CN118045169A - 脂质-带电分子偶联物、可吸入式脂质纳米颗粒及其制备方法和应用 - Google Patents
脂质-带电分子偶联物、可吸入式脂质纳米颗粒及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了脂质‑带电分子偶联物、可吸入式脂质纳米颗粒及其制备方法和应用。本发明的脂质‑带电分子偶联物包括脂质单元和带电单元;所述带电单元选自负电荷单元和/或正电荷单元。本发明的脂质纳米颗粒包括可离子化脂质、辅助磷脂、胆固醇和聚乙二醇化脂质和脂质‑带电分子偶联物。本发明的脂质纳米颗粒经雾化吸入给药后可以同时激活体液、细胞、黏膜免疫应答,免疫应答强度显著高于现有商品化脂质纳米颗粒剂型,在防治经黏膜传播的传染病领域有巨大应用前景。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种脂质-带电分子偶联物、可吸入式脂质纳米颗粒及其应用。
背景技术
信使核糖核酸(mRNA)作为一类核酸药物可制备的疫苗范围非常广阔。与传统的蛋白质、病毒疫苗相比,mRNA仅通过改变核苷酸序列即可在被转染的细胞内表达不同蛋白质,可用于制备几乎所有传染病疫苗或肿瘤疫苗;其次,mRNA 通过体外转录方法合成,整个过程简单、产率高,可快速批量化生成,无需提纯病毒,极大缩短了疫苗的研发和生产周期;最后,mRNA可在细胞质内瞬时表达蛋白,无需进入细胞核,因此没有破坏基因组或引起基因突变的风险,相较于质粒DNA疫苗安全性更高。但mRNA分子量大、表面带负电荷,因而难以进入细胞内,且mRNA稳定性差、易被核酸酶降解,所以需要合适的递送载体协助其转染进靶细胞内才能够发挥作用。
Moderna、Pfizer和BioNTech公司开发的mRNA新冠疫苗以创纪录的速度获批上市。获批的两款mRNA疫苗均采用脂质纳米颗粒作为递送载体,通过肌肉注射激活皮下淋巴结内的免疫细胞产生系统免疫反应。然而,绝大多数传染性疾病是通过黏膜(主要包括呼吸道、胃肠道、生殖系统黏膜等)进入体内的,肌肉注射的免疫方式虽然可以杀灭或中和已经进入体内的病原体,却无法抑制病原体在黏膜表面的存活,使得接种疫苗后的感染者依然能够作为宿主继续传播病原体。因此,只有激活黏膜免疫应答,才能够有效清除黏膜表面的病原体,在源头阻断病原体的感染和传播。
通过吸入给药的方式直接将mRNA疫苗递送到鼻腔、气管、肺部黏膜,可以模拟病原体的自然感染过程,直接激活黏膜免疫应答。呼吸道免疫具有抗原用量少、不受消化酶影响、不易引起免疫耐受、避免肝脏首过效应、给药方便、服药顺从性好等一系列优点,在临床应用上具有巨大潜力。但是,呼吸道自身的生理学特点也为吸入mRNA疫苗带来了额外的挑战。通过自组装方式制备的脂质纳米颗粒在雾化形成气溶胶的过程中受气动力和液体表面张力变化的影响极易破裂、稳定性差,并且其穿过黏膜表面黏液层的效率较低,无法有效激活黏膜下的免疫细胞。因此,只有提高脂质纳米颗粒在吸入给药过程中的抗雾化稳定性,才有希望实现吸入式mRNA疫苗的进一步临床转化。
发明内容
为了解决现有脂质纳米颗粒在雾化过程中不稳定、吸入给药后表达效率低的难题,本发明的技术方案如下:
一种脂质-带电分子偶联物,所述脂质-带电分子偶联物包括脂质单元和带电单元。
根据本发明的实施方案,所述脂质-带电分子偶联物可以带正电或负电,优选为带负电。
根据本发明的实施方案,所述带电单元选自负电荷单元和/或正电荷单元。
根据本发明的实施方案,所述负电荷单元选自下述负电物质中的至少一种构成的单元:第一多肽、核酸单元(DNA,RNA等)、负电荷高分子等。
优选地,所述第一多肽选自带负电荷氨基酸且长度为1-50个氨基酸的亲水肽链,所述带负电荷氨基酸例如为天冬氨酸、谷氨酸。示例性地,所述亲水肽链选自天冬氨酸-丝氨酸-丝氨酸-半胱氨酸。
优选地,所述核酸单元选自长度为1-40个碱基的、具有任意序列的DNA或 RNA。
优选地,所述负电荷高分子选自透明质酸、聚丙烯酸等亲水高分子。
根据本发明的实施方案,所述正电荷单元选自下述正电物质中的至少一种构成的单元:第二多肽、正电荷高分子等。
优选地,所述第二多肽选自带正电荷氨基酸且长度为1-50个氨基酸的亲水肽链等中的至少一种,所述带正电荷氨基酸选自组氨酸、精氨酸、赖氨酸等。优选地,所述正电荷高分子选自聚赖氨酸、壳聚糖、聚(β-氨基酯)阳离子聚合物等中的至少一种。
根据本发明的实施方案,所述脂质单元包括疏水基团,所述疏水基团可选用本领域已知的疏水基团,本发明中不做具体限定。示例性地,所述疏水基团选自疏水烷基链,例如为取代或未取代的烃基(例如为C10~C20的烃基)或含有双键的烃基(C10~C20的烃基);当含有取代基时,取代基例如选自芳基、酯、醚、胺、酰胺等中的至少一种。
