM12、AM14、AM16、AM18的合成,合成路线示意图如下:
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分别将1,3-苯二甲胺与1,2-环氧癸烷或1,2-环氧十二烷或1,2-环氧十四烷或1,2-环氧十六烷或1,2-环氧十八烷以摩尔比为1:2.2于95%乙醇中85℃反应48小时,依次对应制得AM10、AM12、AM14、AM16、AM18。
其中,AM12的核磁图谱如图2所示。
实施例3:阳离子脂质化合物的合成
AP10、AP12、AP14、AP16、AP18的合成,合成路线示意图如下:
分别将1,4-苯二甲胺与1,2-环氧癸烷或1,2-环氧十二烷或1,2-环氧十四烷或1,2-环氧十六烷或1,2-环氧十八烷以摩尔比为1:2.2于95%乙醇中85℃反应48小时,依次对应制得AP10、AP12、AP14、AP16、AP18。
其中,AP12的核磁图谱如图3所示。
实施例4:阳离子脂质化合物的合成
BO10、BO12、BO14、BO16、BO18的合成,合成路线示意图如下:
分别将1,2-苯二甲胺与1,2-环氧癸烷或1,2-环氧十二烷或1,2-环氧十四烷或1,2-环氧十六烷或1,2-环氧十八烷以摩尔比为1:4.4于95%乙醇中85℃反应48小时,,依次对应制得BO10、BO12、BO14、BO16、BO18。
实施例5:阳离子脂质化合物的合成
BM10、BM12、BM14、BM16、BM18的合成,合成路线示意图如下:
分别将1,3-苯二甲胺与1,2-环氧癸烷或1,2-环氧十二烷或1,2-环氧十四烷或1,2-环氧十六烷或1,2-环氧十八烷以摩尔比为1:4.4于95%乙醇中85℃反应48小时,依次对应制得BM10、BM12、BM14、BM16、BM18。
实施例6:阳离子脂质化合物的合成
BP10、BP12、BP14、BP16、BP18的合成,合成路线示意图如下:
分别将1,4-苯二甲胺与1,2-环氧癸烷或1,2-环氧十二烷或1,2-环氧十四烷或1,2-环氧十六烷或1,2-环氧十八烷以摩尔比为1:4.4于95%乙醇中85℃反应48小时,依次对应制得BP10、BP12、BP14、BP16、BP18。
实施例7:阳离子脂质化合物的合成
CO10、CO12、CO14、CO16、CO18、CO22的合成,合成路线示意图如下:
分别将1,2-苯二甲胺与丙烯酸癸酯或丙烯酸十二酯或丙烯酸十四酯或丙烯酸十六酯或丙烯酸十八酯或丙烯酸二十二酯以摩尔比为1:2.2于异丙醇中85℃反应48小时,依次对应制得CO10、CO12、CO14、CO16、CO18、CO20。
其中,CO14的核磁图谱如图4所示。
实施例8:阳离子脂质化合物的合成
CM10、CM12、CM14、CM16、CM18、CM22的合成,合成路线示意图如下:
分别将1,3-苯二甲胺与丙烯酸癸酯或丙烯酸十二酯或丙烯酸十四酯或丙烯酸十六酯或丙烯酸十八酯或丙烯酸二十二酯以摩尔比为1:2.2于异丙醇中85℃反应48小时,依次对应制得CM10、CM12、CM14、CM16、CM18、CM20。
其中,CM14的核磁图谱如图5所示。
实施例9:阳离子脂质化合物的合成
CP10、CP12、CP14、CP16、CP18、CP22的合成,合成路线示意图如下:
分别将1,4-苯二甲胺与丙烯酸癸酯或丙烯酸十二酯或丙烯酸十四酯或丙烯酸十六酯或丙烯酸十八酯或丙烯酸二十二酯以摩尔比为1:2.2于异丙醇中85℃反应48小时,依次对应制得CP10、CP12、CP14、CP16、CP18、CP20。
其中,CP14的核磁图谱如图6所示。
以下实施例或对比例中,Luci mRNA:EZ CapTMFirefly Luciferase mRNA试剂;Lipo2000:Lipofectamine2000脂质体2000;氮磷比(N:P)指阳离子类脂上所含氮元素与RNA中所含的磷元素的摩尔比。
实施例10:脂质纳米粒的制备
以AO10或AO12或AO14或AO16或AO18或AM10或AM12或AM14或AM16或AM18或AP10或AP12或AP14或AP16或AP18为阳离子类脂的三组分LNP@Luci mRNA的制备:
乙醇相制备:将阳离子类脂、DOPE、胆固醇以摩尔比为47.4:31.6:21.1分别溶解在乙醇中。
水相制备:Luci-mRNA溶解于PBS中至22.22ng/uL。
取1uL乙醇相与9μL水相,1uL乙醇相中含阳离子类脂的量分别为0.22nmol、0.44nmol、0.88nmol、1.76nmol、3.53nmol、5.29nmol,9uL水相中含Luci-mRNA为200ng,将1uL乙醇相用移液枪加入9uL水相中并吹打混匀,静置十分钟,分别得到N:P=0.75、1.5、3、6、12、18的LNP@Luci mRNA。
