CN110577557A - 唾液酸脂质衍生物及其制备方法和应用 - Google Patents
唾液酸脂质衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN110577557A CN110577557A CN201810585471.1A CN201810585471A CN110577557A CN 110577557 A CN110577557 A CN 110577557A CN 201810585471 A CN201810585471 A CN 201810585471A CN 110577557 A CN110577557 A CN 110577557A
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- Prior art keywords
- compound
- derivative
- sialic acid
- dox
- sialyllipid
- Prior art date
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- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 title claims abstract description 97
- -1 sialic acid lipid Chemical class 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 53
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- 239000003814 drug Substances 0.000 claims abstract description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 4
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 claims description 68
- 239000002502 liposome Substances 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 22
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 14
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 2
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
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- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 claims description 2
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 2
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Abstract
本发明属于医药技术领域,提供了一种可用于微粒制剂修饰的唾液酸脂质衍生物及其制备方法和应用。所述的唾液酸脂质衍生物的结构通式如下,其中R1为H原子或C1‑C6烷基;R2为H、(CH2)m、C2‑C6烯基,m=1‑17;当X为H原子或O原子时,R3为(CH2)n或胆固醇基,n=1‑17;当X为羰基时,R3为C12‑C24烷氧基、C12‑C24烷基取代氨基或胆固醇基;R4为‑OH、‑NHCOCH3或‑NHCOCH2OH。本发明所述的唾液酸脂质衍生物可以用于修饰微粒制剂,并根据药物的性质,实现不同的治疗或诊断目的。特别是在抗肿瘤方面,该唾液酸脂质衍生物可赋予微粒制剂优异的肿瘤靶向能力,提升抑瘤效果。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种唾液酸脂质衍生物及其制备方法和 应用,尤其是在微粒制剂的制备和修饰中的应用。
背景技术
唾液酸(Sialic acid,SA)是一类含有九碳原子并具有吡喃糖结构的酸性氨 基糖的总称,其系统命名为5-氨基-3,5-二脱氧-D-甘油-D-半乳壬酮糖,按5号位 碳原子上连接的基团来划分不同的SA衍生物。N-乙酰羟神经氨酸(Neu5Gc)、 N-乙酰神经氨酸(Neu5Ac)和3-脱氧-D-甘油-D-半乳壬酮糖(KDN)是SA家 族中最常见的三种,其中以Neu5Ac最为常见。物理性质上,SA为白色固体粉 末,易溶于水,在甲醇中微溶,在乙醚和轻石油中不溶,在水溶液中稳定且不发 生变旋作用。其结构如下:
SA在自然界分布很广,存在于许多生物体内。随着生物进化程度的增加, SA在生物体内的含量及其衍生物类型亦增加,哺乳动物的脑脊液和黏液中SA 最多。但对于进化程度较低的生物,如原生动物、星虫、环节动物、节肢动物等, 其体内均极少或没有SA存在(Vimr E,Steenbergen S,Cieslewicz M.Biosynthesis of the polysialic acidcapsule inEscherichia coli K1[J].Journal of Industrial Microbiology&Biotechnology,1995,15(4):352-360.)。SA是生物杂聚物的重要 组成部分,主要以短链残基的形式存在于寡糖、糖蛋白和糖脂的末端,直接或间 接参与发生在细胞膜上的反应。因此,SA在细胞间、细胞和外环境之间的交流 中扮演着重要角色,参与了机体众多生理和病理过程。SA的多种生物活性是由 SA与其受体特异性识别所介导的,SA的受体主要有I型凝集素的唾液酸结合免 疫球蛋白超家族Siglec,C型凝集素的选择素(Selectin)和H因子(Blaum B S, Hannan J P,Herbert A P,et al.Structural basis for sialic acid–mediated self-recognition by complement factor H[J].Nature Chemical Biology,2015, 11(1):77-82.)。鉴于Siglec受体与SA的亲和力对SA糖基结构修饰的敏感性, 并且随着人们对Siglec受体在人类健康与疾病中作用的不断了解,以及糖生物工 程的不断发展,越来越多的研究者将目光转移到SA-Siglec介导的疾病靶向治疗 策略上(Büll C,Heise T,Adema G J,et al.Sialic Acid Mimetics to Target the Sialic Acid-SiglecAxis[J].Trends in Biochemical Sciences,2016,41(6):519-531.)。