根据本发明的实施方案,所述脂质单元选自下述物质中的至少一种:可离子化脂质、磷脂、固醇类化合物、脂肪酸等。本发明中,所述离子化脂质、磷脂、固醇类化合物、脂肪酸可选用本领域已知的物质,本发明中不做具体限定。
示例性地,所述可离子化脂质选自下述物质中的至少一种:8-[(2-羟乙基)(6- 氧代-6-癸氧基己基)氨基]辛酸(十七烷-9-基)酯(SM-102)、[(4-羟基丁基)氮杂二基] 双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315)、4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯(DLin-MC3-DMA)、3,6-双{4-[双(2-羟基十二烷基)氨基]丁基}哌嗪-2,5- 二酮(cKK-E12)、9-(4-(二甲氨基)丁酰氧基)十七烷二酸二((Z)-壬-2-烯-1-基)酯 (L319)、N2,2-二亚油基-4-二甲氨基乙基-[1,3]-二氧戊环(DLin-KC2-DMA)、8-[(2- 羟乙基)(8-壬氧基-8-氧代辛基)氨基]辛酸(十七烷-9-基)酯(Lipid5)、 1,1'-[(2-{4-[2-({2-[双(2-羟基十二烷基)氨基]乙基}(2-羟基十二烷基)氨基)乙基]哌嗪-1-基}乙基)氮杂二烷基]双(十二烷-2-醇)(C12-200)、(2,3-二油酰基-丙基)-三甲基氯化铵(DOTAP)、双甲基双十八烷基溴化铵(DDAB)、四(8-甲基壬基)3,3',3”,3”'-{[(甲基氮杂二烷基)双(丙烷-3,1二基)]双(氮杂三基)}四丙酸酯 (306Oi10)中的至少一种;优选为8-[(2-羟乙基)(6-氧代-6-癸氧基己基)氨基]辛酸(十七烷-9-基)酯(SM-102)或[(4-羟基丁基)氮杂二基]双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315)。
示例性地,所述磷脂选自1,2-二硬脂酰基-sn-甘油基-3-磷脂酰胆碱(DSPC)、 1,2-二油酰基-sn-甘油基-3-磷脂酰胆碱(DOPC)、1,2-二棕榈酰基-sn-甘油基-3- 磷脂酰胆碱(DPPC)、2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰胆碱(POPC)、 1,2-二油酰基-sn-甘油基-3-磷脂酰乙醇胺(DOPE)、2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺(POPE)、1,2-二硬脂酰基-sn-甘油基-3-磷脂酰乙醇胺 (DSPE)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺(DPPE)中的一种或多种。
示例性地,所述固醇类化合物选自β-谷甾醇、胆甾烷醇、胆甾烷酮、胆固醇、胆甾烯酮、7β-羟基胆固醇、7α-羟基胆固醇中的一种或多种。
示例性地,所述脂肪酸选自饱和脂肪酸或不饱和脂肪酸。饱和脂肪酸包括软脂酸、硬脂酸、月桂酸、豆蔻酸、花生酸等;不饱和脂肪酸包括豆蔻油酸、棕榈油酸、菜籽油酸、亚油酸、亚麻酸、油酸、花生四烯酸等。
根据本发明示例性的方案,所述脂质-带电分子偶联物包括多肽单元和脂质单元,记为多肽-脂质偶联分子。例如,所述多肽-脂质偶联分子具有如式(I) 所示的结构。
本发明还提供上述脂质-带电分子偶联物的制备方法包括:交联剂与脂质单元反应后,再与带电单元混合反应,得到所述脂质-带电分子偶联物。
根据本发明的实施方案,所述脂质单元通过下述物质中的至少一种制备得到:可离子化脂质、磷脂、固醇类化合物、脂肪酸,所述可离子化脂质、磷脂、固醇类化合物、脂肪酸具有如上文所述的含义。
优选地,所述脂质单元通过磷脂与交联剂反应得到。
优选地,所述交联剂选自琥珀酰亚胺3-(2-吡啶基二硫基)-丙酸酯(SPDP)。
根据本发明的实施方案,所述脂质单元和带电单元的摩尔比为(0.8~1.2): (0.8~1.2),例如为1:1。
根据本发明示例性的方案,所述制备方法包括:将脂质单元与交联剂混合,反应后除去未反应的交联剂,随后再加入负电物质,得到所述脂质-带电分子偶联物。优选地,所述脂质单元与交联剂的摩尔比为(0.8~1.2):(0.8~1.2),例如为1:1。优选地,所述脂质单元与负电单元的摩尔比为(0.8~1.2):(0.8~1.2),例如为1:1。
本发明还提供上述脂质-带电分子偶联物在制备脂质纳米颗粒或生物制品中的应用;优选地,所述生物制品为可吸入生物制品,例如可吸入疫苗,还优选为可吸入mRNA疫苗。
