CN116251195B - 一种紫杉醇靶向肽偶联物及其应用 - Google Patents
一种紫杉醇靶向肽偶联物及其应用 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明公开一种紫杉醇靶向肽偶联物及其应用，属于抗肿瘤技术领域。本发明的目的是为了解决紫杉醇药物水溶性差，没有靶向性，生物利用度低，会产生很多副反应的技术问题。本发明公开一种紫杉醇靶向肽偶联物，所述紫杉醇靶向肽偶联物是由紫杉醇或紫杉醇的衍生物通过连接键与靶向肽连接获得的。本发明偶联物在保留了紫杉醇抗肿瘤药物活性的同时，提高了化合物的水溶性，避免了添加对人体有害或有刺激性的助溶剂；增加了化合物的靶向性，提高了药物的吸收利用度，同时，降低了对正常细胞的损伤，降低副作用。
Description
技术领域
本发明属于抗肿瘤技术领域，具体涉及一种紫杉醇靶向肽偶联物及其应用。
背景技术
肿瘤是严重威胁人类健康的疾病之一，化疗作为肿瘤治疗的重要手段，常用于全身播撒倾向或已转移肿瘤的医治。紫杉醇作为经典化疗药物之一，临床上常用于乳腺癌、卵巢癌等疾病的治疗。然而紫杉醇自身缺陷限制了其临床应用，如水溶性差，注射时需借助聚氧乙烯蓖麻油和乙醇混合溶液助溶，而聚氧乙烯蓖麻油可引起机体过敏反应、肾毒性和神经毒性等问题；靶向性不佳，因无法区分正常细胞和肿瘤细胞，常导致严重毒副作用，如贫血、脱发、外周神经病变等。因此，开发溶解性好、靶向性强的新型紫杉醇衍生物具有良好的市场前景和临床应用价值。
常规肿瘤药物大多存在水溶性差、代谢不及时等问题，链接靶向多肽后，可改善链接后产物的水溶性，提供了成药性，避免了添加对人体有害或有刺激性的助溶剂，也提高了体外和体内的生物利用度。传统肿瘤药物，随着使用次数增加，肿瘤细胞膜会产生阻碍药物进入细胞的蛋白，使得药物吸收利用率降低，药效下降。链接靶向肽的药物，可通过靶向肽与肿瘤细胞表面特异性受体结合，有效的把药物带入肿瘤细胞内，避免了耐药性的问题。
紫杉醇是二萜生物碱类化合物，对许多实体瘤具有很好的抗肿瘤活性，但是由于其水溶性差，没有靶向性，生物利用度低，会产生很多副反应。
发明内容
本发明的目的是为了解决紫杉醇药物水溶性差，没有靶向性，生物利用度低，会产生很多副反应的技术问题。
本发明提供一种紫杉醇靶向肽偶联物，其特征在于，所述紫杉醇靶向肽偶联物是由紫杉醇或紫杉醇的衍生物通过连接键与靶向肽连接获得的。
进一步地限定，所述紫杉醇的化学式如下：
进一步地限定，所述连接键为可断裂的二硫键。
进一步地限定，所述可断裂的二硫键的结构为
进一步地限定，所述靶向肽为[Arg-Gly-Pro-Asp]n，n≥1的正整数。
进一步地限定，靶向肽为Arg-Gly-Pro-Asp，靶向肽的结构为
进一步地限定，紫杉醇靶向肽偶联物的结构为：
本发明提供一种上述的紫杉醇靶向肽偶联物在制备抗癌药物中的应用。
进一步地限定，抗癌肺癌、抗胰腺癌。
有益效果：本发明偶联物在保留了紫杉醇抗肿瘤药物活性的同时，提高了化合物的水溶性，避免了添加对人体有害或有刺激性的助溶剂；增加了化合物的靶向性，提高了药物的吸收利用度，同时，降低了对正常细胞的损伤，降低副作用。
由靶向肽携带二硫基丙酸-紫杉醇-2'-酯透过细胞膜进入肿瘤细胞内部，在胞浆中富含的谷胱甘肽和二硫键异构酶的作用下，切断二硫基丙酸-紫杉醇-2'-酯的二硫基结构，使紫杉醇分子脱落而发挥治疗作用。由此可见，本发明所述的多肽-紫杉醇偶联物实现了药物的精准释放，解决了紫杉醇本身所存在的对正常组织和细胞毒副作用大等缺点，达到了提高治疗肿瘤效果的目的。本发明靶向肽肽序短，易于通过固相合成获得，成本低收率高，安全高效，可适用于大规模生产。
附图说明
图1为Mpa-S-S-Py质谱检测结果；
图2为巯基丙酸HPLC检测图谱；
图3为Mpa-S-S-Py反应液检测图谱；
图4为Mpa-S-S-Py HPLC检测图谱；
图5为紫杉醇HPLC检测图谱；
图6为PTX-Mpa-S-S-Py反应液HPLC检测图谱；
图7为PTX-Mpa-S-S-Mpa-Arg-Gly-Pro-Asp反应液HPLC检测结果；
图8为PTX-Mpa-S-S-Mpa-Arg-Gly-Pro-Asp质谱检测图；
图9为在PANC1和A549细胞系，JP-001-B4在高、中、低浓度下作用三天数据柱状图。
具体实施方式
在本发明中使用的缩写具有下面的含义：