Siglec是属于免疫球蛋白样凝集素家族的一种黏附分子,目前发现的Siglec 已超过16种,除Siglec-4和Siglec-6以外,其余Siglec主要表达于造血细胞和 免疫细胞表面,能够识别带有唾液酸的糖链结构而促进细胞之间的相互作用,在 介导胞吞、病原体识别、介导细胞信号转导、调节免疫细胞和造血细胞的功能等 方面起着重要作用。Siglec家族主要有两个亚群:一种是序列保守的Siglecs,包 括Sialoadhesin(Sn,Siglec-1),CD22(Siglec-2),MAG(Siglec-4)和Siglec-15;另 一种是与CD33相关的序列可变的Siglecs(Siglec-3,-5,-6,-7,-8,-9,-10,-11,-14, and-16),Siglec-12失去与唾液酸结合能力,而Siglec-13和Siglec-17随着人类的 进化已经失活(Varki A.Glycan-basedinteractions involving vertebrate sialic-acid-recognizing proteins.[J].Nature,2007,446(7139):1023-9)。2010年, Bondioli等将SA的C2号位羟基与PLGA进行偶联,并用该材料制备了纳米粒, 研究表明SA的修饰增加了单核细胞对纳米粒的吞噬(Bondioli L,Costantino L, Ballestrazzi A,et al.PLGA nanoparticles surfacedecorated with the sialic acid, N-acetylneuraminic acid[J].Biomaterials,2010,31(12):3395-3403.)。2013年, Pfrengle F等将SA衍生物修饰于脂质体表面,通过SA不断刺激Siglec-10,抑制 B细胞的信号传导,诱导B细胞耐受(Pfrengle F,Macauley M S,Kawasaki N,et al. Copresentation of antigen and ligands of Siglec-G induces Bcell tolerance independent of CD22[J].Journal of Immunology,2013,191(4):1724-1731.)。2016 年,Masashi Ohmae等将SA的C2位羟基与聚肌氨酸-聚(L-乳酸)的嵌段聚合物(Lactsome)进行偶联,通过SA与Siglec-9的识别,降低了巨噬细胞对已调 理纳米粒子的吞噬作用,减弱了聚合物胶束的ABC现象(Ohmae M,Kojima M, Mihara K,et al.Reducedimmune response to polymeric micelles coating sialic acids[J].Bioorganic&Medicinal Chemistry Letters,2016,26(20):4976-4982.)。可 见,SA可以触发Siglec介导的多种免疫调节功能,具有很高的治疗自身免疫疾 病或炎症价值。
不仅如此,由于Siglec-1属于内吞性受体,在TAM表面高表达,其C2结 构域较长,使之更易与自身细胞之外的SA结合。使得Siglec-1在肿瘤靶向治疗 中可作为潜在的靶点(Nath D,Hartnell A,Happerfield L,et al.Macrophage-tumour cell interactions:identification of MUC1on breast cancer cells as a potential counter-receptorfor the macrophage-restricted receptor,sialoadhesin[J].Immunology, 1999,98(2):213-219.Oetke C,Vinson M C,Jones C,et al.Sialoadhesin-Deficient MiceExhibit Subtle Changes in B-and T-Cell Populations and Reduced ImmunoglobulinM Levels[J].Molecular and Cellular Biology,2006,26(4): 1549-1557.)。She Z等将SA的C1羧基与十八胺的氨基酰胺化,合成唾液酸- 十八胺偶联物(SA-ODA),将其修饰于包载抗肿瘤药物匹杉琼(pixantrone, Pix)的脂质体表面,可有效减少肿瘤组织中TAM的数量,出现肿瘤脱落(She Z, Zhang T,Wang X,et al.The anticancer efficacy ofpixantrone-loaded liposomes decorated with sialic acid-octadecylamineconjugate[J].Biomaterials,2014, 35(19):5216-5225.)。Zhou S等将胆固醇的羟基与丙烯酰氯酯化偶联,然后利用 α,β-不饱和共轭羰基与巯基乙胺的巯基发生点击反应而偶联合成胆固醇脂质片 段,最终将SA的羧基与此合成脂质片段的伯胺反生酰胺化反应,从而合成唾液 酸-胆固醇偶联物(SA-CH),SA-CH较SA-ODA有更低的毒性,将其修饰于包 载抗肿瘤药物表柔比星(epirubicin,EPI)的脂质体表面,可有效耗竭TAM,抑 制肿瘤细胞的生长,并出现肿瘤脱落现象(Zhou S,Zhang T,Bo P,et al.Targeted delivery of epirubicin totumor-associated macrophages by sialic acid-cholesterol conjugate modifiedliposomes with improved antitumor activity[J].International Journal ofPharmaceutics,2017,523(1):203-216.)。可见SA与Siglec的特异性识 别在靶向肿瘤治疗中有重要意义。
专利CN101160326A中报道的SA衍生物C7位连接了N-羟基琥珀酰亚胺酯, 可以与含胺基基团的药物、蛋白(肽)或药物递送系统反应实现连接,这种连接 属于化学反应,并且连接物必须含有胺基,这极大的限制了应用范围。专利 CN102276662A所合成的SA衍生物与本发明所述的SA衍生物相比,也存在如 上缺陷。专利CN106986901A中报道的SA-羧酸类药物的合成方法,该专利中的 SA衍生物C2位所连接的药物必须为羧酸类化合物,这极大的限制了其在药物 治疗领域的应用。专利CN106554425A中所报道的聚唾液酸(PSA)衍生物,该 衍生物以含有羧基的脂质化合物与SA单体的C9位羟基进行偶联,但是含羧基 的脂质化合物的选择性并不好,会与SA单体的C4、C7位羟基也发生反应,导 致产物纯度下降,合成的PSA衍生物结构紊乱,不利于微粒制剂表面的修饰。 此外,专利CN104031097A和专利CN106188169A中报道SA衍生物均是以SA C1 位羧基为偶联位点,以酰胺键连接脂质化合物,但是SA的羧基是其发挥生物学 功能重要基团,可与Siglec的N末端区域(V区)的保守的精氨酸序列形成盐 桥从而介导识别(Büll C,Heise T,Adema G J,et al.Sialic AcidMimetics to Target the Sialic Acid-Siglec Axis[J].Trends in BiochemicalSciences,2016, 41(6):519-531.)。将SA的羧基酰胺化后,羧基无法暴露,不利于其在体内生物 学的发挥。