本发明还提供了一种脂质纳米颗粒,所述脂质纳米颗粒包括上述脂质-带电分子偶联物、脂质组份和负载物;其中,所述脂质-带电分子偶联物通过疏水作用和静电相互作用与脂质组份、负载物自组装形成所述脂质纳米颗粒。本发明中,所述脂质-带电分子偶联物在所述脂质纳米颗粒的表面,降低了纳米颗粒表面的电位,增强了脂质纳米颗粒间的静电排斥作用,有效降低了脂质纳米颗粒间的碰撞、聚集,从而提高了脂质纳米颗粒在溶液中的分散稳定性;与此同时,在同一个脂质纳米颗粒上,脂质-带电分子偶联物分子间的静电排斥力增强了脂质分子间的疏水相互作用,进一步提高了脂质纳米颗粒自身的稳定性。
根据本发明的实施方案,通过在所述脂质纳米颗粒的表面引入脂质-带电分子偶联物,通过调控颗粒表面的静电排斥力,提高了脂质纳米颗粒的稳定性,所述脂质纳米颗粒具有优异的抗雾化性质。
根据本发明的实施方案,所述脂质纳米颗粒的给药方式可以为静脉给药、皮下给药、肌肉给药、吸入给药、滴鼻给药等,优选为吸入给药。
根据本发明的实施方案,所述脂质-带电分子偶联物在加入脂质纳米颗粒后可以显著提高经吸入给药后的核酸药物递送效率。
根据本发明的实施方案,所述脂质纳米颗粒中,所述脂质-带电分子偶联物可以带正电或负电,优选为带负电。
根据本发明的实施方案,在所述脂质纳米颗粒中,所述脂质-带电分子偶联物与所述脂质组份的摩尔比为(0.1~20):100,优选为(0.6~10):100,优选为2.5:97.5。
根据本发明的实施方案,所述脂质组份中的氮含量与核酸中的磷含量的摩尔比为(1~50):1;优选为(5~20):1,例如为1、2、3、4、5、6、7、8、9、 10,又例如为5.67。
根据本发明的实施方案,所述脂质组份包括可离子化脂质、辅助磷脂、胆固醇及其衍生物和聚乙二醇化脂质。
根据本发明的实施方案,所述可离子化脂质占所述脂质组份总量的摩尔百分比为30%~70%,例如30%、40%、50%、60%、70%。
根据本发明的实施方案,所述可离子化脂质具有如上文所述的含义,例如选自下述物质中的至少一种:8-[(2-羟乙基)(6-氧代-6-癸氧基己基)氨基]辛酸(十七烷-9-基)酯(SM-102)、[(4-羟基丁基)氮杂二基]双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315)、4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯(DLin-MC3-DMA)、3,6- 双{4-[双(2-羟基十二烷基)氨基]丁基}哌嗪-2,5-二酮(cKK-E12)、9-(4-(二甲氨基) 丁酰氧基)十七烷二酸二((Z)-壬-2-烯-1-基)酯(L319)、N2,2-二亚油基-4-二甲氨基乙基-[1,3]-二氧戊环(DLin-KC2-DMA)、8-[(2-羟乙基)(8-壬氧基-8-氧代辛基)氨基] 辛酸(十七烷-9-基)酯(Lipid5)、1,1'-[(2-{4-[2-({2-[双(2-羟基十二烷基)氨基]乙基}(2-羟基十二烷基)氨基)乙基]哌嗪-1-基}乙基)氮杂二烷基]双(十二烷-2- 醇)(C12-200)、(2,3-二油酰基-丙基)-三甲基氯化铵(DOTAP)、双甲基双十八烷基溴化铵(DDAB)、四(8-甲基壬基)3,3',3”,3”'-{[(甲基氮杂二烷基)双(丙烷-3,1二基)] 双(氮杂三基)}四丙酸酯(306Oi10)中的一种或多种;优选为8-[(2-羟乙基)(6-氧代-6-癸氧基己基)氨基]辛酸(十七烷-9-基)酯(SM-102)或[(4-羟基丁基)氮杂二基] 双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315)。
根据本发明的实施方案所述,所述辅助磷脂占所述脂质组份的总量的0 mol%~20mol%,例如5mol%、6mol%、7mol%、8mol%、9mol%、10mol%、 15mol%、20mol%。
根据本发明的实施方案,所述辅助磷脂包括但不限于1,2-二硬脂酰基-sn-甘油基-3-磷脂酰胆碱(DSPC)、1,2-二油酰基-sn-甘油基-3-磷脂酰胆碱(DOPC)、 1,2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱(DPPC)、2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰胆碱(POPC)、1,2-二油酰基-sn-甘油基-3-磷脂酰乙醇胺(DOPE)、 2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺(POPE)、1,2-二硬脂酰基-sn- 甘油基-3-磷脂酰乙醇胺(DSPE)、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺 (DPPE)中的一种或多种,优选为DSPC。