CTC Resin：2-氯三苯甲基氯树脂
Fmoc：9-芴甲氧羰基
Arg：精氨酸
Asp：天冬氨酸
Pro：脯氨酸
Gly：甘氨酸
Mpa：巯基丙酸
Trt：三苯甲基
Pbf：2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰
tBu：叔丁基
DIC：N,N'-二异丙基碳二亚胺
HOBt：1-羟基苯并三唑
TBTU:O-苯并三氮唑-N,N,N',N'-四甲基脲鎓四氟硼酸盐
DIEA:N,N-二异丙基乙胺
TFA：三氟乙酸
EDT：1,2-乙二硫醇
DMF：N,N-二甲基甲酰胺。
实施例1.制备紫杉醇靶向肽偶联物
紫杉醇靶向肽偶联物的结构：(在本申请称JP-001-B4)。
靶向肽结构：
紫杉醇与靶向肽合成方法：
紫杉醇与靶向肽通过含有一对二硫键的连接臂连接，连接臂一端的巯基丙酸与紫杉醇2'羟基形成酯键得到改构紫杉醇化合物，连接臂另一端与靶向肽N端氨基形成酰胺键。
一、制备靶向肽
靶向肽制备路线：
1、靶向肽树脂合成
以替代度1.14mmol/g的2-CTC树脂为固相载体，取10g树脂加入10ml DMF溶胀1h，称氨基酸14.07g Fmoc-Asp(OtBu)-OH(3eq)加15ml DMF溶解，搅拌下加入11ml DIEA(6eq),将氨基酸混合液倒入反应柱中，室温条件反应4h。量取10ml甲醇(1ml/g树脂)直接倒入反应柱中，继续反应1h。反应结束，抽滤，加入15ml DMF洗涤6次、再加入10ml甲醇洗涤收缩三次，干燥后，得到Fmoc-Asp(OtBu)-CTC resin 13.5g，收率94.4％，替代度0.69mmol/g。
称取13g Fmoc-Asp(OtBu)-CTC resin，合成规模8.97mmol。加入适量15ml DMF溶胀1h，加入25％的哌啶/DMF(v/v)脱保护液15ml，反应5min后抽滤，再次加入脱保护液反应15min后抽滤。加入15ml DMF洗涤6次，取树脂用茚三酮检测为阳性。按照合成规模3倍投料，以HOBT/DIC为缩合剂，依次偶联氨基酸Fmoc-Pro-OH、Fmoc-Gly-OH、Fmoc-Arg(pbf)-OH、Mpa(Trt)得到全保护肽树脂，Mpa(Trt)-Arg(pbf)-Gly-Pro-Asp(OtBu)-CTC resin 40g。
2、制备靶向肽(Mpa-Arg-Gly-Pro-Asp)
配制切割液，1g肽树脂对应10ml切割液，配比为TFA/EDT/H2O(95/2.5/2.5)。取20gMpa(Trt)-Arg(pbf)-Gly-Pro-Asp(OtBu)-CTC resin加入200ml裂解液，室温反应2h后过滤，用适量三氟乙酸洗涤树脂，合并滤液。加入5倍体积的甲基叔丁醚中析出肽。过滤除去液体，滤饼用甲基叔丁基醚洗涤5次，甲基叔丁基醚每次用量约100ml。将洗涤后的滤饼干燥，得到粗肽Mpa-Arg-Gly-Pro-Asp 13g。通过制备型高效液相使用乙腈和0.1％的三氟乙酸水溶液纯化，冻干后得到Mpa-Arg-Gly-Pro-Asp。
二、制备紫杉醇交联接头
1、合成交联接头(Mpa-S-S-Py)
称取11.25g 2,2-二硫二吡啶，加入90ml乙醇溶解，并加入1.2ml冰乙酸；移取2.22ml(1.0eq，2.7g)巯基丙酸用60ml乙醇稀释后倒入恒压滴液漏斗中，在氮气保护下滴加，30min内滴加完毕，室温继续反应过夜。后处理过程：1、反应液真空浓缩,浓缩液用10ml二氯甲烷溶解，上样。层析柱填料为碱性Al2O3，并用二氯甲烷预处理，填料柱高度15cm，直径3cm。先用二氯甲烷/乙醇(4:1)柱层析，除去带颜色部分(杂质及未反应原料)，更换二氯甲烷：乙醇＝3:2(加入0.5％冰乙酸)至二氯甲烷：乙醇＝3:2(加入2％冰乙酸)，得到目标收集液后，真空浓缩。浓缩液用150ml二氯甲烷重新溶解，加入50ml纯化水，萃取3次，饱和食盐水洗涤，除去冰乙酸后真空浓缩得油状物。油状物放置于冰箱冷冻结晶，得到白色固体4.1g，收率74.9％。质谱检测，理论分子量215.29，实测分子量214.90，质谱确认正确。HPLC检测色谱条件如下：A相为0.01％TFA/水，B相为乙腈，0-60min B相3-63％线性梯度洗脱，RT27.4min。
结果如图1-图4所示。
2、紫杉醇与交联接头反应