发明内容
本发明所解决的技术问题是克服现有技术的缺陷,提供了一种可用于微粒制 剂修饰的唾液酸(SA)脂质衍生物,并根据微粒制剂所载药物的性质,实现不 同的治疗或诊断目的。特别是在抗肿瘤方面,该唾液酸脂质衍生物可赋予微粒制 剂优异的肿瘤靶向能力,提升抑瘤效果。
本发明是通过如下技术方案实现的:
本发明提供一种具有如下通式结构的唾液酸脂质衍生物:
其中,
R1为H原子或C1-C6烷基;
R2为H、(CH2)m、C2-C6烯基,m=1-17;
当X为H原子或O原子时,R3为(CH2)n或胆固醇基,n=1-17;
当X为羰基时,R3为C12-C24烷氧基、C12-C24烷基取代氨基或胆固醇基;
R4为-OH、-NHCOCH3或-NHCOCH2OH;
优选地,
R1为C1~C4的烃基;
R2为H、(CH2)m、C2-C4烯基,m=1-17;
X为H原子或O原子时,R3为(CH2)n或胆固醇基,n=1-17;
X为羰基时,R3为二十四烷氧基、二十二烷氧基、二十烷氧基、十八烷氧 基、十六烷氧基、十四烷氧基、十二烷氧基、胆固醇基、24-氨基二十四烷基、 22-氨基二十二烷基、20-氨基二十烷基、18-氨基十八烷基、16-氨基十六烷基、 14-氨基十四烷基、12-氨基十二烷基;
R4为-OH、-NHCOCH3或-NHCOCH2OH;
优选地,
R1为H原子、甲基、乙基;
R2为亚甲基时、X为H原子或O原子,R3为十四烷基、十五烷基、十六烷 基、十七烷基、十八烷基、胆固醇基。
R2为-CH2-CH2-、-CH=CH-、-CH2-CH2-CH2-时,X为羰基,R3为十六烷氧 基、十八烷氧基、胆固醇基;
R4为-NHCOCH3;
更优选地,
本发明所述的唾液酸脂质衍生物的结构如下:
化合物11:
化合物12:
化合物13:
化合物14:
化合物15:
化合物16:
化合物17:
化合物18:
化合物19:
化合物20:
化合物21:
化合物22:
本发明所述的唾液酸脂质衍生物可以单独或者与其他物质联合用于制备乳 剂、脂质体、固体纳米粒、囊泡、胶束等微粒载体。
本发明所述的唾液酸脂质衍生物的合成方法如下:
方法一:
第一步,将唾液酸C1位羧基在酸性醇溶液中加热酯化,得到唾液酸的酯化 物;
第二步,将含羧基的脂质化合物转化成酰氯;
第三步,在4-二甲氨基吡啶(DMAP)的催化下于吡啶中与唾液酸酯化物的 C9位上的羟基进行酰化,得到含有唾液酸基团的脂质衍生物。
方法二:
第一步,将唾液酸C1位羧基在酸性醇溶液中加热酯化,得到唾液酸的酯化 物;
第二步,将酸酐与醇或胺进行酰化,得到含羧基的酯或者酰胺;或将含氯的 羧酸化合物与醇或胺进行反应,得到含氧或氮的羧酸化合物;
第三步,将第二步得到的化合物的羧基转化成酰氯,在4-二甲氨基吡啶 (DMAP)的催化下于吡啶中与唾液酸酯化物的C9位上的羟基进行酰化,得到 含有唾液酸基团的脂质衍生物。
无论方法一还是方法二所得的产物均可水解掉唾液酸酯化物C1位置的酯 键,使得唾液酸的羧基重新暴露出来。
本发明的SA脂质衍生物可用于修饰微粒制剂,从而提高微粒制剂的靶向性, 所述的微粒制剂为:乳剂、脂质体、固体纳米粒、囊泡、胶束等。
本发明的SA脂质衍生物,可修饰于多种微粒制剂表面,而不同的微粒载体 可装载不同理化性质的药物,实现不同的治疗目的,并且可赋予药物缓释、控释、 靶向等特性。
本发明的SA脂质衍生物,可修饰于多种微粒制剂表面,而微粒载体不仅可 以装载如FITC此类水溶性荧光素,还可装载如尼罗红,DiR等脂溶性荧光素, 并且可根据成像需要选择各个波段荧光素,实现不同的诊断目的。
本发明所述SA脂质衍生物以含有酰氯的脂质化合物与SA C9位羟基偶联, 反应选择性要优于含羧酸的脂质化合物直接与SA C9位羟基酯化偶联,产物纯 度更高。
本发明中的SA脂质衍生物是以SA C9位羟基为偶联位点,虽然在合成过程 中,为了优化反应,将SA的羧基酯化以提高SA的脂溶性和反应的选择性,但 是由于生物体内大量酯酶的存在,当该SA脂质衍生物修饰的微粒制剂进入体内 后,体内丰富的酯酶会水解被酯化的羧基,使得羧基重新暴露,SA正常发挥其 生物学功能。此外SA的羧基酯化有助于所修饰微粒制剂稳定性的放置稳定性。
综上所述,本发明的SA脂质衍生物具有如下优势:首先,该SA衍生物合 成时,为提高反应的活性和选择性,将SA的羧基进行了酯化处理,并将羧酸脂 质化合物转化成相应酰氯,使得脂质化合物能更好的与SA C9位的羟基偶联, 并且酯化处理有助于提高所修饰制剂的放置稳定性。其次,该唾液酸脂质衍生物 可用于多种微粒制剂的修饰,修饰过程均是自组装过程,操作简单、耗时少,并 且可根据微粒载体装载化学药、生物药、荧光素等种类的不同,实现不同的治疗 或诊断作用。最后,该SA衍生物用于修饰微粒制剂,治疗肿瘤时,该唾液酸脂 质衍生物可赋予微粒制剂优异的肿瘤靶向能力,提升抑瘤效果,具有更高的肿瘤 靶向性和更优的抑瘤活性。
附图说明:
图1 MT-18(化合物3)质谱图
图2 MT-18(化合物3)氢谱图
图3 SA-18(化合物6)质谱图
图4 SA-18(化合物6)氢谱图
图5 DA-16(化合物12)质谱图
图6 DA-16(化合物12)氢谱图
图7 ML-16(化合物16)氢谱图
图8 ML-16(化合物16)质谱图
图9 LYS-16(化合物9)氢谱图
图10 LYS-16(化合物9)质谱图
图11 WE-DGC(化合物22)氢谱图
图12 WE-DGC(化合物22)质谱图
图13 SA-18的HPLC-ELSD图
图14长期放置稳定性
图15抑瘤指数图
图16肿瘤组织分布图。
具体实施方式:
实施例中所用的各成分的简称如下:
氢化大豆卵磷脂HSPC 蛋黄卵磷脂E80 大豆卵磷脂S75
二棕榈酰磷脂酰胆碱DPPC 蛋黄磷脂酰甘油EPG 胆固醇CH
唾液酸SA 十八胺ODA 维生素E烟酸酯TN 吲哚菁绿ICG
吐温80Tween-80 司盘80Span-80 多柔比星DOX
地塞米松棕榈酸酯DMP 紫杉醇PTX 甘油Gly
单硬脂酸甘油酯GMS
材料来源:
SA(Neu5Ac,Neu5Gc,KDN)纯度>95%,HPLC检测,购自美国Sigma-Aldrich 公司。十二醇、十四醇、十六醇、十八醇购自上海高信化学仪器有限公司。胆固 醇购自南京新百药业有限公司。硬脂酸、棕榈酸、十五烷酸、肉豆蔻酸、月桂酸、 丁二酸酐、马来酸酐、戊二酸酐、己二酸酐、庚二酸酐、辛二酸酐购自上海迈瑞 尔化学技术有限公司。氯乙酸、氯丙酸、氯丁酸氯、戊酸氯、己酸氯、庚酸氯、 辛酸、二氯亚砜购自上海默恩化学科技有限公司。