根据本发明的实施方案,所述胆固醇及其衍生物占所述脂质组份的总量的20mol%~50mol%,例如20mol%、25mol%、30mol%、35mol%、40mol%,又例如为38.5mol%。
根据本发明的实施方案,所述胆固醇及其衍生物包括但不限于β-谷甾醇、胆甾烷醇、胆甾烷酮、胆固醇、胆甾烯酮、7β-羟基胆固醇、7α-羟基胆固醇中的一种或多种,优选为胆固醇。
根据本发明的实施方案,所述聚乙二醇化脂质占所述脂质组份的总量的0.1mol%-10mol%,优选为1mol%~5mol%,例如1.0mol%、1.5mol%、2.0mol%、 3.0mol%、4.0mol%、5.0mol%。
根据本发明的实施方案,所述聚乙二醇化脂质包括但不限于1,2-二肉豆蔻酰基-rac-甘油基-3-甲氧基聚乙二醇(DMG-PEG)、1,2-二硬脂酰基-rac-甘油基-3- 甲氧基聚乙二醇(DSG-PEG)、1,2-二棕榈酰基-rac-甘油基-3-甲氧基聚乙二醇(DPG-PEG)、1,2-二硬脂酰基-sn-甘油基-3-磷脂酰乙醇胺-甲氧基聚乙二醇 (DSPE-PEG)中的一种或多种,优选为DMG-PEG。
根据本发明的实施方案,所述负载物选自核酸,从而实现递送核酸。优选地,所述核酸包封在所述脂质纳米颗粒中。
根据本发明的实施方案,所述核酸选自mRNA、小干扰核糖核酸(siRNA)、质粒、反义DNA、适配体aptamer、microRNA、环状RNA,siRNA等中的至少一种。优选地,所述mRNA例如选自mLuc(编码萤火虫荧光素酶蛋白的mRNA)、 S-Omicron(编码新冠病毒奥密克戎毒株刺突蛋白的mRNA)、mOVA(编码鸡卵清蛋白的mRNA)。
根据本发明的实施方案,所述脂质纳米颗粒中,核酸的包封率为30~99%,优选为70%-90%,比如70%、75%、80%、85%、90%。
根据本发明的实施方案,所述脂质纳米颗粒的水合粒径为50~200nm,优选为100~200nm,例如120~180nm,又例如为124nm、153nm、145nm和151nm。
在一些实施方案中,所述脂质组份中,可离子化脂质:辅助磷脂:胆固醇:聚乙二醇脂质的摩尔比为50:10:38.5:1.5。
根据本发明示例性的方案,所述脂质纳米颗粒包括脂质-带电分子偶联物、脂质组份和被包封的核酸;
所述脂质-带电分子偶联物的结构式如式(I)所示;
所述脂质组份由SM102:DSPC:胆固醇:DMG-PEG2000组成,其摩尔比为50:10:38.5:1.5或50:9.4:38.5:1.5或50:7.5:38.5:1.5或50:0:38.5:1.5;
所述核酸为mLuc或mOVA。
本发明还提供上述脂质纳米颗粒的制备方法,包括将所述核酸、脂质-带电分子偶联物和脂质组份混合后,通过微流控法制备得到所述脂质纳米颗粒。
根据本发明的实施方案,所述微流控法包括如下步骤:分别取所述核酸、脂质-带电分子偶联物和脂质组份,注入微流控芯片混合,得到所述脂质纳米颗粒。
根据本发明的实施方案,所述微流控法可选用本领域已知的方法进行。示例性地,将含有所述核酸的水相与含有脂质-带电分子偶联物和脂质组份的有机相以1:3的流量注入微流控芯片混合,注射器中水相溶液流空后停止收液,得到所述脂质纳米颗粒。
本发明还提供上述脂质纳米颗粒在制备生物制品中的应用。
根据本发明的实施方案,所述生物制品为可吸入生物制品,优选地,其包括上述脂质纳米颗粒。
在一些实施方案中,所述生物制品为疫苗,优选为mRNA疫苗。
在一些实施方案中,所述生物制品可以为流感疫苗、艾滋病(HIV)疫苗、病毒性肺炎(SARS、SARS-CoV-2等)疫苗、结核病疫苗、呼吸道合胞病毒(RSV) 疫苗,肠道病毒(如EV71)疫苗,肺癌疫苗等。
根据本发明的实施方案,所述生物制品的给药方式为吸入给药。
根据本发明的实施方案,所述生物制品用于防治和/或治疗经黏膜传播的传染病、黏膜相关肿瘤、呼吸道疾病等。比如,所述传染病选自流行性感冒、新型冠状病毒肺炎、非典型肺炎(SARS)、肺结核、RSV感染导致的支气管炎和肺炎、艾滋病、肠道病毒感染导致的手足口病等;比如,所述黏膜相关肿瘤可以为口腔癌、肺癌等;比如,所述呼吸道疾病可以为肺纤维化、支气管炎、哮喘、肺气肿、支气管扩张、棉尘症、过敏性肺炎、胸膜炎等。
本发明还提供一种生物制品,所述生物制品具有如上文所述的含义。
有益效果
(1)本发明提供一种脂质-带电分子偶联物及提高脂质纳米颗粒稳定性的方法。本发明使用脂质-带电分子偶联物来构建脂质纳米颗粒,提高了脂质纳米颗粒表面的带电量,实现同时增强脂质分子间的疏水相互作用力和脂质纳米颗粒间的静电排斥力,从而显著提高了脂质纳米颗粒的稳定性。
