CN103509066A - 一种含有唾液酸片段的脂质衍生物及其应用 - Google Patents
一种含有唾液酸片段的脂质衍生物及其应用 Download PDFInfo
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- CN103509066A CN103509066A CN201210208428.6A CN201210208428A CN103509066A CN 103509066 A CN103509066 A CN 103509066A CN 201210208428 A CN201210208428 A CN 201210208428A CN 103509066 A CN103509066 A CN 103509066A
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- sialic acid
- psa
- dspe
- acid fragment
- peg
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Abstract
Description
技术领域
本发明属于药物制剂领域,具体涉及一种含有唾液酸片段的脂质衍生物,其制备方法以及应用,尤其是用于微粒制剂的制备和修饰。
背景技术
在药物传递系统(Drug Delivery System,DDS)的发展历史中,药物分子及载体的聚合物修饰可以增加药物制剂放置稳定性、降低药物分子的体内降解、改变药物的体内药动学行为从而提高药物治疗效率。其中又以载体及药物分子的PEG化(PEGylated,又称为聚乙二醇化)技术最具开发潜力和实用价值。长期以来,世界各国政府都投入大量人财物力,进行诸如PEG化小分子药物、PEG化大分子药物、PEG化脂质体、PEG化纳米粒、PEG化乳剂、PEG化胶束、PEG化树枝状载体和PEG化聚合物等方面的研究;PEG化技术在肿瘤靶向、肝脏靶向、心脏靶向、肾脏靶向、脑靶向、骨靶向、细胞核靶向及线粒体靶向等研究中也得到广泛的应用;各种功能化载体的构建、基因转染、RNA干扰治疗等21世纪热点领域的主攻方向中同样也都有PEG化技术的身影。以“PEGylated”为关键词,在PubMed上检索1990年~2011年的文献,可得到6263篇相关文章,从1990年的1篇增加至2011年的1182篇,其趋势变化如图。PEG化技术所取得的不俗成绩和勃勃生机使科学家们乐观地认为它能够解决DDS所面临的从制剂学领域到生物学领域的一系列问题。
涉及PEG化技术的研究文献(1990~2011)
诚然,PEG化技术能够显著降低蛋白多肽类物质的免疫原性,显著延长载体循环时间,并实现药物的靶向治疗,但PEG化药物/载体的免疫学问题从未被科学家所忽视。早在1964年,Khomyakov等就对PEG用于体内给药的安全性提出过质疑(Khomyakov K, Virnik A, Rogovin Z. The prolongation of the action of pharmaceutical preparations by mixing or combining them with polymers[J]. Russian Chemical Reviews, 1964,33: 462.),随着研究者对机体免疫系统与DDS间相互作用的不断了解,以及多种PEG化制剂进入临床应用,PEG化技术在药物治疗安全性和有效性方面所显现的问题日趋严重。最近有文报道,约1/3使用PEG化门冬酰氨酶(PEG-Asparaginase,商品名Oncaspar?)的患者出现了免疫反应(Armstrong JK, Hempel G, Koling S, et al. Antibody against poly (ethylene glycol) adversely affects PEG‐asparaginase therapy in acute lymphoblastic leukemia patients[J]. Cancer, 2007,110(1): 103-111.);PEG化尿酸酶(Pegloticase,商品名Krystexxa?)则由于抗-PEG抗体的产生导致58%的患者不能得到治疗(Garay R, Labaune J. Immunogenicity of Polyethylene Glycol (PEG)[J]. The Open Conference Proceedings Journal, 2011,(2): 104-107.)。此类问题的出现不仅给临床治疗带来巨大风险,同时也导致社会资源的极大浪费。对于PEG化脂质体、PEG化胶束、PEG化纳米粒等PEG化载体而言,同样会在首次注射时诱导机体产生抗体,使得第二次注射的PEG化载体快速从血液中清除,并大量聚集于肝脾,该现象被称为“加速血液清除(Accelerated Blood Clearance,ABC)”(佘振南, 翟文君, 邓意辉. “加速血液清除”现象中的免疫机制分析[J]. 沈阳药科大学学报, 2011,28(9): 760-768.)。本课题组的研究表明,PEG化乳剂和PEG化固体脂质纳米粒的重复注射均可导致小鼠、大鼠和比格犬产生强烈的ABC现象(国家自然科学基金资助项目No. 81072602),其中比格犬在出现ABC现象时往往伴随有严重的类似过敏的反应,如呕吐、腹泻、面部严重水肿等,部分比格犬甚至因此死亡。我们的研究还证明,在低剂量注射时,PEG化阿霉素脂质体、PEG化表阿霉素脂质体和PEG化拓扑替康脂质体均会导致强烈的ABC现象,这给PEG化制剂的连续低剂量注射治疗方案敲响了警钟。