下面结合实例,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 发明的保护范围。
检测手段:
本发明中所制备微粒制剂的粒径及Zeta电位使用SPSS NICOMP 380激光粒 度测定仪测定;核磁检测使用Bruker ARX-400及Bruker 600-MHz核磁共振仪(美 国Bruker公司);质谱检测使用Agilent 1100Series MSD Trap测定(美国Agilent 公司);HPLC-ELSD分析使用EDEX75型蒸发光散射检测器(法国Sedere公司), P230高压恒流泵(大连依利特分析仪器有限公司),EC2000色谱数据处理工作 站(大连依利特分析仪器有限公司),AT-130柱温箱(天津市金洲科学仪器有 限公司),高精度全自动交流稳压器(中川电气科技有限公司)。
实例部分:
实施例1唾液酸甲酯(MT)的合成
于500mL三颈瓶中加入SA(20g,0.064mol),甲醇250mL,3.68N的HCl 甲醇溶液1.7mL(0.0064mol),于50℃油浴锅中搅拌反应2.5h。抽滤,滤液蒸干 得19.3g白色固体,加入80mL甲醇重结晶,冷却析晶,抽滤后得到白色固体 17.90g,收率86.5%。
结构式如下:
熔点:182-183℃。
质谱:m/z 346.1,MT[M+Na]+峰;未见SA峰。
实施例中的SA均以Neu5Ac为例,在相同反应条件下,使用相同摩尔比例的 Neu5Gc和KDN代替Neu5Ac,可得到相对应产物。
实施例2十八烷酰氯的合成
于100mL茄型瓶中加入十八烷酸(8.53g,0.03mol),二氯亚砜(28.56g,0.24 mol),于80℃油浴锅中回流反应1h。于65℃下减压蒸馏除去剩余二氯亚砜,得 到橘黄色液体8.9g,收率98.2%,其余实施例用用到的酰氯均由相同的反应条件, 使用相同的摩尔比例合成得到。
结构式如下:
实施例3 MT-18(化合物3)的合成
向250mL三颈瓶中加入MT(5g,15mmol),4-二甲氨基吡啶(0.19g,1.5 mmol),用50mL吡啶溶解,于冰浴下滴加十八烷酰氯(7.1g,23mmol)的THF 溶液40mL,控制温度在5℃左右,20min滴毕后移至室温下继续反应,反应10h 后加入50mL水,用二氯甲烷40mL*3萃取,30mL饱和食盐水洗涤,无水MgSO4 干燥,抽滤、旋干、拌样、装柱,经硅胶柱色谱分离,得到白色固体2.82g,收 率:55.6%。
结构式如下:
熔点:140-142℃。
质谱:m/z:612.4,MT-18[M+Na]+峰。谱图见附图1。
核磁共振氢谱:1H-NMR(600MHz,DMSO-d6):δ8.12(d,J=8.4Hz,1H),6.38(s, 1H),4.85(s,1H),4.63(s,2H),4.22(d,J=11.3Hz,1H),3.94-3.91(m,1H),3.87-3.83 (m,1H),3.75-3.70(m,5H),3.50(q,J=10.2Hz,18.8Hz,1H),3.23(d,J=9.2Hz,1H), 2.26(t,J=7.4Hz,2H),2.03(q,J=4.9Hz,12.8Hz,1H),1.90(s,3H),1.73(t,J=13.2Hz, 1H),1.50(t,J=7.1Hz,2H),1.24(s,28H),0.85(t,J=6.8Hz,3H)。谱图见附图2。
实施例4 SA-18(化合物6)的合成
于50mL茄型瓶中加入MT-18(0.5g,0.91mmol),碳酸氢钠(0.38g, 4.57mmol),加入10mL丙酮和3mL水,于45℃油浴锅中搅拌下反应2h。反应 完全后趁热抽滤,滤液用1N盐酸调节pH值至4,旋干得白色固体0.47g,加入 5mL甲醇重结晶,冷冻析晶,抽滤得到白色固体0.39g,收率82.2%。
结构式如下:
熔点:137-139℃。
质谱:m/z:574.6,SA-18[M-H]-峰。谱图见附图3。
核磁共振氢谱:1H-NMR(600MHz,DMSO-d6):δ12.74(s,1H),8.11(d,J=8.5Hz,1H),6.14(s,1H),4,75(s,2H),4.22(d,J=11.2Hz,1H),3.94-3.91(m,1H),3.85(d, J=3.7Hz,1H),3.74(t,J=8.2Hz,2H),3.50(q,J=10.5Hz,18.9Hz,1H),3.35(s,1H), 3.22(d,J=8.7Hz,1H),2.27(t,J=7.4Hz,2H),2.01-1.98(m,1H),1.89(s,3H),1.72(t, J=12.0,1H),1.50(t,J=6.2Hz,2H),1.24(s,28H),0.85(t,J=6.8Hz,3H)。谱图见附图 4。
实施例5丁二酸十六醇单酯的合成
于100mL茄型瓶中加入丁二酸酐(0.45g,4.54mmol),十六醇(1g,4.12 mmol),4-二甲氨基吡啶(0.1g,0.83mmol),加入15mL甲苯,于110℃油浴锅 中回流1.5h。待温度降至室温后加入10mL水,用10%盐酸调节pH值至2,乙 酸乙酯20mL*3萃取,20mL饱和食盐水洗涤,无水MgSO4干燥、抽滤、旋干 得到白色固体1.38g,用6mL甲醇重结晶,冷冻析晶,抽滤得到白色固体1.12g。 收率79.4%。
结构式如下:
熔点:64-65℃。
质谱:m/z:341.3,[M-H]-峰。
实施例6 DA-16(化合物12)的合成
于100mL三颈瓶中加入MT(0.8g,2.48mmol),10mL吡啶,4-二甲氨基 吡啶(0.07g,0.50mmol),于冰浴条件搅拌下滴加丁二酸十六醇单酯酰氯(0.98g, 2.73mmol)的二氯甲烷溶液5mL,控制温度在5℃以下,15分钟滴毕,1h后移 至室温反应12h。加入30mL水,用二氯甲烷30mL*3萃取,30mL饱和食盐水 洗涤,无水MgSO4干燥,抽滤、旋干、拌样、装柱,经柱色谱分离,得到白色 固体0.87g,收率54.2%。
结构式如下:
熔点:146-148℃。
质谱:m/z:648.3,[M+H]+峰。谱图见附图5。
核磁共振氢谱:1H-NMR(600MHz,DMSO-d6):δ8.12(d,J=8.3Hz,1H),6.34(d, J=2.4Hz,1H),4.85(d,J=6.4Hz,1H),4.71(d,J=4.7Hz,1H),4.66(d,J=5.8Hz,1H), 4.25(d,J=10.9Hz,1H),4.00(t,J=6.7Hz,2H),3.90(q,J=7.6Hz,11.2Hz,1H), 3.87-3.83(m,1H),3.75-3.68(m,5H),3.52(q,J=10.1Hz,18.7Hz,1H),3.24-3.22(m, 1H),2.54(s,4H),2.05-2.02(m,1H),1.90(s,3H),1.73(t,J=13.3Hz,1H),1.56-1.51 (m,2H),1.24(s,26H),0.85(t,,J=6.8Hz,3H)。谱图见附图6。
实施例7马来酸十六醇单酯的合成