(2)本发明提供一种可经吸入给药递送核酸药物(例如为mRNA,环状 RNA,siRNA,microRNA,反义核酸、质粒等)的新型脂质纳米颗粒及其制备方法和应用。本发明通过在脂质纳米颗粒中加入一种脂质-带电分子偶联物,所制备的新型脂质纳米颗粒可以抵抗吸入给药装置的雾化破坏作用,并显著提高了脂质纳米颗粒的抗雾化稳定性和吸入给药后的核酸递送效率,实现核酸(例如mRNA)在肺组织内的高效表达,解决了现有脂质纳米颗粒吸入递送效率低的难题。
(3)本发明提供新型脂质纳米颗粒经雾化吸入给药后可以同时激活体液、细胞、黏膜免疫应答,免疫应答强度显著高于现有商品化脂质纳米颗粒剂型,在防治经黏膜传播的传染病领域有巨大应用前景。
附图说明
图1是本发明测试例1中不同脂质纳米颗粒的水合粒径图;
图2是本发明测试例2中不同脂质纳米颗粒的ζ电势图;
图3是本发明测试例3中不同脂质纳米颗粒雾化前后的包封率;
图4是本发明应用例1中不同脂质纳米颗粒雾化吸入后在小鼠体内的mRNA 表达图;其中,(a)为主要脏器离体生物发光成像图;(b)为肺组织生物发光强度值的统计结果图;
图5是本发明应用例2中不同脂质纳米颗粒雾化吸入后在小鼠肺组织内引起的组织驻留记忆T细胞的占比;其中,(a)为流式细胞实验的散点图;(b)为组织驻留记忆T细胞占比值的统计结果图;
图6是本发明应用例2中不同脂质纳米颗粒雾化吸入后在小鼠脾脏内产生的抗原特异性T细胞数量;其中,(a)为ELISpot孔的光学照片;(b)为ELISpot孔中斑点数量的统计结果图。
图7是制备例1中吡啶基二硫基修饰的1,2-二油酰-sn-甘油-3-磷酰乙醇胺(DOPE-PDP)的质谱谱图。
图8是制备例1中多肽-脂质偶联分子(DOPE-DSSC)的质谱谱图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
制备例1
制备式(I)所示的多肽-脂质偶联分子,具体步骤如下:
(1)取等摩尔量的1,2-二油酰-sn-甘油-3-磷酰乙醇胺(DOPE)与琥珀酰亚胺3-(2-吡啶基二硫基)-丙酸酯(SPDP)溶于二氯甲烷中,加入五当量的三乙胺后,室温反应过夜,所得反应混合物通过硅胶层析柱分离得到吡啶基二硫基修饰的1,2-二油酰-sn-甘油-3-磷酰乙醇胺(DOPE-PDP),对DOPE-PDP分子的质谱表征结果参见图7。
(2)取等摩尔量的DOPE-PDP与含有巯基的负电多肽(天冬氨酸-丝氨酸- 丝氨酸-半胱氨酸,DSSC)溶于二甲基亚砜中,室温反应过夜,所得反应混合物在水中透析除去二甲基亚砜溶剂后,再分别用水和乙醇萃取除去未反应的DSSC 和DOPE-PDP,由此得到纯化后的DSSC-DOPE偶联物,即式(I)所示的多肽- 脂质偶联分子,对多肽-脂质偶联分子的质谱表征结果参见图8。
实施例1-3
可吸入式脂质纳米颗粒的制备方法如下:
参照对比例1的mRNA-1273剂型的制备方法制备本实施例的可吸入式脂质纳米颗粒,不同在于:将对比例1临床脂质纳米颗粒中的DSPC替换或部分替换为多肽-脂质偶联分子,其中,实施例1、实施例2、实施例3中的多肽-脂质偶联分子占SM102、DSPC、胆固醇、DMG-PEG2000和多肽-脂质偶联分子总量的摩尔量为0.6%、2.5%和10%,其余条件与对比例1的mRNA-1273剂型保持一致,随后通过微流控制备形成含有不同占比多肽-脂质偶联分子的可吸入式脂质纳米颗粒,分别记为0.6%多肽-脂质、2.5%多肽-脂质和10%多肽-脂质。
对比例1:
临床脂质纳米颗粒的制备方法如下:
临床脂质纳米颗粒选用Moderna公司新冠mRNA-1273的剂型,具体包括: 8-[(2-羟乙基)[6-氧代-6-(十一烷基氧基)己基]氨基]辛酸1-辛基壬基酯(SM-102)、二硬脂酰基磷脂酰胆碱(DSPC)、胆固醇、二肉豆蔻酰甘油-聚乙二醇2000 (DMG-PEG2000)以及mRNA,其中,SM102:DSPC:胆固醇:DMG-PEG2000 的摩尔比为50:10:38.5:1.5,SM102与mRNA的氮磷比为5.67,通过微流控法制备形成本对比例的临床脂质纳米颗粒,其中,mRNA选用mFluc,其是指编码萤火虫荧光素酶的mRNA。
测试例1:临床脂质纳米颗粒与可吸入式脂质纳米颗粒的水合粒径
分别取对比例1的临床脂质纳米颗粒和实施例1-3的三种可吸入式脂质纳米颗粒0.6%多肽-脂质、2.5%多肽-脂质和10%多肽-脂质加入磷酸缓冲盐溶液 (PBS缓冲液)中得到含20ng/μL mRNA的PBS溶液,分别取60μL上述含20 ng/μL mRNA的PBS溶液,采用动态光散射法测定四种不同脂质纳米颗粒在PBS 缓冲液中的水合粒径,结果参见图1。