ABC现象的产生不仅导致各种PEG化载体的治疗价值极大降低,甚至由于强烈的免疫反应而引起用药对象死亡(Semple SC, Harasym TO, Clow KA, et al. Immunogenicity and rapid blood clearance of liposomes containing polyethylene glycol-lipid conjugates and nucleic acid[J]. Journal of Pharmacology and Experimental Therapeutics, 2005,312(3): 1020.)。另外,PEG在体内难以降解,会在溶酶体内蓄积并导致毒性反应,少量PEG在体内氧化后产生的过氧化物及副产物亦对人体有害(Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly (ethylene glycol)-protein conjugates[J]. Advanced drug delivery reviews, 2003,55(10): 1261-1277.)。当患者大剂量使用PEG化制剂时,如正在研究的血红蛋白脂质体(人造血液,含有DSPE-PEG2000),这类问题可能带来极为严重的后果。相似的现象还可以在Poloxamine-908 包衣的聚苯乙烯纳米球重复注射时观察到(Moghimi SM, Gray T. A single dose of intravenously injected poloxamine-coated long-circulating particles triggers macrophage clearance of subsequent doses in rats[J]. Clin Sci, 1997,93(4): 371-379.)。
此外,除了抗原抗体介导的免疫反应外,聚合物修饰制剂(如Doxil?,用于静脉注射给药,含有由FDA批准的可用于静脉注射的PEG)或是含有人工合成聚合物的制剂(如Zoladex?,含有PLGA)在临床应用中还具有发生类过敏反应(pseudoallergy)的风险(Hunter, A. C. and S. M. Moghimi (2002). "Therapeutic synthetic polymers: a game of Russian roulette?" Drug discovery today 7(19): 998-1001. ABPI (1999) Compendium of data sheets and summaries of product characteristics. Pub. Datapharm Publications ISBN 0-907-102182-1821)。其中与补体激活相关的类过敏反应(complement activation-related pseudoallergy, CARPA)在美国每年导致约420000例临床显著的过敏反应及约20400例由过敏性休克产生的死亡(Szebeni, J. (2001) Complement activation-related pseudoallergy caused by liposomes, micellar carriers of intravenous drugs, and radiocontrast agents. Crit. Rev. Ther. Drug Carrier Syst. 18, 567–606)。
DDS与免疫系统间所产生的强烈相互作用会严重影响药物治疗的安全性、有效性和患者的顺应性。虽然可以通过调整PEG衍生物的修饰密度、改变PEG衍生物种类,或者采用可断裂PEG脂质化合物等方法来减弱ABC现象(佘振南, 翟文君, 邓意辉. “加速血液清除”现象中的免疫机制分析[J]. 沈阳药科大学学报, 2011,28(9): 760-768.),但从长远发展来看,在DDS的设计和开发过程中,避免使用对人体具有潜在免疫原性(或非人源性)的材料将会成为主流,以PEG为代表的具有免疫原性和蓄积毒性的材料的应用将会逐渐受到限制。因此,探索一种新的“免疫伪装”技术,以帮助进入体内的药物对免疫系统“隐形”,成为DDS设计和开发过程中亟待解决的关键问题。
唾液酸(Sialic acid,SA)又称糖酸,是一类九碳单糖,作为生物杂聚物的重要组成部分,SA主要以短链残基的形式通过2-位异头碳的羟基以α-糖苷键连接于糖蛋白、糖脂和寡糖的末端。聚唾液酸(Polysialic acid,PSA)是SA单体以α-2,8-或α-2,9-酮苷键等方式连接而成的直链聚合物。将PSA进行酶解,或是对天然来源的PSA进行分离,可以得到各种聚合度的PSA。SA普遍存在于哺乳动物的细胞膜表面,如人红细胞及血管内皮细胞表面均是高度唾液酸化的。研究表明,红细胞经唾液酸酶处理后其寿命从原来的120天锐减到几个小时(Deninno MP. The Synthesis and Glycosidation of-Acetylneuraminic Acid[J]. Synthesis, 1991,1991(8): 583-593.)。另外,许多病原体 利用SA“装扮”自身 , 以掩蔽其抗原表位 ,抑制补体旁路途径的激活,降低了免疫原性,从而 成功逃脱宿主免疫系统的攻击 (Charland N, Kobisch M, Martineau‐Doizé B, et al. Role of capsular sialic acid in virulence and resistance to phagocytosis of Streptococcus suis capsular type 2[J]. FEMS Immunology & Medical Microbiology, 1996,14(4): 195-203. Madico G, Ngampasutadol J, Gulati S, et al. Factor H binding and function in sialylated pathogenic neisseriae is influenced by gonococcal, but not meningococcal, porin[J]. The Journal of Immunology, 2007,178(7): 4489.)。肿瘤的转移也与SA/PSA的“免疫伪装”作用有关(Suzuki M, Nakayama J, Suzuki A, et al. Polysialic acid facilitates tumor invasion by glioma cells[J]. Glycobiology, 2005,15(9): 887.)。