于100mL茄型瓶中加入马来酸酐(1.5g,0.015mol),十六醇(3.53g,0.014 mol),于80℃油浴锅中熔融反应,4h后冷却至室温,加入石油醚10mL,搅拌 30min,抽滤得白色固体4.31g,用36mL石油醚重结晶,冷却析晶,抽滤得到 白色固体3.85g,收率80.7%。
结构式如下:
熔点:72-73℃。
质谱:m/z:339.3,[M-H]-峰。
实施例8 ML-16(化合物16)的合成
向100mL三颈瓶中加入MT 2.19g(6.77mmol),用20mL吡啶溶解,加入 4-二甲氨基吡啶0.13g(1.35mmol),于冰浴下滴加马来酸十六醇单酯酰氯(3.2g, 8.8mmol)的二氯甲烷溶液10mL,控制温度在5℃以下,15分钟滴毕,反应1h 后移至室温下反应15h,加入30mL水,用二氯甲烷30mL*3萃取,30mL饱和 食盐水洗涤,无水MgSO4干燥,抽滤、旋干、拌样、装柱,经柱色谱分离,得 到白色固体2.14g,收率49.8%。
结构式如下:
熔点:154-156℃。
质谱:m/z:668.6[M+Na]+峰。谱图见附图7。
核磁共振氢谱:1H-NMR(600MHz,DMSO-d6):δ8.13(d,J=8.3Hz,1H),6.75(d, J=1.4Hz,2H),6.41(d,J=2.3Hz,1H),4.85(d,J=6.4Hz,1H),4.79(d,J=5.8Hz,1H), 4.75(d,J=4.8Hz,1H),4.39(d,J=11.2Hz,1H),4.15(t,J=6.6Hz,2H),4.10(q, J=7.1Hz,11.2Hz,1H),4.04-4.02(m,1H),3.89-3.84(m,1H),3.77-3.75(m,2H),3.71 (s,3H),3.55-3.50(m,1H),2.06-2.03(m,1H),1.90(s,3H),1.73(t,J=13.3Hz,2H), 1.63-1.53(m,2H),1.24(s,26H),0.85(t,,J=6.9Hz,3H)。谱图见附图8
实施例9 2-(十六烷氧基)乙酸
于100mL茄型瓶中加入石油醚洗涤过的60%钠氢(0.66g,16.5mmol),无 水甲苯10mL,十六醇(2g,8.25mmol),于50℃油浴锅中反应1h后,滴加氯 乙酸(0.94g,9.9mmol)的甲苯溶液5mL,7min滴毕,升温至110℃回流反应9h。 冷却至室温,加入20mL水,用2N盐酸调节pH值至1,用30mL*3乙酸乙酯 萃取,30mL饱和食盐水洗一次,无水硫酸镁干燥、抽滤、旋干得白色固体2.52 g。用18mL甲醇重结晶,冷却析晶,抽滤得到白色固体1.90g,收率76.6%。
结构式如下:
熔点:67~69℃
质谱:m/z:299.3,[M-H]-峰。
实施例10 LYS-16(化合物9)的合成
向100mL三颈瓶中加入MT(1.84g,5.69mmol),4-二甲氨基吡啶(0.14g,1.26mmol),用20mL吡啶溶解,于冰浴条件下滴加2-(十六烷氧基)乙酰氯(2.3g, 6.32mmol)的二氯甲烷溶液8mL,控制温度在5℃以下,11min滴毕,反应30min 后移至室温下继续反应,11h后加入30mL水,用二氯甲烷30mL*3萃取,30mL 饱和食盐水洗涤,无水MgSO4干燥,抽滤、旋干、拌样、装柱,经柱色谱分离, 白色固体2.02g,收率58.5%。
结构式如下:
熔点:127-129℃。
质谱:m/z:628.4[M+Na]+峰。谱图见附图9。
核磁共振氢谱:1H-NMR(600MHz,DMSO-d6):δ8.12(d,J=8.3Hz,1H),6.38(s, 1H),4.68(s,2H),4.30(dd,J=2.0Hz,11.2Hz,1H),4.06(s,2H),4.01-3.98(m,1H), 3.88-3.83(m,1H),3.75-3.68(m,5H),3.52(q,J=10.3Hz,18.8Hz,1H),3.43(t, J=6.5Hz,2H),3.23(d,J=9.1Hz,1H),2.05-2.02(m,1H),1.90(s,3H),1.73(t, J=12.1Hz,1H),1.49(t,J=6.8Hz,2H),1.24(s,26H),0.85(t,J=6.8Hz,3H)。谱图见附 图10。
实施例11戊二酸胆固醇单酯的合成
向100mL茄型瓶中加入胆固醇(1.50g,3.87mmol),戊二酸酐(0.53g,4.65 mmol),用15mL吡啶溶解,于至80℃油浴锅中反应5h,加入50mL二氯甲烷, 用20mL*2的3N盐酸洗涤,20mL水洗一次,20mL饱和食盐水洗一次,无水 硫酸镁干燥,抽滤,滤液旋干得到白色固体1.81g,用6mL的二氯甲烷重结晶, 得到白色固体1.41g,收率75.1%。
结构式如下:
熔点:154~156℃
质谱:m/z:499.4[M-H]-峰。
实施例12 WE-DGC(化合物22)的合成
向100mL三颈瓶中加入MT(0.8g,2.48mmol),4-二甲氨基吡啶(0.07g,0.57 mmol),用10mL吡啶溶解,于冰浴条件下滴加戊二酸胆固醇单酯酰氯(1.41g, 2.73mmol)的二氯甲烷溶液5mL,控制温度在5℃以下,13min滴毕,反应30min 后移至室温下继续反应,12h后加入30mL水,用二氯甲烷30mL*3萃取,30mL 饱和食盐水洗涤,无水MgSO4干燥,抽滤、旋干、拌样、装柱,经柱色谱分离, 得到白色固体1.12g,收率55.9%。
结构式如下:
熔点:168-170℃。
质谱:m/z:828.5[M+Na]+峰,谱图见附图11。
核磁共振氢谱:1H-NMR(600MHz,DMSO-d6):δ8.12(d,J=8.3Hz,1H),6.38(d, J=2.3Hz,1H),5.34(d,J=3.3Hz,1H),4.85(d,J=6.4Hz,1H),4.71(d,J=4.7Hz,1H), 4.66(d,J=5.8Hz,1H),4.50-4.44(m,1H),4.24(d,J=11.2Hz,1H),3.95-3.92(m,1H), 3.88-3.83(m,1H),3.75-3.68(m,5H),3.53-3.48(m,1H),3.25-3.22(m,1H), 2.54-2.50(m,4H),2.34-2.30(m,4H),2.25(d,J=7.7Hz,2H),2.05-2.02(m,1H), 1.98-1.88(m,5H),1.84-1.71(m,4H),1.54-1.48(m,5H),1.41-1.31(m,5H), 1.25-1.21(m,1H),1.16-1.03(m,7H),0.98-0.95(m,5H),0.91-0.89(m,4H), 0.85-0.83(m,6H),0.65(s,3H)。谱图见附图12。
实施例13 SA-18纯度分析与比较