从图1可以看出,上述四种不同脂质纳米颗粒均能够在PBS缓冲液中形成稳定的纳米结构,其中,临床脂质纳米颗粒的平均水合粒径为124nm,0.6%多肽 -脂质、2.5%多肽-脂质和10%多肽-脂质的平均水合粒径分别为153nm、145nm 和151nm,上述四种不同脂质纳米颗粒粒径的多分散系数均在0.2以下,说明所形成的纳米颗粒尺寸较为均一。
测试例2:临床脂质纳米颗粒与可吸入式脂质纳米颗粒的ζ电势
分别取对比例1制备的临床脂质纳米颗粒和实施例1-3的三种可吸入式脂质纳米颗粒加入PBS缓冲液中得到含4ng/μL mRNA的PBS溶液,分别取500μL上述含4ng/μL mRNA的PBS溶液,利用Zetasizer Nano ZSP仪器测定了四种脂质纳米颗粒的ζ电势,结果参见图2。
从图2可知,临床脂质纳米颗粒的ζ电势为-3.7mV,0.6%多肽-脂质的ζ电势与临床脂质纳米颗粒的ζ电势基本相同,由于多肽-脂质偶联分子中的多肽端使用的是一种带负电荷的多肽,所以随着多肽-脂质组份占比的增加,脂质纳米颗粒的表面电荷逐渐下降,2.5%多肽-脂质和10%多肽-脂质的ζ电势分别降至-11.4 mV和-16.3mV。
测试例3:临床脂质纳米颗粒与可吸入式脂质纳米颗粒雾化前后的包封率
分别取对比例1制备的临床脂质纳米颗粒和实施例1-3制备的三种可吸入式脂质纳米颗粒加入PBS溶液中得到含25ng/μL mRNA的溶液,取400μL该溶液,利用临床使用的雾化给药装置Aerogen Solo对四种不同的脂质纳米颗粒分别进行雾化处理,再利用RiboGreen试剂和Triton X-100破膜剂检测四种脂质纳米颗粒在雾化前后的mRNA包封率,以此评价雾化给药装置对脂质纳米颗粒的破坏程度,结果参见图3。
从图3可以看出,在雾化前,四种脂质纳米颗粒的mRNA包封率均在 85%~89%之间。而在雾化后,临床脂质纳米颗粒的包封率降至21%,0.6%多肽 -脂质、2.5%多肽-脂质、10%多肽-脂质的包封率分别降至48%、62%和45%。由此可见,实施例1-3制备的三种可吸入式脂质纳米颗粒的抗雾化能力均优于对比例1的临床脂质纳米颗粒,且含2.5%多肽-脂质的剂型抗雾化能力最强。
应用例1
临床脂质纳米颗粒与可吸入式脂质纳米颗粒雾化吸入后在小鼠体内的 mRNA表达效率
方法:选用6~7周龄的雌性C57BL/6小鼠作为模型,检测脂质纳米颗粒通过雾化吸入后在活体水平的mRNA表达效率。
取对比例1和实施例1-3制备的脂质纳米颗粒,加入PBS缓冲液,配制得到含 20ng/μL mFluc的溶液,备用。
选取上述对比例1中所制备的临床脂质纳米颗粒和实施例1-3制备的三种可吸入式脂质纳米颗粒分别经过Aerogen Solo雾化处理后,通过气管吸入的给药方式对每只小鼠给药50μL含20ng/μL mFluc的雾化后的脂质纳米颗粒。在给药24 小时后,每只小鼠腹腔注射200μL含20mg/mL D-荧光素钾盐的PBS溶液,15分钟后,分别取小鼠的心、肝、脾、肺、肾进行生物发光成像。
测试结果参见图4,四种不同的脂质纳米颗粒在经过雾化吸入后均仅在小鼠的肺组织内表达mFluc所编码的萤光虫荧光素酶,其中抗雾化性质最差的临床脂质纳米颗粒肺组织表达程度最低;而抗雾化性质最强的2.5%多肽-脂质肺组织表达程度最强,其肺组织表达程度是临床脂质纳米颗粒的7倍;0.6%多肽-脂质和 10%多肽-脂质的肺组织表达程度也分别是临床脂质纳米颗粒的3.5倍和2.5倍。
对比例2
本对比例基本同对比例1,区别在于,将mFluc替换为编码鸡卵白蛋白(OVA) 的mRNA即mOVA,其余同对比例1,得到临床脂质纳米颗粒。
实施例4
实施例4制备吸入式脂质纳米颗粒的方法分别参考实施例2,不同在于:
将实施例2中的mFluc替换为mOVA,记为2.5%多肽-脂质。
应用例2
临床脂质纳米颗粒与可吸入式脂质纳米颗粒负载编码模型抗原的mRNA,评价经雾化吸入后的疫苗药效:
方法:选取对比例2中所制备的临床脂质纳米颗粒和实施例4中所制备的可吸入式脂质纳米颗粒通过雾化吸入后,评估在6~7周龄的雌性C57BL/6的小鼠模型中的疫苗药效。
取对比例2和实施例4制备的脂质纳米颗粒,加入PBS缓冲液,配制得到含40 ng/μLmOVA的溶液,备用。
6~7周龄的雌性C57BL/6小鼠在第0天和第14天通过气管吸入的给药方式,每只小鼠每次分别给药50μL含40ng/μL mOVA的雾化后的临床脂质纳米颗粒或 2.5%多肽-脂质,另取给药50μL PBS的小鼠作为空白对照组。在第一次给药后第21天取小鼠的肺组织制备为单细胞悬液,利用不同荧光修饰的抗体分别标记 CD8、CD44、CD69和CD103,进一步通过流式细胞术检测CD69和CD103双阳性细胞在CD8和CD44双阳性细胞中的百分比以此反映肺组织内组织驻留记忆T细胞的占比,测试结果参见图5。