作为一种药物分子或载体的修饰材料,PSA与PEG具有一些相似点,如水溶性、长循环性(Gregoriadis G, McCormack B, Wang Z, et al. Polysialic acids: potential in drug delivery[J]. FEBS letters, 1993,315(3): 271-276.)、易于工业化生产(PSA 可通过发酵及合成工艺获得)和分子量的可选择性(控制聚合度得到高至3万的不同分子量)等。但相比于PEG,PSA具有生物可降解性、无免疫原性以及保持被修饰物活性能力强等优势。
鉴于SA/PSA用于药物传递的独特优势,研究者们将其用于蛋白多肽类药物的修饰并取得了可喜的结果。如门冬酰氨酶经PEG修饰后(PEG-Asparaginase,商品名Oncaspar?),不仅活性严重下降,还可导致机体产生较强的免疫反应(Fernandes AI, Gregoriadis G. Polysialylated asparaginase: preparation, activity and pharmacokinetics[J]. Biochimica et Biophysica Acta (BBA)-Protein Structure and Molecular Enzymology, 1997,1341(1): 26-34.)。但PSA化门冬酰氨酶却无免疫原性(Fernandes AI, Gregoriadis G. The effect of polysialylation on the immunogenicity and antigenicity of asparaginase: implication in its pharmacokinetics[J]. International journal of pharmaceutics, 2001,217(1-2): 215-224.),而且活性几乎得到100%的保持。另外,PSA在消除所修饰蛋白/多肽的免疫原性和抗原性的同时似乎并不影响它们与相应受体的结合。例如,肿瘤特异性抗体Fab片段经PSA修饰后,不仅循环时间延长,而且在肿瘤部位的分布量增加(Gregoriadis G, Jain S, Papaioannou I, et al. Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids[J]. International journal of pharmaceutics, 2005,300(1-2): 125-130.)。需要特别强调的是,PSA是一种人体内源性物质,可被组织神经氨酸酶完全降解为无毒性的SA。而PEG是合成聚合物,它在细胞色素P450酶催化下以极低速率氧化为醛和酮,而且其高/低分子量形式都倾向于在组织内蓄积,大量长期注射时会造成毒性积累。
综上可见, PSA是PEG的绝佳替代物 ,但目前SA/PSA在药物传递系统中的应用主要被限于蛋白多肽类药物的修饰,由Lipoxen公司开发的PSA修饰制剂长效胰岛素SuliXen?和长效促红细胞生成素ErepoXen?在英国已经进入了2期临床研究。将PSA或结构类似的多糖连接在蛋白或多肽上的方法可见US-A-5846951或WO-A-0187922,这些方法中的一些方法依靠对聚合物“非还原”端的化学衍生以生成醛基,并借助此醛基实现PSA与蛋白多肽的缀合。但为了获得满意的反应收率需要在较高温度下进行一定的时间,这不利于所修饰的蛋白多肽等药物的稳定(例如干扰素α-2b),其次,所需的反应物浓度(即聚合物过量)可能是无法实现或者是不经济的。因此,将PSA/SA衍生物用于药物载体的修饰,再将药物载入载体,将能够克服药物的不稳定性与PSA化反应所需条件间的矛盾。而且将药物装载于SA/PSA衍生物修饰载体中,相比于将SA/PSA衍生物与药物直接相连的策略,往往能获得较高的载药量。
但至今为止,将PSA用于药物载体的修饰研究仅有一篇文献报道,技术尚不成熟。该文献利用PSA分子中的羧基与正癸胺(n-decylamine)反应,合成了PSA正癸胺衍生物,该物质可以自组装成为胶束,并装载难溶性药物(Bader RA, Silvers AL, Zhang N. Polysialic acid-based micelles for encapsulation of hydrophobic drugs[J]. Biomacromolecules, 2011,12(2): 314-320.)。但该合成反应具有极大的随机性,控制性差;而且PSA所连接的脂肪链短,胶束在体内易于解体,靶向递药能力低;并且该材料难以稳固的插入到脂质体表面。
发明内容
为了开拓唾液酸衍生物在药物载体中的应用,我们提供了一种可广泛用于微粒制剂修饰的含有唾液酸片段的脂质衍生物(本专利中也称为唾液酸/聚唾液酸脂质衍生物),其特征在于,唾液酸片段包含至少1个唾液酸单元,唾液酸单元间通过α-2,8-糖苷键连接,并且脂质片段与唾液酸片段中非还原端唾液酸单元的7号碳通过C-N键连接。
本发明中所述的含有唾液酸片段的脂质衍生物具有如下结构:
其中SA表示唾液酸单元,n表示最小为1的整数;
R-HN片段来自R-NH2,R-NH2是含有伯胺基团的化合物,即R-HN可以看做是 R-NH2失去伯胺基团上的一个质子后的结构。
