CN114957390B - 肿瘤靶向多肽及其应用 - Google Patents
肿瘤靶向多肽及其应用 Download PDFInfo
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- CN114957390B CN114957390B CN202210503963.8A CN202210503963A CN114957390B CN 114957390 B CN114957390 B CN 114957390B CN 202210503963 A CN202210503963 A CN 202210503963A CN 114957390 B CN114957390 B CN 114957390B
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- targeting polypeptide
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Landscapes
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- Chemical & Material Sciences (AREA)
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Abstract
本发明涉及一种肿瘤靶向多肽及其应用,该肿瘤靶向多肽包括式(I)所示的多肽类化合物或其药学上可以接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物。以上肿瘤靶向多肽可用于制备肿瘤靶向药物或肿瘤诊断制剂。
Description
技术领域
本发明涉及化学医药技术领域,尤其涉及一种肿瘤靶向多肽及其应用。
背景技术
目前,肿瘤靶向制剂一般是多肽类制剂,一般通过与肿瘤血管或者肿瘤细胞表面分子特异性结合,在肿瘤血管或者肿瘤细胞中富集。
肿瘤靶向多肽在肿瘤的诊断和治疗中有着非常重要的作用,一方面它可以通过与抗肿瘤药物偶联,起到肿瘤的靶向治疗作用;另一方面,通过与肿瘤诊断试剂和成像试剂偶联,可以起到肿瘤的标记和显影的目的。此外,通过将多肽与不同功能的探针偶联,可以用来研究肿瘤的相关病理生理过程。例如美国科学院院士Ruoslahti Errki教授发现一类含RGD基序的肿瘤靶向多肽,这类肿瘤靶向多肽结合靶点是肿瘤新生血管中的整合素αv。根据Ruoslahti Errki教授的研究成果,目前许多含RGD基序的肿瘤靶向多肽,已经进入各期临床实验中,其中部分已经取得了良好的效果。
因此,越来越多的科学工作者致力于开发新型的肿瘤靶向制剂。
发明内容
为解决上述技术问题,本发明的目的是提供一种肿瘤靶向多肽及其应用。
本发明的一种肿瘤靶向多肽,包括一种或几种式(I)所示的多肽类化合物或其药学上可以接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物:
其中,X为S、O或N原子,n1和n2分别独立地选自0、1、2或3;
优选地,取代基R1为
取代基R2为
取代基R3为
其中,n3为0、1、2或3;Ar基团为含0-3个取代基的苯基、苄基、萘基、芳杂基或苯并芳杂基,所述苯基、苄基、芳杂基或苯并芳杂基的苯环或芳杂环上的取代基分别独立地选自一个至六个碳原子的烷基、取代一个至六个碳原子的烷基、三元至七元的环烷基、取代三元至七元的环烷基、卤素、羟基、氨基、巯基、氰基、硝基、甲氧基、乙氧基、乙酰基、羧基、甲酰胺基或磷酸酯基;
取代基R4为n4为0、1、2或3;
取代基R5为n5为0、1、2或3;
取代基R6为甲基、乙基、烷基取代甲基或环烷基取代甲基。
进一步地,Ar基团中,所述芳杂基为吡啶基、噻吩基、呋喃基、嘧啶基、吡咯基或N-氧化吡啶基,所述苯并芳杂基为喹啉基、异喹啉基或吲哚基。
进一步地,R3选自如下结构中的一种:
最优选地,式(I)所示多肽类化合物的结构式如以下(S1)-(S50)中的一种:
本发明中,式(I)所示的多肽类化合物可通过以下方法获得,其包括用已知的液相合成法和固相合成法。