采用十八烷酸与C9位直接反应所得的SA-18,记为SA-18-1,分别取 1mg·mL-1的SA-18-1甲醇溶液和1mg·mL-1实施例4中合成的SA-18的甲醇溶液, 采用HPLC-ELSD进行含量分析,色谱柱:Kromasil Si色谱柱(4.6×200mm,5 μm);流动相:甲醇-异丙醇(80:20,v/v,含0.5%TEA,v/v);流速:1mL·min-1; 柱温:30℃;进样量:20μL。蒸发光散射检测器条件:漂移管温度:45℃;氮 气压力:3.0bar;增益值(GAIN):5.0。由图13可知SA-18-1有明显的杂质峰, 而本发明中合成的SA-18无明显杂质峰,表明本发现所用的合成方法选择性更 好,产物纯度更高。采用面积归一化法计算纯度为99.8%。
实施例14 DOX脂质体的制备及其稳定性
表1 各DOX脂质体的处方及基本理化性质。
制备工艺:按表1处方称取脂质体膜材置于西林瓶中,其中SA-ODA为专 利CN104031097A中的Neu5Ac-ODA,SA-CH为专利CN104031097A中的 Neu5Ac-AE-AC-CH。加入空白制剂终体积10%(v/v)的无水乙醇并于65℃水 浴中搅拌溶解。待膜材溶解后,敞开体系,继续搅拌以挥除大部分无水乙醇。以 4mL·min-1的速度将预热至相同温度的柠檬酸-柠檬酸钠溶液(200mM,pH 4.0) 注入膜材中。65℃水浴搅拌20min,得到脂质体初品。将初品超声分散处理(功 率和时间:200W×2min+400W×6min,工作1s间歇1s)后,依次通过0.80、0.45、0.22μm微孔滤膜,即得空白脂质体(磷脂浓度50mg·mL-1)。取空白脂 质体混悬液适量,加入磷酸钠(500mM)调节外水相pH至7.0,再加入适量灭 菌注射用水,混合均匀,即得pH梯度脂质体。按照药脂比1:10(w/w)将上述 梯度脂质体与DOX药物溶液混合,60℃水浴搅拌孵育,20min后取出置于冰水 浴中终止载药,即得各SA脂质衍生物修饰的DOX脂质体(DOX-SAL)和普通 DOX脂质体(DOX-CL),其基本理化性质见表1。
通常认为微粒制剂的Zeta电位绝对值大于30mV制剂的稳定性良好。由表 1可知,只有DOX-MT-18的Zeta电位绝对值大于30mV,表明其稳定性优于其 他各组。此外,DOX-MT-18的包封率均高于其他各组。
长期放置稳定性:
将DOX-MT-18、DOX-SA-CH、DOX-SA-ODA、DOX-CL分装于棕色西林瓶, 充氮密封。在4±2℃条件下避光保存,分别于0、1、2和3个月取样,测定粒径 及包封率。结果见图13。由图13可知,在4±2℃贮藏条件下放置3个月,只有 DOX-MT-18的粒径和包封率无显著性变化,说明长期放置稳定性良好。其余各 组DOX脂质体在保存过程中发生聚集,融合导致粒径增大,包封率降低,稳定 性不如DOX-MT-18。
RAW264.7/S180细胞对各DOX脂质体的摄取:
取处于对数生长期的RAW264.7细胞制成细胞悬液,调整细胞浓度,以每孔 900μL接种于24孔板,使得每孔细胞数为2×105个,培养4h后,每孔分别加 入100μL DOX浓度为50μg·mL-1的DOX-MT-18、DOX-SA-CH、DOX-SA-ODA、 DOX-CL,每组3复孔。每块板上设置空白孔(培养液中含细胞不含制剂),对 照孔(培养液中含细胞,用于后续与制剂混合)。置于5%CO2培养箱中孵育4h 后,弃去培养液。经PBS清洗后,每孔加入200μL细胞裂解液(对照孔加入50 μL细胞裂解液和50μL相应制剂)。待细胞完全裂解后,每孔加入600μL无水 乙醇。摇匀后,将孔内液体转移至1.5mL EP管中,10000rpm离心10min。取 上清液200μL于96孔板中,使用酶标仪于激发波长543nm和发射波长598nm 下测定荧光强度F,空白组吸光度为F0。计算摄取率,判断摄取能力。
取处于对数生长期的S180细胞制成细胞悬液,调整细胞浓度,以每孔900μL 接种于24孔板,使得每孔细胞数为5×104个,培养4h后,每孔分别加入100μL DOX浓度为50μg·mL-1的DOX-MT-18、DOX-SA-CH、DOX-SA-ODA、DOX-CL, 每组3复孔。每块板上设置空白孔(培养液中含细胞不含制剂),对照孔(培养 液中含细胞,用于后续与制剂混合)。置于5%CO2培养箱中孵育4h后,移取 培养液于1.5mL EP管中,1000rpm离心5min,弃去上清液。经PBS清洗后, 加入100μL细胞裂解液。待细胞完全裂解后每孔加入300μL无水乙醇。24孔板 板孔经PBS清洗后,每孔加入100μL细胞裂解液(对照空加入150μL细胞裂解 液和50μL相应制剂),待细胞完全裂解后每孔加入300μL无水乙醇。摇匀后, 将孔内液体与1.5mL EP管中的液体合并,10000rpm离心10min。取上清液200 μL于96孔板中,使用酶标仪于激发波长543nm和发射波长598nm下测定荧光 强度F,空白组吸光度为F0。计算摄取率,判断摄取能力。
细胞摄取率=(实验组F值-空白组F0值)/(对照组F值-空白组F0值)×100%
RAW264.7/S180细胞对各DOX脂质体的摄取率见表2。
表2 RAW264.7/S180细胞对各DOX脂质体的摄取率(n=3)。
由表2可知,RAW264.7细胞对DOX-SAL组的摄取率均大于DOX-CL组, 其原因在于RAW264.7细胞表面有SA的受体Siglec,S180细胞表面有SA的受 体Selectin,有助于两种细胞对DOX-SAL的摄取。RAW264.7对DOX-SA-CH 组和DOX-SA-ODA组的摄取率无显著性差异(p>0.05),且均小于DOX-MT-18 组的摄取率,原因在于RAW264.7是常用的炎症细胞模型之一,其活性氧簇 (ROS)通常会升高,并过量表达水解酶(如酯酶、蛋白酶、磷酸酶等)(Wu Y,Huang S,Zeng F,et al.A ratiometric fluorescent system for carboxylesterasedetection with AIE dots as FRET donors.[J].Chemical Communications,2015, 51(64):12791-4.)。RAW264.7分泌的酯酶会水解MT-18C1位置的酯键,使得C1 位羧基重新暴露。而羧基又是SA与Siglec受体识别的重要基团,可与Siglec的 N末端区域(V区)的保守的精氨酸序列形成盐桥从而介导识别。因此RAW264.7 对DOX-MT-18组的摄取率高于DOX-SA-CH组和DOX-SA-ODA组。
S180细胞对DOX-SAL组的摄取率均大于DOX-CL,其原因在于S180细胞 表面有SA的受体Selectin,有助于两种细胞对DOX-SAL的摄取。S180对各 DOX-SAL的摄取率无显著性差异(p>0.05),其原因在于Selectin受体的顶端 是一个广泛的糖类识别区域,可能对MT-18、SA-CH、SA-ODA识别无区别,所 以三组的摄取率无显著性差异。
MTT法测定各DOX脂质体对RAW264.7/S180的IC50:
取处于对数生长期的RAW264.7/S180细胞制成细胞悬液,调整细胞浓度, 以5×103/孔接种于96孔板中,置于37℃,5%CO2培养箱中培养4h后,每孔 分别加入10μL浓度梯度的DOX制剂,使得DOX终浓度为0.5,1,2.5,5,12.5, 25μM,每个样本浓度设置6复孔。每块板上另设空白孔(培养液中不含细胞和 制剂)和对照孔(培养液中含细胞不含制剂)。加药完毕后,将96孔板置于37℃、5%CO2培养箱中培养48h。培养结束后,每孔加入10μL MTT(5mg·mL-1), 培养箱中孵育4h,使MTT还原为甲瓒。孵育结束后,每孔加入100μL三联液, 于培养箱继续孵育12h。孵育结束后,使用酶标仪于570nm波长下扫描96孔板 的光密度(OD)值,并拟合半数抑制浓度(IC50),IC50越低,表明毒性越强。 结果见表3。
表3各DOX脂质体对RAW264.7/S180细胞的IC50(n=3)。
表2中数据可知,无论对于RAW264.7细胞还是S180细胞,DOX-SA-ODA 组均具有最小的IC50,即毒性最强。其原因在于SA-ODA材料本身的毒性,并 且在实验中证实,10μg·mL-1的SA-ODA对RAW264.7的抑制率为30.29±0.36%, 对S180的抑制率为22.44±0.50%,而其余SA衍生物在此浓度下对两种细胞均 无抑制作用,这提示了SA-ODA在体内会对机体产生较强的非特异性损伤。
无论对于RAW264.7细胞还是S180细胞,各DOX-SAL组的毒性均强于 DOX-CL组,其原因在于RAW264.7和S180对DOX-SAL组的摄取率大于 DOX-CL组。对于RAW264.7细胞,由于其对DOX-MT-18的摄取率大于 DOX-SA-CH,使得DOX-MT-18的毒性大于DOX-SA-CH。对于S180细胞,由 于其对DOX-MT-18和DOX-SA-CH的摄取率无显著性差异,所以DOX-MT-18 组的毒性与DOX-SA-CH组的毒性无显著差异(p>0.05)。
S180抗肿瘤试验:
将30只接种S180瘤株的小鼠随机分为5组,即5%Glu、DOX-MT-18、 DOX-SA-CH、DOX-SA-ODA、DOX-CL,每组6只。于接种后第3、6、9、12 和15天分别尾静脉注射给药。给药剂量为5mg·kg-1DOX,对照组给予相同体积 5%Glu。评价指标如下:
肿瘤体积(Tumor volume,V,mm3):V=0.5×a×b2(a:肿瘤长径,b: 肿瘤短径);
肿瘤抑制率(Tumor inhibition rate,TIR),包括体积抑瘤率(TIRV,%)、 质量抑瘤率(TIRM,%)以及肿瘤生长曲线下面积抑瘤率(TIRAUTGC,%):
TIRV=(VControl group-VTreated group)/VControl group×100%;
TIRM=(MControl group-MTreated group)/MControl group×100%;
TIRAUTGC=(AUTGCControl group-AUTGCTreated group)/AUTGCControl group×100%;
抑瘤指数(Tumor-inhibition index,TIindex,g·g-1)=体重/瘤重。
各组抑瘤率见表4。将各抑瘤指数对接种后天数作图,抑制指数图见图13。 表4各给药组的抑瘤率。
由表4可知,无论是以TIRV、TIRM还是TIRAUTGC计算,各DOX制剂对小 鼠体内S180肿瘤的抑制作用强弱顺序均一致,抑制作用从强到弱依次为 DOX-MT-18>DOX-SA-CH>DOX-SA-ODA>DOX-CL。
抑瘤指数可综合评价各组制剂对肿瘤细胞的抑制作用和对机体非特异性损 伤,其值越大,抑瘤效果越好。由图13可知,DOX-MT-18组的抑瘤指数大到小 为DOX-MT-18>DOX-SA-CH>DOX-SA-ODA>DOX-CL。说明DOX-MT-18抑 瘤效果最好,且对机体的非特异性损伤较小。
脾指数和胸腺指数
将30只接种S180瘤株的小鼠随机分为5组,即5%Glu、DOX-MT-18、 DOX-SA-CH、DOX-SA-ODA、DOX-CL组,每组6只。于接种后第3、6、9、 12和15天分别尾静脉注射给药。给药剂量为5mg·kg-1DOX,对照组给予相同 体积5%Glu。于第16天将荷瘤小鼠脱颈处死,剥离脾脏和胸腺,称定质量并计 算指数,计算公式如下:
脾脏/胸腺指数(mg·g-1)=脾脏(胸腺)质量/体质量
结果见表5。
表5各组S180荷瘤小鼠的胸腺脾指数(n=6)
a p代表与5%Glu组脾指数相比;
b p代表与DOX-MT-18组脾指数相比;
c p代表与DOX-SA-CH组脾指数相比;
d p代表与DOX-SA-ODA组脾指数相比;
e p代表与DOX-CL组脾指数相比;
f p代表与5%Glu组胸腺指数相比;
g p代表与DOX-MT-18组胸腺指数相比;
h p代表与DOX-SA-CH组胸腺指数相比;
i p代表与DOX-SA-ODA组胸腺指数相比;
j p代表与DOX-CL组胸腺指数相比。
由表5可知,与5%Glu组的脾指数和胸腺指数相比,DOX-CL组和 DOX-SA-ODA组均有所降低,DOX-CL由于没有SA脂质衍生物的修饰,体内 靶向肿瘤的部位的能力弱,所以对免疫器官的损伤较大,而DOX-SA-ODA组则 是由于SA-ODA自身毒性所致。DOX-MT-18和DOX-SA-CH与5%Glu组均无 显著性差异,说明DOX-MT-18与DOX-SA-CH对免疫器官的毒性弱。
肿瘤组织分布实验:
将18只荷瘤昆明小鼠随机分成6组,每组3只,每组按5mg DOX·kg-1分 别尾静脉注射为DOX-CL、DOX-MT-18、DOX-SA-CH、DOX-SA-ODA,24h 后将小鼠处死,取出肿瘤生理盐水清洗后用滤纸吸干,取0.5g肿瘤组织于7mL EP管中,加入1.0mL生理盐水,进行高速分散匀浆。精密移取组织匀浆液100μL 于1.5mL EP管中,0.3mol·L-1HCl的甲醇-水(50:50,v/v)继续12000rpm离 心10min,取上清液200μL于96孔板中,在λex=472nm和λem=588nm条件 下测定荧光强度F,计算肿瘤组织中DOX浓度(μg·g-1)。结果见附图14。由图 可知,DOX-MT-18肿瘤部位的浓度要大于DOX-MT-CH和DOX-SA-ODA,说 明MT-18具有很好的肿瘤靶向性。
实施例15SA脂质衍生物羧基酯化对所修饰DOX脂质体稳定性的影响
表6 MT-18、SA-18修饰DOX脂质体处方
按处方称取脂质体膜材置于西林瓶中,加入空白制剂终体积10%(v/v)的 无水乙醇并于65℃水浴中搅拌溶解。待膜材溶解后,敞开体系,继续搅拌以挥 除大部分无水乙醇。以4mL·min-1的速度将预热至相同温度的柠檬酸-柠檬酸钠 溶液(200mM,pH 4.0)注入膜材中。65℃水浴搅拌20min,得到脂质体初品。 将初品超声分散处理(功率和时间:200W×2min+400W×6min,工作1s间 歇1s)后,依次通过0.80、0.45、0.22μm微孔滤膜,即得空白脂质体(磷脂浓 度50mg·mL-1)。取空白脂质体混悬液适量,加入磷酸钠(500mM)调节外水 相pH至7.0,再加入适量灭菌注射用水,混合均匀,即得pH梯度脂质体。按照 药脂比1:10(w/w)将上述梯度脂质体与DOX药物溶液混合,60℃水浴搅拌孵 育,20min后取出置于冰水浴中终止载药,即得SA脂质衍生物修饰的DOX脂 质体DOX-MT-18和DOX-SA-18。