所述R-NH2是二硬脂酰磷脂酰乙醇胺、二棕榈酰磷脂酰乙醇胺、二油酰磷脂酰乙醇胺、二月桂酰磷脂酰乙醇胺、二肉豆蔻酰磷脂酰乙醇胺、大豆磷脂酰乙醇胺、蛋黄磷脂酰基乙醇胺、硬脂酰油酰磷脂酰乙醇胺、硬脂酰亚油酰磷脂酰乙醇胺、棕榈酰油酰磷脂酰乙醇胺、棕榈酰亚油酰磷脂酰乙醇胺、二癸酰磷脂酰乙醇胺、二辛酰磷脂酰乙醇胺、二己酰磷脂酰乙醇胺、磷脂酰基乙醇胺聚乙二醇氨基(PE-PEG-NH2)、脂肪胺。
脂肪胺可以是直链脂肪胺或支链脂肪胺,对于直链脂肪胺,可以举出含有8-22个碳的直链脂肪胺,如二十二胺、二十胺、十八胺、十六胺、十四胺、十二胺。作为含有分支烷基的胺,可以举出如3-甲基-n-戊胺(3-methyl-n-pentylamine)。
作为优选的化合物,所述R-NH2是二硬脂酰基磷脂酰乙醇胺、二棕榈酰基磷脂酰乙醇胺、PEG片段分子量为1000-10000道尔顿的磷脂酰基乙醇胺聚乙二醇氨基(PE-PEG-NH2)、二十二胺、二十胺、十八胺、十六胺、十四胺、十二胺、3-甲基-n-戊胺。
最为最优选的化合物,所述R-NH2是二硬脂酰磷脂酰乙醇胺(DSPE)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰乙醇胺聚乙二醇2000氨基、二硬脂酰磷脂酰乙醇胺聚乙二醇5000氨基、二棕榈酰磷脂酰乙醇胺聚乙二醇2000氨基、二棕榈酰磷脂酰乙醇胺聚乙二醇5000氨基、二十二胺、二十胺、十八胺、十六胺、十四胺、十二胺、3-甲基-n-戊胺。
值得注意的是,本发明所提供的化合物,如DSPE-PEG2000-SA,DSPE-PEG5000-SA,DPPE-PEG2000-SA,DPPE-PEG5000-SA等,不仅能够使所修饰制剂获得较长的体内循环时间,而且可以借助于肿瘤表面的唾液酸受体实现肿瘤靶向。
所述的含有唾液酸片段的脂质衍生物的应用,其特征在于所述化合物单独或与其他物质联合用于制备乳剂、微乳、脂质体、固体脂质纳米粒、囊泡、胶束或纳米结构载体。
本发明所述的含有唾液酸片段的脂质衍生物采用如下方法合成:
将SA或PSA的邻二醇结构用高碘酸盐氧化为单醛基(可称为PSA的活化),此醛基与R-NH2上的伯胺基团反应生成希夫碱,再进行希夫碱的选择性还原,从而形成稳定的、不可逆的C-N键。其中,希夫碱的选择性还原可采用氰基硼氢化钠(NaCNBH3)、硼氢化钠、硼氢化钾。
本发明带来的有益结果
利用本发明所提供的含有唾液酸片段的脂质衍生物修饰脂质体、乳剂、纳米粒和胶束等微粒制剂时,可以获得较长的体内循环时间和肿瘤靶向性。相比于经典的聚乙二醇化制剂,含有唾液酸片段的脂质衍生物修饰制剂免疫原性较低,在重复注射时不会产生ABC现象。
附图说明
图1:ODA-PSA红外图谱;
图2:PSA红外图谱;
图3:已经活化的PSA的红外图谱;
图4:ODA红外图谱;
图5:DSPE-PSA C13-NMR图谱及信号归属,单位δ×106。其中R为聚唾液酸片段残基;
图6:ODA-SA C13-NMR图谱及信号归属,单位δ×106;
图7:DSPE-PSA(十聚体) C13-NMR图谱及信号归属,单位δ×106。其中R代表8个唾液酸残基的聚合链;
图8:DSPE-PEG2000-PSA C13-NMR图谱及信号归属,单位δ×106;
图9:DSPE-PEG2000-SA C13-NMR图谱及信号归属,单位δ×106;
图10:图中由上至下依次表示注射生理盐水组、BBR 2778溶液组和BBR 2778脂质体组的小鼠的肿瘤,动物模型为昆明小鼠,S180皮下移植瘤;
图11:背景技术中1990-2011年相关文章趋势变化图。
具体实施方式:
实施例中所用各成分的简称如下:
大豆磷脂(SPC)
氢化大豆磷脂(HSPC)
蛋黄磷脂(EPC)
氢化蛋黄磷脂(HEPC)
二油酰磷脂酰胆碱(DOPC)
二棕榈酰磷脂酰胆碱(DPPC)
二硬脂酰磷脂酰胆碱(DSPC)
二反式油酰磷脂酰胆碱(DEPC)
二肉豆蔻酰磷脂酰胆碱(DMPC)
二山嵛酰磷脂酰胆碱(DBPC)
1-棕榈酰-2-油酰磷脂酰胆碱(POPC)
单棕榈酰磷脂酰胆碱(MPPC)
单硬酯酰胆碱(MSPC)
二硬脂酰磷脂酰乙醇胺(DSPE)
二棕榈酰磷脂酰乙醇胺(DPPE)
蛋黄磷脂酰甘油(EPG)
二硬脂酰磷脂酰甘油(DSPG)
二棕榈酰磷脂酰甘油(DPPG)
鞘磷脂(SM)
磷脂酸(PA)
磷脂酰丝氨酸(PS)
磷脂酰肌醇(PI)
聚乙二醇单甲醚-二硬脂酰磷脂酰乙醇胺(mPEG-DSPE)
聚乙二醇单甲醚-胆固醇半琥珀酸酯(mPEG-CHS)
聚乙二醇单甲醚-二棕榈酰磷脂酰胆碱乙醇胺(mPEG-DPPE)
聚乙二醇单甲醚-二肉豆蔻酰磷脂酰乙醇胺(mPEG-DMPE)
胆固醇(CH)
d-α生育酚琥珀酸聚乙二醇酯(TPGS)
唾液酸(SA)
聚唾液酸(PSA)
十八胺(ODA)
维生素E烟酸酯(TN)
中链甘油三酸酯(MCT)
大豆磷脂S75(S75)
钙黄绿素(CF)
胆固醇(CH)
十八(烷)酸丙三醇酯(GMS)
聚乙二醇(PEG)
N-(7-硝基苄基-2-氧杂-1, 3-重氮-4-基)磷脂酰乙醇胺(NBD-PE),NBD-PE是荧光磷脂,在实施例中作为部分药物载体的示踪分子。
下面结合实施例,更具体地说明本发明的内容。应当理解,本发明的实施并不局限于下面的实施例,对本发明所做的任何形式上的变通和/或改变都将落入本发明保护范围。
材料来源:
本发明中,所用PSA为线性α-2,8-连接的大肠杆菌K1 PSA(平均分子量22.7 kDa,多分散指数(p.d.)1.34;平均分子量39.0 kDa,多分散系数(p.d.)1.40;平均分子量11.0 kDa,多分散系数(p.d.)1.17),来自Camida,爱尔兰。
聚合度为2至10的PSA,纯度>95,HPLC检测,购买自Nacalai tesque,日本。
SA,纯度>95,HPLC检测,购买自江苏长兴制药。
DSPE、DPPE、DMPE、DOPE、DEPE、POPE、DSPE-PEG2000-NH2、DSPE-PEG5000-NH2,购买自Avanti,美国。