称取200mg紫杉醇(PTX)，70mg DMAP，184mg SPDP-COOH，用20ml二氯甲烷溶解，不溶，加入186ul DIC，室温搅拌过夜。待TLC检测原料紫杉醇反应完，浓缩除去溶剂，制备液相纯化。检测色谱条件如下：A相为0.01％TFA/水，B相为乙腈，0-60min B相3-63％线性梯度洗脱，PTX：RT41.3min；PTX-Mpa-S-S-Py：RT48.7min。
结果如图5和图6。
紫杉醇与交联接头反应
三、紫杉醇交联接头与靶向肽偶联
称100mg PTX-Mpa-S-S-Py加5ml DMF溶解，加入200ul DIEA；另称取200mg Mpa-Arg-Gly-Pro-Asp加10ml DMF溶解，滴加至反应液中，室温反应4h。反应产物使用制备液相进行分离纯化。色谱条件如下：A相为0.01％TFA/水，B相为乙腈，0-60min B相3-63％线性梯度洗脱，收集含有产物纯品的流份，冻干得产物80mg，收率为47％。HPLC检测梯度：3-63(60min)，RT34.5min。质谱检测，理论分子量1471.60，实测分子量1471.10。
结果如图7和图8。
利用以下实验验证实验效果：
一、急性毒性试验
1.目的：确认PDC药物JP-001-B4与其毒性药物(紫杉醇)的毒性强弱。
2.实验原理：医学上通常以半数致死量(LD50)来衡量。通过对实验动物进行动物静脉或腹腔注射试验材料或其浸提液来观察实验动物体重在1周内的变化、运动、呼吸状态以及死亡情况作为评价的指标，判定供试材料的急性毒性作用。PTX(紫杉醇)最大给药剂量45mg/kg，将PDC药物换算成紫杉醇的给药剂量给药。按小鼠体重20mg计算给药量，详见下表1：
表1
| 样品名称 | 20mg小鼠给药量 |
| JP-001-B4 | 1.55mg |
| 紫杉醇(PTX) | 0.9mg |
3.实验对象：小鼠
4.实验器材和药品：蒸馏水，灭菌注射用水，注射器(1ml)，量筒(10ml)，小烧杯(50、100ml)PTX，JP-001-B4。
5.实验步骤
1.将称重后的健康、未做过其他实验的小鼠随机分为实验组和对照组，每组雌各3只。
2.将不同浓度的供试品溶液腹腔注射于实验组小鼠。
3.记录JP-001-B4药物注射后7天各组小鼠的体重，观察其各种生物学反应情况。
6.评价方法：
注射后动物反应观察指标如表2所示：
表2
7.实验结果：
供试品配制：
PTX：-mg，用生理盐水配制成3.3mg/ml。
JP-001-B4：(批号D20220217)mg，用生理盐水配制成3.7mg/ml。
实验结果如表3所示：
表3
结果证明：JP-001-B4毒性低于原型紫杉醇，且溶解性较紫杉醇好。
二、药效
药物用量、浓度及实验步骤
组别:
1.实验组：药物分别设置三个浓度，分别为高、中、低。
2.对照组：不加药物正常培养的细胞
本次试验所用细胞系：
A549:人非小细胞肺癌细胞
PANC-1:人胰腺癌细胞(胰头癌原发肿瘤)
3.实验步骤：
(1)在96孔板中接种细胞悬液(100μL/孔，5000细胞/孔)，将培养板放在培养箱中预培养(37℃，5％ CO2)；
(2)培养过夜后测定第0天OD值；
(3)将加药组的正常培养基弃掉，换有待测药物的培养基，将培养板放在培养箱中培养(37℃，5％ CO2)；
(4)根据时间依次测定第一天至第三天的OD值(每孔扣入10μL CCK8溶液)；
(5)将培养板在培养箱内孵育3小时；
(6)用酶标仪测定在450nm处的吸光度。
紫杉醇试验结果：
JP-001-B4实验结果如表4和图9所示：
表4实验结果(平均数汇总)
结果证明：JP-001-B4在高、中、低浓度下对人非小细胞肺癌细胞、人胰腺癌细胞均存在抑制作用。且抑制作用明显优于紫杉醇的效果。
对比例1.
JP-001-B5
结构：c[CDGRRGDC]-Mpa-S-S-Mpa-PTX
试验方法与JP-001-B4相同
试验结果：
结论：JP-001-B5与JP-001-B4癌细胞药效试验结果基本一致，未见明显优势，但B5的制备工艺较B4复杂很多，生产成本高。
Claims (2)
1.一种紫杉醇靶向肽偶联物，其特征在于，所述紫杉醇靶向肽偶联物的结构为：
2.权利要求1所述的紫杉醇靶向肽偶联物在制备抗胰腺癌药物中的应用。
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