实施例11:脂质纳米粒的制备
以AO10或AO12或AO14或AO16或AO18或AM10或AM12或AM14或AM16或AM18或AP10或AP12或AP14或AP16或AP18为阳离子类脂的四组分LNP@Luci mRNA的制备:
乙醇相制备:将阳离子类脂、DSPC、胆固醇、ALC-0159分别以摩尔比46.3:9.4:42.7:1.6溶解在乙醇中。
水相制备:Luci-mRNA溶解于PBS中至22.22ng/uL。
取1uL乙醇相与9uL水相,1μL乙醇相中含阳离子类脂的量分别为0.88nmol、1.76nmol、3.53nmol、5.29nmol、7.06nmol,9μL水相中含Luci-mRNA为200ng,将1μL乙醇相用移液枪加入9μL水相中并吹打混匀,静置十分钟,分别得到N:P=3、6、12、18、24的LNP@LucimRNA。
实施例12:脂质纳米粒的制备
以BO10或BO12或BO14或BO16或BO18或BM10或BM12或BM14或BM16或BM18或BP10或BP12或BP14或BP16或BP18为阳离子类脂的三组分LNP@Luci mRNA的制备:
乙醇相制备:将阳离子类脂、DOPE、胆固醇以摩尔比为47.4:31.6:21.1分别溶解在乙醇中。
水相制备:Luci-mRNA溶解于pH=4的柠檬酸-柠檬酸钠缓冲液中至22.22ng/μL。
取1μL乙醇相与9μL水相,1μL乙醇相中含阳离子类脂的量分别为0.22nmol、0.44nmol、0.88nmol、1.76nmol、3.53nmol、5.29nmol,9μL水相中含Luci-mRNA为200ng,将1μL乙醇相用移液枪加入9μL水相中并吹打混匀,静置十分钟,分别得到N:P=0.75、1.5、3、6、12、18的LNP@Luci mRNA。
实施例13:脂质纳米粒的制备
以CO10或CO12或CO14或CO16或CO18或CO22或CM10或CM12或CM14或CM16或CM18或CM22或CP10或CP12或CP14或CP16或CP18或CP22为阳离子类脂的三组分LNP@Luci mRNA的制备:
乙醇相制备:将阳离子类脂、DOPE、胆固醇以摩尔比为47.4:31.6:21.1分别溶解在乙醇中。
水相制备:Luci-mRNA溶解于pH=4的柠檬酸-柠檬酸钠缓冲液中至22.22ng/μL。
取1μL乙醇相与9μL水相,1μL乙醇相中含阳离子类脂的量分别为0.44nmol、0.88nmol、1.76nmol、3.53nmol、5.29nmol、7.06nmol,9μL水相中含Luci-mRNA为200ng,将1μL乙醇相用移液枪加入9μL水相中并吹打混匀,静置十分钟,分别得到N:P=1.5、3、6、12、18、24的LNP@Luci mRNA。
实施例14:脂质纳米粒的制备
以CO10或CO12或CO14或CO16或CO18或CO22或CM10或CM12或CM14或CM16或CM18或CM22或CP10或CP12或CP14或CP16或CP18或CP22为阳离子类脂的四组分LNP@Luci mRNA的制备:
乙醇相制备:将阳离子类脂、DSPC、胆固醇、ALC-0159分别以摩尔比46.3:9.4:42.7:1.6溶解在乙醇中。
水相制备:将Luci-mRNA用pH=4的柠檬酸-柠檬酸钠缓冲液溶解至22.22ng/μL。
取1μL乙醇相与9μL水相,1μL乙醇相中含阳离子类脂的量分别为0.88nmol、1.76nmol、3.53nmol、5.29nmol、7.06nmol,9μL水相中含Luci-mRNA为200ng,将1μL乙醇相用移液枪加入9μL水相中并吹打混匀,静置十分钟,分别得到N:P=1.5、3、6、12、18、24的LNP@Luci mRNA。
对比例1:lipo2000@Luci mRNA的制备
用PBS将lipo2000溶解至0.1mg/ml,将Luci-mRNA用PBS溶解至25ng/μL,取2μLlipo2000(0.1mg/ml)与8μL Luci mRNA混合均匀后静置10分钟,得lipo2000@Luci mRNA。
对比例2:以ALC-0315为阳离子类脂的Pfizer/BioNTech LNP@Luci-mRNA的制备:
乙醇相制备:将ALC-0315、DSPC、胆固醇、ALC-0159分别以摩尔比46.3:9.4:42.7:1.6溶解在乙醇中.