DSPE-PEG1000-NH2,DSPE-PEG10000-NH2购买自Nanocs Inc,美国。
NaIO4、KBH4、NaBH4、NaCNBH3为分析纯,购买自国药集团。
检测手段:
本发明中所制备制剂的粒径及Zeta电位使用PSS NICOMP 380 激光粒度测定仪测定,制剂的磷脂浓度使用ELSD-HPLC测定。
PSA的定量测定按照(Svennerholm, L. (1957). "Quantitive estimation of sialic acids: II. A colorimetric resorcinol-hydrochloric acid method." Biochimica et biophysica acta 24: 604-611.)所述的间苯二酚法测定。
PSA的纯化分级:使用Q-琼脂糖凝胶 FF(快流速型)填充层析柱(XK50柱,GE health)并用3个柱体积的缓冲溶液(20mM 三乙醇胺;pH7.4)以50mL/min的流速进行平衡;将PSA溶液上样到柱上,然后用1.5个柱体积的缓冲溶液冲洗;用1.5柱体积的不同缓冲洗脱液(三乙醇胺缓冲液,20 mM,pH7.4,以两级之间25mM NaCl的步长从0 mM变化到475 mM NaCl)将结合的PSA洗脱;最终用含有1000 mM NaCl的相同缓冲溶液进行洗脱以移除所有残留的PSA。
使用超滤装置将分级后PSA的溶剂置换为去离子水并进行浓缩。
采用高效凝胶过滤色谱法(HPGFC)测定PSA的相对分子质量。色谱条件:色谱柱:UltrahydrogelTM Linear (300 mm ×7.8 mm ID)两柱串联;流动相 0.1mol/L NaNO3,流速0.9 mL/min;柱温45℃,以低相对分子质量的右旋糖苷为标准。
实施例1:聚唾液酸十八胺衍生物(ODA-PSA)的合成
15-25℃下将新制备的0.2 M/L的偏高碘酸钠(NaIO4)与PSA(平均分子量11.0 kDa)溶液混合后避光搅拌约15 min;之后向反应体系中加入丙二醇并避光搅拌30 min(PSA: NaIO4: 丙二醇=1:6:2.5,mol/mol);在此体系中加入十八胺(ODA)的乙醇溶液(PSA:ODA=1:1,mol/mol)并避光搅拌直至溶液澄清有乳光;向反应体系中逐步滴加硼氢化钾(KBH4)(KBH4:ODA=4:1,mol/mol),继续反应约4 h。使用去离子水作为透析介质对反应液透析约24 h,透析介质约为反应液的100倍体积,约每6 h更换一次透析介质,共更换4次。对透析后的反应液进行冻干得白色絮状物,即为聚唾液酸十八胺衍生物,缩写为ODA-PSA(PSA片段平均分子量11.0 kDa)。
反应过程中使用薄层色谱(TLC)进行反应进度检测和纯度分析,使用预制硅胶板;展开剂:二氯甲烷:甲醇=7:3。PSA:Rf=0.360;活化的PSA(即醛基形式的PSA):Rf=0.375;ODA-PSA:Rf=0.5。反应完全后,反应液中仅有ODA-PSA的点。
对ODA-PSA(PSA 片段平均分子量为11.0 kDa)进行红外分析,测试图谱见附图:附图1为ODA-PSA,附图2为PSA,附图3为活化的PSA(即醛基形式的PSA),附图4为ODA。红外谱图证明有ODA-PSA的生成。
使用元素分析仪对冻干获得的物质进行元素分析,其中C:43.03%;H:5.34%;O:39.91%;N:4.49%;测定结果与理论计算结果一致。
实施例2:DSPE-PSA的合成:
PSA的活化:15-25℃下将新制备的0.2 M/L的偏高碘酸钠(NaIO4)与PSA(平均分子量11.0 kDa)溶液混合(NaIO4:PSA=6:1,mol/mol),将反应混合物避光磁力搅拌15 min。用70%(最终浓度)的乙醇将氧化的PSA沉淀并将混合物在3000 g下离心20 min,去除上清液,将颗粒物用最小量的去离子水溶解,再用70%的乙醇将PSA沉淀,然后在12000 g下离心。将颗粒物用最小量的水溶解,得到活化的PSA水溶液,将其冻干并在-20℃下储存待用。
已活化PSA与DSPE的连接:将已活化PSA与DSPE溶解于乙醇中(1:1,mol/mol),避光搅拌直至溶液澄清有乳光,并逐步滴加硼氢化钾(KBH4)(KBH4:DSPE=4:1,mol/mol),继续反应4 h。使用去离子水作为透析介质对反应液透析24 h,透析介质为反应液的100倍体积,每6 h更换一次透析介质,共更换4次。对透析后的反应液进行冻干得白色絮状物。
使用BRUKER AVANCE-600MHz超导核磁共振 (瑞士 Bruker 公司)对所得产物进行碳谱分析,各峰化学位移数据及结构归属见附图5,证明合成得到DSPE-PSA。
在本实施例中,使用相同物质的量的DPPE或DOPE代替DSPE进行反应,在相同的反应条件下可以得到DPPE-PSA和DOPE-PSA,产物的结构鉴定方法同DSPE-PSA。
实施例3:ODA-SA的合成
将唾液酸(SA)0.027 g、0.1 mol/L高碘酸钠水溶液2 mL和乙二醇4 mL混合均匀并于15-25℃下避光搅拌约1 h;向此体系中加入4 mL十八胺(ODA)的乙醇溶液(内含ODA 0.0151 g)并继续搅拌约15 h;在此体系中加入硼氢化钠(NaBH4)(NaBH4:ODA=4:1,mol/mol),继续反应约6 h后终止反应,冻干溶剂后用二氯甲烷体系对冻干物复溶,离心后取上清液浓缩,得到产物中主要成分为唾液酸十八胺衍生物(简称为ODA-SA)。使用硅胶柱层析,氯仿及石油醚的混合溶剂为展开剂精制得到ODA-SA。
使用BRUKER AVANCE-600MHz超导核磁共振 (瑞士 Bruker 公司)对所得产物进行碳谱分析,各峰化学位移数据及结构归属见附图6,证明合成得到ODA-SA。