另外,取小鼠的脾脏制备为单细胞悬液,在检测分泌IFN-γ细胞的ELISpot 孔板中每孔加入30万细胞,再加入4μg/mL的OVA抗原肽对脾脏细胞进行刺激,刺激24h后,通过显色实验检测ELISpot孔底产生的斑点数目,以此反映脾脏中抗原特异性T细胞数量,测试结果参见图6。由于大部分临床脂质纳米颗粒在雾化过程中已被破坏,因此抗原蛋白OVA在肺组织内的表达程度较弱,其疫苗药效也较弱,而具有抗雾化能力的实施例4的可吸入式脂质纳米颗粒2.5%多肽-脂质在雾化吸入后,疫苗药效显著强于临床脂质纳米颗粒。其中,2.5%多肽-脂质在肺组织内引起的组织驻留记忆T细胞占比是临床脂质纳米颗粒的2倍,在脾脏中产生的抗原特异性T细胞数量是临床脂质纳米颗粒的7倍。由此证明,本发明制备的可吸入式脂质纳米颗粒在经过雾化吸入后能发挥优异的疫苗药效,并能够提供有效的黏膜免疫保护。
将上述实施例中的mRNA替换为小干扰核糖核酸(siRNA)、质粒、反义DNA、适配体aptamer、microRNA、环状RNA,siRNA等时,制备得到的可吸入式脂质纳米颗粒也与上述实施例的可吸入式脂质纳米颗粒的效果基本相当。
以上对本发明示例性的实施方式进行了说明。但是,本申请的保护范围不拘囿于上述实施方式。本领域技术人员在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种脂质-带电分子偶联物,其特征在于,所述脂质-带电分子偶联物包括脂质单元和带电单元;
所述带电单元选自负电荷单元和/或正电荷单元。
2.根据权利要求1所述的脂质-带电分子偶联物,其特征在于,所述脂质-带电分子偶联物带正电或负电。
优选地,所述负电荷单元选自下述负电物质中的至少一种构成的单元:第一多肽、核酸单元、负电荷高分子。
优选地,所述第一多肽选自带负电荷氨基酸且长度为1-50个氨基酸的亲水肽链。
优选地,所述核酸单元选自长度为1-40个碱基的、具有任意序列的DNA或RNA。
优选地,所述负电荷高分子选自透明质酸、聚丙烯酸亲水高分子。
优选地,所述正电荷单元选自下述正电物质中的至少一种构成的单元:第二多肽、正电荷高分子。
优选地,所述第二多肽选自带正电荷氨基酸、且长度为1-50个氨基酸的亲水肽链中的至少一种。优选地,所述正电荷高分子选自聚赖氨酸、壳聚糖、聚(β-氨基酯)阳离子聚合物中的至少一种。
3.根据权利要求1或2所述的脂质-带电分子偶联物,其特征在于,所述脂质单元包括疏水基团。示例性地,所述疏水基团选自疏水烷基链。
优选地,所述脂质单元选自下述物质中的至少一种:可离子化脂质、磷脂、固醇类化合物、脂肪酸。
示例性地,所述可离子化脂质选自下述物质中的至少一种:8-[(2-羟乙基)(6-氧代-6-癸氧基己基)氨基]辛酸(十七烷-9-基)酯(SM-102)、[(4-羟基丁基)氮杂二基]双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315)、4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯(DLin-MC3-DMA)、3,6-双{4-[双(2-羟基十二烷基)氨基]丁基}哌嗪-2,5-二酮(cKK-E12)、9-(4-(二甲氨基)丁酰氧基)十七烷二酸二((Z)-壬-2-烯-1-基)酯(L319)、N2,2-二亚油基-4-二甲氨基乙基-[1,3]-二氧戊环(DLin-KC2-DMA)、8-[(2-羟乙基)(8-壬氧基-8-氧代辛基)氨基]辛酸(十七烷-9-基)酯(Lipid5)、1,1'-[(2-{4-[2-({2-[双(2-羟基十二烷基)氨基]乙基}(2-羟基十二烷基)氨基)乙基]哌嗪-1-基}乙基)氮杂二烷基]双(十二烷-2-醇)(C12-200)、(2,3-二油酰基-丙基)-三甲基氯化铵(DOTAP)、双甲基双十八烷基溴化铵(DDAB)、四(8-甲基壬基)3,3',3”,3”'-{[(甲基氮杂二烷基)双(丙烷-3,1二基)]双(氮杂三基)}四丙酸酯(306Oi10)中的至少一种。
示例性地,所述磷脂选自1,2-二硬脂酰基-sn-甘油基-3-磷脂酰胆碱、1,2-二油酰基-sn-甘油基-3-磷脂酰胆碱、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱、2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰胆碱、1,2-二油酰基-sn-甘油基-3-磷脂酰乙醇胺、2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺、1,2-二硬脂酰基-sn-甘油基-3-磷脂酰乙醇胺、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺中的一种或多种。