DOX-MT-18的初始粒径为101.3±5.7nm,包封率为96.5±0.4%,在4±2℃ 贮藏条件下放置3个月后,粒径为108.1±3.5nm,包封率为95.2±1.1%,与初 始粒径和包封率相比无显著性差异(p>0.05)。DOX-SA-18初始粒径为103.7± 3.4nm,包封率为94.5±0.5%,在4±2℃贮藏条件下放置3个月后粒径和包封 率均发生了显著性变化,粒径增长至231.2±4.4,包封率下降至88.7±0.5%。以 上结果表明SA脂质衍生物中SA C1位羧基酯化有利于提高所修饰微粒制剂的稳 定性。
实施例16:MT-18修饰TN乳剂的制备
表7 MT18修饰TN乳剂处方。
制备工艺:将处方量油相(TN、MCT、E80、MT-18)于55℃下搅拌至全 部溶解。搅拌下将预热至相同温度的灭菌注射用水加入油相,孵育20min,即得 初乳。探头超声(功率和时间:200W×2min+400W×6min,工作1s间歇1s) 处理后,过0.22μm微孔滤膜除菌即得MT-18修饰的TN乳剂。所得TN乳剂粒 径为128.2±4.3nm,无分层、絮凝、合并和破裂现象,稳定性良好。
实施例17DA-16修饰的固态脂质纳米粒制备
表8 DA-16修饰TN固态脂质纳米粒处方。
制备工艺:称取处方量的GMS,E80,TN,DA-16,加入适量无水乙醇于 65℃搅拌下溶解。挥干乙醇,恒速注入预热至相同温度的灭菌注射用水,孵育 10min,即得初品。探头超声(功率和时间:200W×2min+400W×6min,工 作1s间歇1s)处理后,过0.22μm微孔滤膜除菌即得DA-16修饰的TN固态脂 质纳米粒,其粒径为145±4.2nm。4℃放置3个月粒径和包封率无显著性变化, 表明制剂稳定性良好。
实施例18ML-16修饰DMP胶束的制备
表9 ML-16修饰DMP胶束处方。
制备工艺:称取处方量的DMP、DPPC、ML-16,加入适量无水于60℃搅拌 下溶解。将乙醇挥干后,在60℃水浴超声情况下加入预热至相同温度的灭菌注 射用水,即得ML-16修饰的DMP胶束。其粒径在50.3±3.6nm。72h未见结晶 析出,稳定性良好。
实施例19LYS-16修饰ICG囊泡的制备
表10 LYS-16修饰ICG囊泡处方。
制备方法:60℃下将处方量Tween-80、Span-80、CH、LYS-16用适量乙醇 搅拌溶解,挥干乙醇后,搅拌条件下加入溶解有ICG的灭菌注射用水,使用凝 胶层析除去外水相的IGC即得到包封有IGC的LYS-16修饰的囊泡。其粒径为 106.3±2.1nm。4℃放置3个月粒径和包封率无显著性变化,表明制剂稳定性良 好。
实施例20WE-DGC修饰装载PTX脂质体的制备
表11 WE-DGC修饰PTX脂质体处方。
制备方法:称取脂质体膜材及药物置于西林瓶中,加入500uL无水乙醇并 于65℃水浴中搅拌溶解。待膜材及药物溶解后,敞开体系,继续搅拌以挥除大 部分无水乙醇,将预热至相同温度灭菌注射用水恒速注入膜材中,注入5mL。 65℃水浴搅拌20min,得到脂质体初品。将初品超声分散处理(功率和时间: 200W×2min+400W×2min,工作1s间歇1s),后依次通过0.80、0.45、0.22um 微孔滤膜,即得DTX脂质体。实验结果表明,所得DTX的平均粒径为100.2± 4.6nm,包封率为90.3±1.1%。4℃放置3个月粒径和包封率无显著性变化,表明制剂稳定性良好。
实施例21SA-18修饰DMP乳剂的制备。
表12 SA-18修饰DMP处方。
制备方法:将处方量水相55℃预热备用。将处方量油相(MCT、DMP、S75、 SA-18)于55℃下搅拌至全部溶解。搅拌下将预热至相同温度的含Gly的灭菌注 射用水加入油相,高速分散,即得初乳。探头超声(功率和时间:200W×2min+ 400W×6min,工作1s间歇1s)处理后,过0.22um微孔滤膜除菌即得SA-18修 饰的DMP乳剂。实验结果表明,所得DMP乳剂的平均粒径为125.6±1.2nm。
Claims (10)
1.一种唾液酸脂质衍生物:
其中,
R1为H原子或C1-C6烷基;优选为H原子或C1-C4烷基;
R2为H、(CH2)m、C2-C6烯基,m=1-17;
当X为H原子或O原子时,R3为(CH2)n或胆固醇基,n=1-17;
当X为羰基时,R3为C12-C24烷氧基、C12-C24烷基取代氨基或胆固醇基;
R4为-OH、-NHCOCH3或-NHCOCH2OH。
2.如权利要求1所述的唾液酸脂质衍生物,其特征在于,
X为羰基时,R3为二十四烷氧基、二十二烷氧基、二十烷氧基、十八烷氧基、十六烷氧基、十四烷氧基、十二烷氧基、胆固醇基、24-氨基二十四烷基、22-氨基二十二烷基、20-氨基二十烷基、18-氨基十八烷基、16-氨基十六烷基、14-氨基十四烷基、12-氨基十二烷基。
3.如权利要求1所述的唾液酸脂质衍生物,其特征在于,
R2为亚甲基时、X为H原子或O原子,R3为十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、胆固醇基;
R2为-CH2-CH2-、-CH=CH-、-CH2-CH2-CH2-时,X为羰基,R3为十六烷氧基、十八烷氧基、胆固醇基。
4.如权利要求1-3任何一项所述的唾液酸脂质衍生物,其特征在于,所述R1为H原子、甲基、乙基。
5.如下的唾液酸脂质衍生物,
化合物1:
化合物2:
化合物3:
化合物4:
化合物5:
化合物6:
化合物7:
化合物8:
化合物9:
化合物10:
化合物11:
化合物12:
化合物13:
化合物14:
化合物15:
化合物16:
化合物17:
化合物18:
化合物19:
化合物20:
化合物21:
化合物22:
6.如权利要求1所述的唾液酸脂质衍生物的制备方法,其特征在于,
第一步,将唾液酸C1位羧基在酸性醇溶液中加热酯化,得到唾液酸的酯化物;
第二步,将含羧基的脂质化合物转化成酰氯;
第三步,在4-二甲氨基吡啶(DMAP)的催化下于吡啶中与唾液酸酯化物的C9位上的羟基进行酰化,得到含有唾液酸基团的脂质衍生物。
或
第一步,将唾液酸C1位羧基在酸性醇溶液中加热酯化,得到唾液酸的酯化物;
第二步,将酸酐与醇或胺进行酰化,得到含羧基的酯或者酰胺;或将含氯的羧酸化合物与醇或胺进行反应,得到含氧或氮的羧酸化合物;
第三步,将第二步得到的化合物的羧基转化成酰氯,在4-二甲氨基吡啶(DMAP)的催化下于吡啶中与唾液酸酯化物的C9位上的羟基进行酰化,得到含有唾液酸基团的脂质衍生物。
7.权利要求1-5任何一项所述的唾液酸脂质衍生物在修饰微粒制剂中的应用。
8.权利要求1-5中任何一项所述的唾液酸脂质衍生物在制备抗肿瘤药物中的应用。
9.权利要求1-5中任何一项所述的唾液酸脂质衍生物在制备靶向药物中的应用。
10.如权利要求7所述的应用,其特征在于,所述的微粒制剂为乳剂、脂质体、固体纳米粒、囊泡或胶束。
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