60~65℃水浴中,用乙醇溶解膜材(HSPC:NBD-PE :CH:ODA-SA:=3:0.1 :1:0.1,w/w), 挥去部分乙醇后,以中速注入预热至相同温度的PBS缓冲溶液(pH 6.5,20 mmol),孵育20 min,制得脂质体初品,经200 W超声初步混合处理2 min后,400 W超声分散4 min(工作1 s,间歇1 s),依次通过0.8、0.45μm的微孔滤膜,即得SA修饰的脂质体。
实施例4:DSPE-PSA(PSA为十聚体)的合成
室温下将新制备的0.2 M/L的偏高碘酸钠(NaIO4)与PSA十聚体水溶液混合后避光搅拌约15 min;之后向反应体系中加入丙二醇并避光搅拌约30 min(PSA十聚体: NaIO4: 丙二醇=1:6:2.5,mol/mol);向此体系中加入DSPE的乙醇溶液(PSA:DSPE =1:1,mol/mol)并避光搅拌直至溶液澄清有乳光;向反应体系中逐步滴加氰基硼氢化钠(NaCNBH3)(NaCNBH3:DSPE=4:1,mol/mol),继续反应约4 h后停止搅拌。使用去离子水作为透析介质对反应液透析24 h,透析介质约为反应液的100倍体积,约每6 h更换一次透析介质,共更换4次。对透析后的反应液进行冻干得白色絮状物,即为DSPE-PSA(PSA为十聚体)。
采用同样方法合成DSPE-PSA(PSA为五聚体)。
使用BRUKER AVANCE-600MHz超导核磁共振 (瑞士 Bruker 公司)对所得产物进行碳谱分析,各峰化学位移数据及结构归属见附图7,证明合成得到DSPE-PSA(PSA为十聚体)。
实施例5:DSPE-PEG-PSA的合成
室温下,取“实施例2”制备的已活化的PSA(平均分子量11.0 kDa),将其与DSPE-PEG2000共同溶解于乙醇中(1:1,mol/mol),避光搅拌直至溶液澄清有乳光,并逐步滴加硼氢化钾(KBH4)(KBH4:DSPE-PEG2000=5:1,mol/mol),继续反应约4 h。使用去离子水作为透析介质对反应液透析约24 h,透析介质为反应液的100倍体积,每6 h更换一次透析介质,共更换4次。对透析后的反应液进行冻干得白色絮状物,其中主要成分为DSPE-PEG2000-PSA。
使用BRUKER AVANCE-600MHz超导核磁共振 (瑞士 Bruker 公司)对所得产物进行碳谱分析,各峰化学位移数据及结构归属见附图8,证明合成得到DSPE-PEG-PSA(PSA片段为十聚体)。
使用DSPE-PEG1000-NH2、DSPE-PEG10000-NH2代替DSPE-PEG2000-NH2与已活化的PSA(按“实施例2”所述方法制备)进行对接,得到DSPE-PEG1000-PSA和DSPE-PEG10000-PSA。
在本实施例中,使用相同物质的量的DPPE-PEG2000代替DSPE-PEG2000与活化的PSA进行连接,使用相同的反应条件,可以制得DPPE-PEG2000-PSA。
实施例6:DSPE-PSA修饰脂质体的制备
处方1:
HSPC:CH: DSPE-PSA(十聚体):NBD-PE=55:40:5:0.5(mol/mol)
处方2:
HSPC:CH: DSPE-PSA(五聚体):NBD-PE=55:40:5:0.5(mol/mol)
处方3:
HSPC:CH: DSPE-mPEG2000:NBD-PE=55:40:5:0.5(mol/mol)
其中NBD-PE为荧光磷脂,用于表征脂质体的体内行为。
处方1、处方2和处方3表示所制备脂质体的膜材组成,脂质体制备方法如下:60~65℃水浴中,用乙醇溶解处方量膜材,挥去部分乙醇后,以中速注入预热至相同温度的PBS溶液(pH7.0,20 mmol),孵育约20 min,制得脂质体初品,经200 W超声初步混合处理2 min后,400 W超声分散4 min(工作1 s,间歇1 s),依次通过0.8、0.45μm的微孔滤膜,得到脂质体混悬液。脂质体粒径使用PSS NICOMP 380 激光粒度测定仪进行测定。处方1脂质体平均粒径为112 nm,处方2脂质体平均粒径为132 nm;处方3脂质体平均粒径为101 nm。
实施例7:DSPE –PSA修饰乳剂的制备
处方1:PSA修饰乳剂(修饰密度约为总磷脂量的10% mol/mol)
TN 20 mg
MCT 100 mg
S75 23.3 mg
DSPE-PSA(十聚体) 13.0 mg
5%葡萄糖注射液加至 5mL
处方2:PEG修饰乳剂(修饰密度约为总磷脂量的10% mol/mol)
TN 20 mg
MCT 100 mg
S75 23.3 mg
DSPE-mPEG2000 9.3 mg
5%葡萄糖注射液加至 5mL
按处方1及处方2分别制备由PSA和PEG进行表面修饰的乳剂,乳剂中所装载的TN是我们研究该乳剂体内行为的示踪分子,TN作为脂溶性药物,可以较完全地包封于乳剂内部,且释放后很快被水解而失去示踪作用。但荧光磷脂即使从乳剂表面脱落仍然可以在后期检测中提供信号,难以反映载体的体内完整性。所以在此,TN相比于荧光磷脂能够更好地展示载体的体内行为。我们的前期工作证明,使用10% mol PEG修饰的乳剂可获得很好的长循环效果(大鼠尾静脉注射时血液循环半衰期大于约4 h),因此该项研究中将乳剂表面聚合物的修饰密度定为约为10%。
制备工艺:将处方量水相(5 %葡萄糖注射液)55 ℃预热备用。将处方量油相(TN、MCT、S75、DSPE-mPEG2000或DSPE-PSA)于55 ℃下搅拌至全部溶解。搅拌下将水相加入油相,高速分散,即得初乳。探头超声(200 w×2 min;400 w×6 min)处理后,过0.22 μm微孔滤膜除菌即得。
聚合物插入率的分析:使用凝胶色谱法对乳剂和游离态的亲水性高分子聚合物进行分离,再分别采用苦味酸法和间苯二酚法对DSPE-mPEG2000和DSPE-PSA(十聚体)进行定量。处方1中DSPE-PSA(十聚体)的插入率为92%;处方2中DSPE-mPEG2000的插入率为95%.