示例性地,所述固醇类化合物选自β-谷甾醇、胆甾烷醇、胆甾烷酮、胆固醇、胆甾烯酮、7β-羟基胆固醇、7α-羟基胆固醇中的一种或多种。
示例性地,所述脂肪酸选自饱和脂肪酸或不饱和脂肪酸。饱和脂肪酸包括软脂酸、硬脂酸、月桂酸、豆蔻酸、花生酸;不饱和脂肪酸包括豆蔻油酸、棕榈油酸、菜籽油酸、亚油酸、亚麻酸、油酸、花生四烯酸。
4.权利要求1-3任一项所述的脂质-带电分子偶联物的制备方法,交联剂与脂质单元反应后,再与带电单元混合反应,得到所述脂质-带电分子偶联物。
优选地,所述脂质单元通过下述物质中的至少一种制备得到:可离子化脂质、磷脂、固醇类化合物、脂肪酸,所述可离子化脂质、磷脂、固醇类化合物、脂肪酸具有如权利要求3中所述的含义。
优选地,所述脂质单元通过磷脂与交联剂反应得到。
优选地,所述脂质单元和带电单元的摩尔比为(0.8~1.2):(0.8~1.2)。
5.权利要求1-3任一项所述的脂质-带电分子偶联物在制备脂质纳米颗粒或生物制品中的应用。
6.一种脂质纳米颗粒,其特征在于,所述脂质纳米颗粒包括权利要求1-3任一项所述的脂质-带电分子偶联物、脂质组份和负载物;其中,所述脂质-带电分子偶联物通过疏水作用和静电相互作用与脂质组份、负载物自组装形成所述脂质纳米颗粒。
优选地,所述脂质纳米颗粒的给药方式为静脉给药、皮下给药、肌肉给药、吸入给药、滴鼻给药。
7.根据权利要求6所述的脂质纳米颗粒,其特征在于,所述脂质纳米颗粒中,所述脂质-带电分子偶联物带正电或负电。
优选地,在所述脂质纳米颗粒中,所述脂质-带电分子偶联物与所述脂质组份的摩尔比为(0.1~20):100。
优选地,所述脂质组份中的氮含量与核酸中的磷含量的摩尔比为(1~50):1。
优选地,所述脂质组份包括可离子化脂质、辅助磷脂、胆固醇及其衍生物和聚乙二醇化脂质。
优选地,所述可离子化脂质占脂质组份总量的摩尔百分比为30%~70%。
优选地所述,所述辅助磷脂占所述脂质组份的总量的0mol%~20mol%。
优选地,所述辅助磷脂包括1,2-二硬脂酰基-sn-甘油基-3-磷脂酰胆碱、1,2-二油酰基-sn-甘油基-3-磷脂酰胆碱、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱、2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰胆碱、1,2-二油酰基-sn-甘油基-3-磷脂酰乙醇胺、2-油酰基-1-棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺、1,2-二硬脂酰基-sn-甘油基-3-磷脂酰乙醇胺、1,2-二棕榈酰基-sn-甘油基-3-磷脂酰乙醇胺中的一种或多种。
优选地,所述胆固醇及其衍生物占所述脂质组份的总量的20mol%~50mol%。
优选地,所述胆固醇及其衍生物包括β-谷甾醇、胆甾烷醇、胆甾烷酮、胆固醇、胆甾烯酮、7β-羟基胆固醇、7α-羟基胆固醇中的一种或多种。
优选地,所述聚乙二醇化脂质占所述脂质组份的总量的0.1mol%-10mol%。
优选地,所述聚乙二醇化脂质包括1,2-二肉豆蔻酰基-rac-甘油基-3-甲氧基聚乙二醇、1,2-二硬脂酰基-rac-甘油基-3-甲氧基聚乙二醇、1,2-二棕榈酰基-rac-甘油基-3-甲氧基聚乙二醇、1,2-二硬脂酰基-sn-甘油基-3-磷脂酰乙醇胺-甲氧基聚乙二醇中的一种或多种。
8.根据权利要求6或7所述的脂质纳米颗粒,其特征在于,所述负载物选自核酸,从而实现递送核酸。优选地,所述核酸包封在所述脂质纳米颗粒中。
优选地,所述核酸选自mRNA、小干扰核糖核酸、质粒、反义DNA、适配体aptamer、microRNA、环状RNA,siRNA中的至少一种。
优选地,所述脂质纳米颗粒中,核酸的包封率为30~99%。
优选地,所述脂质纳米颗粒的水合粒径为50~200nm。
9.权利要求6-8任一项所述的脂质纳米颗粒在制备生物制品中的应用。
10.一种生物制品,其特征在于,所述生物制品包括上述脂质纳米颗粒。优选地,所述生物制品为可吸入生物制品。
优选地,所述生物制品的给药方式为吸入给药。
优选地,所述生物制品用于防治和/或治疗经黏膜传播的传染病、黏膜相关肿瘤、呼吸道疾病。
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