优选地,式(I)所示的多肽类化合物的具体制备方法为:按照目标多肽的合成序列,将被保护的氨基酸逐个偶联到固相树脂上,在此过程中重复脱Fmoc基团和偶联氨基酸操作,然后将偶联了氨基酸的固相树脂与氯乙酸酐反应,再在裂解试剂的作用下将肽链从树脂上裂解同时去除侧链保护基团,浓缩、纯化后即得到式(I)所示的多肽类化合物。
本发明提供了一种肿瘤靶向试剂,该试剂中包括式(I)所示的多肽类化合物或其药学上可以接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物。
进一步地,肿瘤靶向试剂中还包括与肿瘤靶向多肽直接或间接偶联的检测剂或治疗剂。
进一步地,所述检测剂可为荧光标记物、放射性物等,治疗剂可为肿瘤治疗药物,其中,肿瘤为实体肿瘤。
本发明还公开了式(I)所示的多肽类化合物或其药学上可以接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物在制备肿瘤靶向药物中的应用。
本发明还公开了式(I)所示的多肽类化合物或其药学上可以接受的盐、异构体、外消旋体、前体药物共结晶复合物、水合物或溶剂合物在制备肿瘤诊断制剂中的应用。
进一步地,肿瘤诊断制剂可用于肿瘤靶向成像。
借由上述方案,本发明至少具有以下优点:
1、本发明提供了一种结构新颖的肿瘤靶向多肽,为后续的肿瘤治疗和成像奠定基础。
2、本发明的肿瘤靶向多肽为短肽类药物,活性好,靶向性好,生物相容性高。
3、本发明的肿瘤靶向多肽容易被转化为肿瘤诊疗药物,易于放大生产,应用前景光明。
4、本发明的肿瘤靶向多肽的适应症有很大的扩展性。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合详细说明如后。
附图说明
图1是小鼠体内红外荧光阻断图及相对荧光强度统计结果。
具体实施方式
下面结合实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例1
本实验所涉及的Rink amide resin和HBTU、HOBt、DIC、EDT、Fmoc保护的氨基酸均购于上海吉尔生化有限公司,TFA、EDT、DIEA等试剂均通过商业途径购买获得。
本发明中使用的缩写具有以下含义:
Cys(C)半胱氨酸;Ser(S)丝氨酸;Asn(N)天冬酰胺;Leu(L)亮氨酸;Ala(A)丙氨酸;Arg(R)精氨酸;Glu(E)谷氨酸;Gln(Q)谷氨酰胺;Trp(W)色氨酸;Tyr(Y)酪氨酸;Phe(F)苯丙氨酸;Lys(K)赖氨酸;His(H)组氨酸;Met(M)甲硫氨酸;HOBT 1-羟基苯并三氮唑;DIEA N,N-二乙基丙胺;DIC二异丙基碳乙胺;TFA三氟乙酸;EDT乙二硫醇;TEA三乙胺;HBTU苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸盐;Fmoc芴甲氧酰羰基;t-Bu叔丁基;Trt三苯甲基;Boc叔丁氧羰基;Pbf 2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基;DMF N,N-二甲基甲酰胺;DCM二氯甲烷;ESI-MS电喷雾电离质谱。
本发明以下实施例中,所有的氨基酸除了特别说明为D-型外,均为L-型。
本发明中目标多肽及其制备过程中,所使用的试剂与仪器如下:
化合物的合成采用CEM Liberty1微波多肽合成仪和人工合成两种方式,多肽产物通过反相高效液相色谱分离纯化(RP-HPLC Waters 1525/2489/2707),结构通过质谱ESI-MS鉴定,采用Finnigan LCQ Deca mass spectrometer测定。目标化合物的纯度都大于95%,采用双溶剂系统高效液相色谱进行多肽纯度分析(系统1,溶剂组成A:0.05%TFA水溶液,B:0.05%TFA乙腈溶液;系统2,溶剂组成A:0.05%TFA水溶液,B:0.05%TFA甲醇溶液)。制备柱型号为:Vydac C18,120A(10×250mm);XBridgeTM C18,5μM,19×150mm,210nm处紫外检测;分析柱型号为:SunfireTM,C18,3.5μM,4.6×150mm,210nm处紫外检测。