处方1制剂粒径为124 nm;处方1制剂粒径为105 nm。
实施例8:DSPE-PSA修饰纳米粒的制备
固体脂质纳米粒处方1
TN 10 mg
S75 20 mg
GMS 50 mg
DSPE-PSA(十聚体) 10 mg
5%葡萄糖注射液加至 5 mL
固体脂质纳米粒处方2
TN 10 mg
S75 20 mg
GMS 50 mg
DSPE-mPEG2000 7 mg
5%葡萄糖注射液加至 5 mL
制备方法:适量乙醇溶解处方量的GMS,S75,TN,DSPE-PSA(十聚体)或DSPE-mPEG2000并于65℃搅拌下熔融/溶解;挥干乙醇,恒速注入相同温度的5%葡萄糖溶液,孵育10 min;之后转入预热的探头管中在水浴条件下探头超声8 min,超声工艺为200 w条件下2 min,400 w条件下3 min,过0.22μm微孔滤膜。最终制剂平均粒径约118 nm。
实施例9:DSPE-PSA修饰胶束的制备
处方1:
Q10 6 mg
DPPC 70 mg
DSPE-PSA(十聚体) 50 mg
5%葡萄糖注射液加至 5 mL
处方2:
Q10 6 mg
DPPC 60 mg
DSPE-mPEG2000 37 mg
5%葡萄糖注射液加至 5 mL
制备工艺:约60℃下将处方量的Q10、DPPC、DSPE-mPEG2000或DSPE-PSA(十聚体)用适量乙醇溶解,将乙醇挥干后,在60℃水浴超声情况下加入处方量5%葡萄糖注射液,并搅拌。得到略带淡蓝色乳光的均一液体。
所得胶束粒径分别为,处方1:53nm;处方2:46 nm。由于Q10为水不溶性药物,所以从制剂外观即可初步确证药物基本载入胶束内部。
实施例10:DSPE-PSA修饰的囊泡
处方:
CF 6 mg
CH 3 mg
吐温80 30 mg
司盘80 30 mg
DSPE-PSA(五聚体) 33 mg
5%葡萄糖注射液加至 5 mL
约60℃下将处方量吐温80、司盘80、CH、DSPE-PSA(五聚体)用适量乙醇溶解,挥干乙醇后,搅拌条件下加入溶解有CF的5%葡萄糖注射液,使用凝胶层析除去外水相的CF即得到包封有CF的由PSA脂质衍生物修饰的囊泡。
实施例11:DSPE-PSA修饰脂质体的比格犬体内行为研究
采用“实施例7”所制备的DSPE-PSA和DSPE-PEG所修饰的乳剂对比格犬进行给药,研究修饰制剂的体内药动学行为。
给药方案:比格犬称重后分组,于右前肢静脉注射TN乳剂(“实施例7”中的处方1和处方2),以磷脂剂量2.5 μmol/kg(即0.375 mL/kg乳剂)分别注射。于给药后1 min、3 min、5 min、10 min、15 min、30 min、1 h、2 h、4 h、6 h于右前肢静脉取血。经离心后分离血浆,-20℃保存待测。间隔一定时间(7天)后,给予首次注射同种制剂,同法采集血浆样品。
样品处理:取血浆样品100 μL于2 mL离心管中,加入内标液50μL、甲醇150 μL、正己烷600 μL。涡旋5 min混匀,于10,000 rpm离心10 min,移取正己烷层500 μL,氮气挥干。加入流动相100 μL,涡旋1 min混匀,于10,000 rpm离心10 min,取上清液,进行HPLC分析。
体内分析:取内标溶液(维生素E棕榈酸酯)、空白比格犬血浆适量,精密配制一系列浓度的TN溶液,提取分离处理后,取上清液进行HPLC分析。以药物浓度C(μg/mL)为横坐标,药物和内标物的峰面积比(A s /A i )为纵坐标,用加权最小二乘法进行线性回归,并计算回归直线方程为A s /A i = 0.0629*C + 0.000356 (1.0 ~100.0 μg/mL), R=0.9976。
方法回收率、精密度符合要求。
体内药动学数据见表1
由TN的血液中浓度变化可知,PEG或PSA所修饰的乳剂均可以获得长循环效果,血液循环半衰期达到2 h以上;但二次注射时,PEG化乳剂出现了ABC现象,被从血液循环中快速清除,而PSA所修饰的乳剂长循环效果未受影响。我们前期研究证明,乳剂是验证药物载体修饰材料是否能诱导机体产生ABC现象的典型载体。所以本实验在很大程度上证明PSA脂质衍生物是一种免疫原性极低的可用于制剂修饰的材料。
实施例12:PSA脂质衍生物的溶血性
对SA/PSA衍生物的血液相容性进行考察,简要过程如下:
(1)制备2%比格犬红细胞悬浮液,保存于4℃冰箱中待用.