水相制备:将Luci-mRNA用pH=4的柠檬酸-柠檬酸钠缓冲液溶解至22.22ng/μL。
取1μL乙醇相与9μL水相,1μL乙醇相中含ALC-0315为1.76nmol,9μL水相中含Luci-mRNA为200ng,将1μL乙醇相用移液枪加入9μL水相中并吹打混匀,静置十分钟,得到N:P=3的LNP@Luci mRNA。
试验例1:293T细胞上筛选不同LNP的转染效果
于白底96孔细胞培养板上2w/孔接种293T细胞,细胞液体积为90μL/孔,培养24小时后将实施例或对比例中制备的10μL LNP加入孔中。共孵育24小时后,加入One-umiTM萤火虫萤光素酶报告基因检测试剂(100μL/孔),静置10分钟后于酶标仪测试其生物发光值。
RLU,Raletive luciferase activity,相关荧光素酶活性。
试验结果如下:
表1不同阳离子类脂的三组分LNP@Luci mRNA的筛选结果
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表2不同阳离子类脂的四组分LNP@Luci mRNA的筛选结果
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从表1和表2可看出:
AM12为阳离子类脂的N:P=3的三组分LNP@Luci-mRNA为lipo2000转染效果的1.6倍,为ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的1.4倍。
以CO10为阳离子类脂的三组分LNP@Luci mRNA(N:P=6)转染效果为lipo2000的1.3倍,为ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的1.2倍;
以CP10为阳离子类脂的三组分LNP@Luci mRNA(N:P=1.5)转染效果是lipo2000的2倍,是ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的1.8倍;
以CM12为阳离子类脂的三组分LNP@Luci mRNA(N:P=18)转染效果是lipo2000的1.6倍,是ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的1.4倍;
以CP12为阳离子类脂的三组分LNP@Luci mRNA(N:P=24)转染效果是lipo2000的1.2倍,是ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的1.06倍;
CO14(N:P=12)为阳离子类脂的三组分LNP@Luci mRNA(N:P=24)是lipo2000的2.25倍,是ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的2.02倍;
CM14(N:P=3)是lipo2000的4倍,是ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的3.6倍。
以CP12为阳离子类脂的三组分LNP@Luci mRNA(N:P=3)转染效果是lipo2000的1.6倍,是ALC-0315四组分LNP@Luci-mRNA(N:P=3)转染效果的1.4倍。
试验例2:阳离子类脂质分子递送性能测试
一、以AM12为阳离子类脂的三组分LNP@IDH1(R132H)的制备
乙醇相制备:将阳离子类脂AM12、DOPE、胆固醇以摩尔比为47.4:31.6:21.1分别溶解在乙醇中。
水相制备:将IDH1(R132H)抗原mRNA溶解于PBS中至22.22ng/uL。其中,IDH1(R132H)抗原序列参考:Platten,M.,Bunse,L.,Wick,A.et al.A vaccine targetingmutant IDH1 in newly diagnosed glioma.Nature 592,463–468(2021).