本发明中目标多肽及其制备过程中,所用树脂为Rink amide resin和Wangresin,天然和非天然氨基酸均采用N-Fmoc保护,侧链采用对酸敏感保护基:Glu(tBu)、Arg(pbf)、Asp(tBu)、Tyr(tBu)、Trp(Boc)、Cys(Trt)等。以HOBT/HBTU/DIEA作为偶联反应活化剂,DMF作为偶联反应溶剂;20%哌啶/DMF(v/v)作为脱N-Fmoc试剂;TFA:EDT:H2O(95%:2.5%:2.5%)作为切除树脂和脱边链保护基的裂解试剂。
本发明中目标多肽的通用合成方法如下:
(1)、所有多肽均由手动合成得到,从Rink amide resin或Wang resin(0.1mmol)出发,首先在室温下用DCM和DMF按照1:1的体积比静置溶胀4h。然后用20%的哌啶DMF溶液,脱除Fmoc基团2次,每次20min。之后用DMF和DCM交替2次,洗净树脂。
(2)、根据目标多肽的合成序列,称取相应的0.3mmol的N-Fmoc保护的氨基酸,溶解于10mL DMF中,加入0.3mmol DIEA,0.29mmol HBTU和0.3mmol HOBT,充分振摇15min后,加入上述树脂中,室温振摇4h。
(3)、重复上述脱Fmoc基团和偶联氨基酸操作,直至最后一个氨基酸偶联完毕,并脱除其Fmoc基团并洗净树脂。
(4)、称取0.5mmol的氯乙酸酐,溶解于DMF中,加入0.5mmol的DIEA和0.5mmol的DIC,振摇15min后,加入到上述树脂中,室温振摇6h。
(5)、将反应后的树脂,用DMF洗净,然后用DCM洗净,真空干燥至颗粒状。加入5mL裂解试剂,室温下振摇3h。过滤,收集滤液,用5mL TFA清洗树脂,合并滤液。滤液在氮气下吹至1mL左右,得到多肽浓缩液。
(6)、将10mL冷乙醚加入到多肽浓缩液中,有大量固体析出。离心8分钟(3000r/s)。将上清液小心倒出,再加入冷乙醚,反复此步骤3次,冷冻干燥析出的固体,就得到多肽粗品。
(7)、将上述粗品溶于体积比为乙腈水溶液中使其最终浓度为10-2M,加入TEA将pH至调到10,室温反应6h得到环合的硫醚,将溶液冷冻干燥得粗品。
(8)、使用反相高效液相色谱法纯化多肽。液相条件:溶剂系统:0.05%TFA水溶液;B:0.05%TFA乙腈溶液。分离多肽经冷冻干燥,得产品。并通过ESI-MS确定分子量。表1为说明书上文中S1-S50多肽的ESI-MS测试结果。
表1、不同多肽的ESI-MS结果
实施例 | [M+H]+ | 实施例 | [M+H]+ | 实施例 | [M+H]+ |
S1 | 981.4 | S18 | 1105.3 | S35 | 1006.4 |
S2 | 980.4 | S19 | 1025.4 | S36 | 1009.4 |
S3 | 995.4 | S20 | 996.4 | S37 | 966.4 |
S4 | 983.4 | S21 | 1107.2 | S38 | 995.4 |
S5 | 999.4 | S22 | 997.5 | S39 | 1009.4 |
S6 | 1043.4 | S23 | 1011.4 | S40 | 995.4 |
S7 | 1091.3 | S24 | 1015.4 | S41 | 995.4 |
S8 | 997.4 | S25 | 1015.4 | S42 | 1020.4 |
S9 | 990.4 | S26 | 966.4 | S43 | 1020.4 |
S10 | 1009.4 | S27 | 966.4 | S44 | 981.4 |
S11 | 1009.4 | S28 | 971.4 | S45 | 1006.4 |
S12 | 1008.4 | S29 | 971.4 | S46 | 981.4 |
S13 | 1007.4 | S30 | 955.4 | S47 | 995.4 |
S14 | 1061.4 | S31 | 965.4 | S48 | 995.4 |
S15 | 979.4 | S32 | 981.4 | S49 | 998.4 |
S16 | 995.5 | S33 | 981.4 | S50 | 957.4 |
S17 | 994.4 | S34 | 981.4 |
实施例2
采用荷瘤小鼠肿瘤红外荧光分子成像实验方法,检测多肽裸鼠在裸鼠体内肿瘤靶向富集情况。方法如下:
1、构建荷瘤小鼠
(1)、取4周龄雄性BALB/C裸鼠。
(2)、胰酶消化鼻咽癌CNE2细胞,计数,调整浓度为1.0×106个/mL,20%Matrigel1640培养基重悬,200μL/只裸鼠,后退前皮下注射。