(2)分别取洁净试管进行编号,1-7号管分别加入不同浓度的“实施例6”中处方1的DSPE-PSA(十聚体)修饰的脂质体或是处方3的由DSPE-mPEG2000修饰的脂质,8号管和9号管分别作为阴性对照管和阳性对照管(加入物质见表2),混匀后,立即置(37±0.5)℃的恒温振荡器中进行温浴,开始每隔15 min观察1次,1 h后每隔1 h观察1次,观察3 h。并分别取样品1滴,制片,于Motic摄影显微镜(DMBA450,麦克奥迪实业集团有限公司)下观察。
溶血性试验判断标准:
全溶血:溶液澄明,红色,管底无红细胞残留;
部分溶血:溶液澄明,红色或棕色,底部有少量红细胞残留,镜检红细胞稀少或变形;
不溶血:红细胞全部下沉,上清液体无色澄明,镜检红细胞不凝聚;
红细胞凝聚:溶液中有棕红色或红棕色絮状沉淀,振摇后不分散;
结果:阴性对照管无溶血和凝聚发生,阳性对照管有溶血发生。当DSPE-PSA和DSPE-mPEG2000所修饰脂质体制剂加入量小于0.5mL时均不产生溶血反应(3 h内);制剂加入量达1.0 mL时均出现溶血反应;制剂加入量在0.7 mL时,DSPE-PSA修饰脂质体无溶血反应,DSPE-mPEG2000所修饰脂质体有部分溶血。由此可见,PSA脂质衍生物具有较好的注射安全性。
实施例13:DSPE-PEG2000-SA的靶向作用
肿瘤细胞表面存在“选择素(selectins)”,因此可以利用SA作为配体,通过“选择素”的介导将SA/PSA修饰的药物/载体递送入肿瘤细胞。
本项研究中,我们合成了DSPE-PEG2000-SA,并用其修饰脂质体制剂,研究其体内抗肿瘤效果。
将唾液酸(SA)0.027 g、0.1 mol/L高碘酸钠水溶液2 mL和乙二醇4 mL混合均匀并于15-25℃下避光搅拌约1 h,得到澄清透明溶液;向此体系中加入4 mL DSPE-PEG2000-NH2的乙醇溶液(内含DSPE-PEG2000-NH2 0.245 g)并继续搅拌约15 h;在此体系中加入硼氢化钠(NaBH4)(NaBH4:DSPE-PEG2000-NH2=4:1,mol/mol),继续反应约6 h后终止反应,冻干溶剂并用甲醇复溶,离心后取上清液浓缩,冻干后得到DSPE-PEG2000-SA。
结构确证:使用BRUKER AVANCE-600MHz超导核磁共振 (瑞士 Bruker 公司)对所得产物进行碳谱分析,各峰化学位移数据及结构归属见附图9,证明合成得到DSPE-PEG2000-SA。
同样方法,我们合成了DSPE-PEG5000-SA。
脂质体膜材组成为HSPC:CH: DSPE-PEG2000-SA=3:1:1.1(w/w),梯度建立物质为枸橼酸-枸橼酸钠溶液(浓度为200 mM,pH为4.0)。
60~65℃水浴中,用乙醇溶解膜材(即HSPC、CH和DSPE-PEG2000-SA的混合物),磷脂重量与乙醇的体积之比约为1:2,挥去部分乙醇后,以中速注入预热至相同温度的梯度建立物质溶液,孵育20 min,制得脂质体初品,经200 W超声初步混合处理2 min后,400 W超声分散4 min(工作1 s,间歇1 s),依次通过0.8、0.45μm的微孔滤膜,即得空白脂质体混悬液。取空白脂质体混悬液若干,加入适量Na3PO4溶液(浓度为500 mM)及灭菌注射用水,混合均匀,调节外水相pH至7.0,即得梯度脂质体混悬液。以药脂比1:15(w/w)将梯度脂质体混悬液与BBR 2778溶液(浓度为4.0 mg/mL)混合,60~65℃下水浴搅拌孵育10 min后取出置于冰水浴中终止载药即得BBR 2778脂质体。测得该脂质体制剂包封率为99.8%,粒径为110 nm。所得BBR 2778脂质体在4℃避光放置60 天,外观均一、透明、有乳光,无沉淀,无菌,且粒径及包封率无明显变化。
实验方案:BBR 2778脂质体组(枸橼酸梯度载药,包封率99.8%,粒径110 nm)、BBR 2778溶液组;给药剂量10 mg/kg;动物数5只/组。肿瘤S180接种后5天给药,间隔3天,连续给药3次,于接种后13天脱颈处死小鼠,剖取瘤块并称质量。计算肿瘤抑制率(脂质体组76%;水溶液组19%),测定肿瘤组织药物浓度(脂质体组的浓度约是溶液组浓度的26倍)和肾脏组织药物浓度(脂质体组的浓度约是溶液组浓度的1/9),BBR 2778呈蓝色,照片可直观看出药物分布情况,见附图9。证明DSPE-PEG2000-SA修饰马来酸匹衫琼(BBR 2778)脂质体在S180荷瘤小鼠模型上表现出良好的肿瘤靶向性和治疗作用,同时还能够极大降低药物的肾脏分布量。
Claims (6)
1.一种含有唾液酸片段的脂质衍生物,其特征在于,唾液酸片段包含至少1个唾液酸单元,唾液酸单元间通过α-2,8-糖苷键连接,并且脂质片段与唾液酸片段中非还原端唾液酸单元的7号碳通过C-N键连接。
3.根据权利要求2所述的含有唾液酸片段的脂质衍生物,其特征在于,所述R-NH2是二硬脂酰基磷脂酰乙醇胺、二棕榈酰基磷脂酰乙醇胺、二油酰基磷脂酰乙醇胺、二月桂酰磷脂酰乙醇胺、二肉豆蔻酰磷脂酰乙醇胺、大豆磷脂酰乙醇胺、蛋黄磷脂酰基乙醇胺、硬脂酰油酰磷脂酰乙醇胺、硬脂酰亚油酰磷脂酰乙醇胺、棕榈酰油酰磷脂酰乙醇胺、棕榈酰亚油酰磷脂酰乙醇胺、二癸酰磷脂酰乙醇胺、二辛酰磷脂酰乙醇胺、二己酰磷脂酰乙醇胺、磷脂酰基乙醇胺聚乙二醇氨基、脂肪胺。
4.根据权利要求2所述的含有唾液酸片段的脂质衍生物,其特征在于,所述R-NH2是二硬脂酰磷脂酰乙醇胺、二棕榈酰磷脂酰乙醇胺、磷脂酰乙醇胺聚乙二醇氨基、直链或支链烷基胺。
5.根据权利要求3或4中任意一项所述的含有唾液酸片段的脂质衍生物,其特征在于所述磷脂酰乙醇胺聚乙二醇氨基中聚乙二醇片段的分子量为1000-10000道尔顿。
6.权利要求1至5中任何一项所述的含有唾液酸片段的脂质衍生物的应用,其特征在于所述化合物单独或与其他物质联合用于微粒制剂的制备和修饰。
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CN113304276A (zh) * | 2021-06-04 | 2021-08-27 | 沈阳药科大学 | 用单唾液酸四己糖神经节苷脂修饰的脂质体及其制法和冻干应用 |
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