取1uL乙醇相与9μL水相,1uL乙醇相中含阳离子类脂的量分别为0.88nmol、1.76nmol,将1uL乙醇相用移液枪加入9uL水相中并吹打混匀,静置十分钟,分别得到N:P=3、6的LNP@IDH1(R132H)。
二、LNP@IDH1(R132H)在293T细胞上表达的Western blot实验
细胞接种:于六孔板上接种以50万个细胞/孔的数量,每孔加入2.5mL DMEM完全培养基,接种24小时后,将孔内培养基换成不含胎牛血清的DMEM培养基(1mL/孔),相应加入N:P=3的LNP@IDH1(R132H)、N:P=6的LNP@IDH1(R132H)、游离的IDH1(R132H)mRNA,孵育24小时。
蛋白质的样品制备
六孔板中每孔加入90μL RIPA裂解液,冰上裂解30分钟后收集于EP管中,15000rpm离心10分钟后收集上清,每孔上清加入约10μL的5x loading buffer,混合均匀后于100℃加热10分钟。
SDS-PAGE电泳
将SDS-PAGE胶置于电泳槽中,加入1X电泳液后,于SDS-PAGE胶分别上样5μL蛋白marker,15μL的N:P=3的LNP@IDH1(R132H),15μL的N:P=6的LNP@IDH1(R132H)、15μL的游离的IDH1(R132H)mRNA。于150V电压下电泳45分钟。
转膜
准备一张大概5*7cm的0.2um的PVDF膜(提前泡于甲醇中1min进行激活),在加有转膜液的搪瓷盘中,将夹子打开使黑面于底下,分别按顺序垫一张海绵垫、三层滤纸、PVDF膜、SDS-PAGE胶、三层滤纸和一张海绵垫。将夹子放入转膜槽中(转膜夹的黑面对槽的黑面),于冰上以300mA转膜70分钟。
封闭
将PVDF膜浸泡于含5%脱脂牛奶的TBST中,常温下于摇床上封闭2小时。
洗膜
将封闭后的PVDF膜用TBST于摇床上常温浸泡10分钟后倒去旧的TBST后再加入新的TBST,重复三次。
一抗孵育
用抗体稀释缓冲液将一抗按比例1:20000进行稀释,将PVDF膜浸泡于稀释后的一抗中,于4℃下置于摇床上孵育10小时。
洗膜
将孵育一抗后的PVDF膜用TBST于摇床上常温浸泡10分钟后倒去旧的TBST后再加入新的TBST,重复三次。
二抗孵育
用含2.5%脱脂牛奶的TBST将二抗按比例1:5000进行稀释,将PVDF膜浸泡于稀释后的二抗中,于常温下置于摇床上孵育1.5小时。
洗膜
将孵育二抗后的PVDF膜用TBST于摇床上常温浸泡10分钟后倒去旧的TBST后再加入新的TBST,重复三次。
化学发光显影
将显影液A和B两种试剂1:1混合后滴于PVDF膜表面,约30s后于化学发光仪下显影。
结果如图7所示。
从图7可看出,以AM12为阳离子脂质的、N:P=3的三组分LNP能有效递送脑胶质瘤肿瘤抗原,该LNP有开发成脑胶质瘤肿瘤疫苗载体的潜力。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.式I化合物或其药学上可接受的盐:
其中,R1选自氘、H、R2选自/> L选自C1~C10亚烷基、取代C1~C10亚烷基;G1选自1~8个羟基取代的C1~C6直链或支链亚烷基;G2选自-C(O)O-、-OC(O)-、-C(O)O-取代的C1~C6直链或支链、-OC(O)-取代的C1~C6直链或支链;X1、X2分别独立选自C1~C60直链或支链烷基;n选自1~6的自然数;m、p分别独立选自1~20的自然数。
2.根据权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于:所述的式I化合物中,R1选自氘、H、
R2选自 L选自C1~C10亚烷基、取代C1~C10亚烷基;n选自1~6的自然数;t1~t6分别独立选自1~20的自然数。
3.根据权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于:式I化合物为且苯环上取代基的位置关系为邻位、间位或对位。
4.根据权利要求2所述的式I化合物或其药学上可接受的盐,其特征在于:式I化合物选自:
5.根据权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于:式I化合物选自下列化合物:
6.一种化合物的制备方法,其特征在于:包括以下步骤:
i)将式II化合物与式III化合物/>反应制得式I-A化合物或式I-B化合物;或
ii)将式II化合物与式IV化合物/>反应制得式I-C化合物或式I-D化合物;
其中,L选自C1~C10亚烷基、取代C1~C10亚烷基;n选自1~6的自然数;t1、t4分别独立选自1~20的自然数。
7.一种药物组合物,其特征在于:包括载体,所述载体包括阳离子脂质,所述阳离子脂质包括权利要求1~5任一项所述的式I化合物或其药学上可接受的盐;和/或,所述阳离子脂质占载体的摩尔比为10%~75%。
8.根据权利要求7所述的药物组合物,其特征在于:载体包括阳离子脂质、中性脂质、结构脂质或载体包括阳离子脂质、中性脂质、结构脂质以及聚合物共轭脂质。
9.根据权利要求7~9任一项所述的药物组合物,其特征在于:所述药物组合物还包括治疗剂、预防剂、光敏剂和/或光热剂的至少一种。
10.权利要求1~5任一项所述式I化合物或其药学上可接受的盐、权利要求7~10任一项所述药物组合物在制备治疗疾病或病症药物中的应用,所述疾病或病症选自由以下组成的组:感染性疾病、癌症和增生性疾病、遗传性疾病、自体免疫性疾病、糖尿病、神经退化性疾病、心血管和肾血管疾病以及代谢性疾病。
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