(3)、1-2周观察肿瘤形成情况,测量肿瘤大小,根据肿瘤大小将其随机化分3组,分别为PBS组,测试多肽组以及阳性对照组,每组3只小鼠。
2、构建多肽裸鼠
1.每只裸鼠注入100-150μL的1%戊巴比妥麻药。
2.各取S1-S50多肽及阳性对照多肽2mg,其中,阳性对照多肽的序列氨基酸序列为CRWYDENAC,分别置于试管中并加入200μL生理盐水溶解,如果无法溶解则加入适量的氨水(3-10μL),得到多肽溶液。
3.将荧光肽加入200μL步骤2配制的多肽溶液中,该荧光肽采用cy-3.5染料标记,所得到的混合溶液中,荧光肽的浓度为6μM,分别得到含S1-S50其中之一的混合多肽溶液或含阳性对照多肽的混合多肽溶液。
4.对于测试多肽组,将步骤3得到的含S1-S50其中之一的混合多肽溶液对多肽裸鼠进行尾静脉注射,对于PBS组,注射与测试多肽组等量的PBS溶液,对于阳性对照组,注射与测试多肽组等量的含阳性对照多肽的混合多肽溶液。1h后小动物活体动物成像仪动态检测荧光肽在裸鼠各个脏器和肿瘤中的分布情况和富集情况。
图1a、b分别是小鼠体内红外荧光阻断图及相对荧光强度统计结果。图1a中,自左列向右列,依次为PBS组、阳性对照组、测试多肽组(注射S1)、测试多肽组(注射S2)的体内红外荧光阻断图,图1b是PBS组、阳性对照组、测试多肽组(注射S1)、测试多肽组(注射S2)、测试多肽组(注射S3)的相对荧光强度统计结果。结果表明,本发明的测试多肽组的荧光强度与阳性对照组相当,二者具有相近的阻断效果。表2是分别注射S1-S50多肽的不同测试多肽组的鼠体内荧光测试结果。其中的相对荧光强度值计算方法如下:相对荧光强度=肿瘤的荧光强度/正常组织的荧光强度。
表2、鼠体内荧光结果
表2中,A-C代表小鼠体内荧光强度等级,其中A表示相对应光强度<0.6;B表示相对荧光强度0.6<B<1.5;C表示相对荧光强度1.5<C<2.5。
表中部分多肽表现出与阳性对照相当(如:S1、S2、S4、S5等),甚至比阳性对照更好的肿瘤靶向和阻断效果(如:S3、S7、S8等),且这些多肽具有比阳性对照结构稳定和容易制备的优点。表2中数据结果表明,这些化合物能在小鼠体内有效靶向CNE2细胞。充分说明这类化合物具有肿瘤的诊断、成像与治疗的试剂的开发潜力。
以上所述仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变型,这些改进和变型也应视为本发明的保护范围。
Claims (8)
1.一种肿瘤靶向多肽,其特征在于,所述肿瘤靶向多肽包括一种或几种式(I)所示的化合物或其药学上可以接受的盐、异构体或外消旋体:
其中,X为S、O或N,n1和n2分别独立地选自0、1、2或3;
R1为
R2为
R3为
其中,n3为0、1、2或3;Ar基团为含0-3个取代基的苯基,所述苯基的苯环上的取代基分别独立地选自卤素、羟基、氨基、巯基或甲氧基;
R4为n4为0、1、2或3;
R5为n5为0、1、2或3;
R6为甲基、乙基、烷基取代甲基或环烷基取代甲基。
2.根据权利要求1所述的肿瘤靶向多肽,其特征在于,R3选自如下结构中的一种:
3.根据权利要求1所述的肿瘤靶向多肽,其特征在于,式(I)所示的化合物选自如下结构中的一种:
4.根据权利要求1所述的肿瘤靶向多肽,其特征在于,式(I)所示的化合物由以下步骤制备得到:按照目标多肽的合成序列,将被保护的氨基酸逐个偶联到固相树脂上,在此过程中重复脱Fmoc基团和偶联氨基酸操作,将偶联了氨基酸的固相树脂与氯乙酸酐反应,再在裂解试剂的作用下将肽链从固相树脂上裂解同时去除侧链保护基团,浓缩、纯化后得到式(I)所示的化合物。
5.一种肿瘤靶向试剂,其特征在于:所述肿瘤靶向试剂包括权利要求1-4任一项所述的肿瘤靶向多肽。
6.根据权利要求5所述的肿瘤靶向试剂,其特征在于,所述肿瘤靶向试剂中还包括与肿瘤靶向多肽直接或间接偶联的检测剂或治疗剂。
7.权利要求1-4任一项所述的肿瘤靶向多肽在制备肿瘤靶向药物中的应用,其特征在于,所述肿瘤靶向多肽用于靶向CNE细胞。
8.权利要求1-4任一项所述的肿瘤靶向多肽在制备肿瘤诊断制剂中的应用,其特征在于,所述肿瘤靶向多肽用于靶向CNE细胞。
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