WO2023104048A1 - 一种靶向脑瘤的多肽及其衍生物和应用 - Google Patents

一种靶向脑瘤的多肽及其衍生物和应用 Download PDF

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WO2023104048A1
WO2023104048A1 PCT/CN2022/137005 CN2022137005W WO2023104048A1 WO 2023104048 A1 WO2023104048 A1 WO 2023104048A1 CN 2022137005 W CN2022137005 W CN 2022137005W WO 2023104048 A1 WO2023104048 A1 WO 2023104048A1
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polypeptide
modification
brain
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赵华山
朱雯
张键
张鹏飞
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深圳先进技术研究院
中国科学院深圳理工大学(筹)
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • 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
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    • C07K14/575—Hormones

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  • the invention belongs to the field of medical biology, and relates to a polypeptide targeting brain tumors, derivatives and applications thereof.
  • the purpose of the present invention is to provide a brain tumor targeting polypeptide and its derivatives and applications.
  • One aspect of the present invention provides a use of a polypeptide in the preparation of drugs or detection reagents targeting brain tumors;
  • the polypeptide is selected from Metabolitin or Osteocalcin.
  • metabolin is selected from the polypeptides shown in SEQ ID NO.1 or SEQ ID NO.3,
  • osteocalcin is selected from the polypeptides shown in SEQ ID NO.2 or SEQ ID NO.4,
  • Another aspect of the present invention provides a derivative of a polypeptide targeting brain tumors.
  • the derivative is a product obtained by modifying the terminal or side chain of the above polypeptide or a product obtained by isotope labeling modification;
  • the modified product is selected from a product modified by a fluorescent group, or a product modified by phosphorylation, or a product modified by disulfide bond-based cyclization, or a product modified by biotin labeling, or a product modified by Products modified by photosensitizers, products modified by azide, products modified by PEG, products modified by methylation, products modified by fluorescent quenching groups, or products obtained by protein coupling Modified products, or products modified by small molecule compounds;
  • the polypeptide is selected from Metabolitin or Osteocalcin.
  • metabolin is selected from the polypeptides shown in SEQ ID NO.1 or SEQ ID NO.3,
  • osteocalcin is selected from the polypeptides shown in SEQ ID NO.2 or SEQ ID NO.4,
  • the modification of the terminal is selected from the group consisting of N-terminal acetylation modification and C-terminal amination modification of the polypeptide.
  • the modification of the side chain is selected from the modification on the R group of the amino acid side chain in the polypeptide.
  • the fluorescent dye used in the modification of the fluorescent group is selected from FITC, Rhodamine, Cy3, Cy5, Cy5.5, Cy7, ICG, and the modification can be used for fluorescence detection.
  • the phosphorylation modification is selected from one or a combination of p-Ser, p-Thr, p-Tyr.
  • the biotin is selected from D-biotin, biotin hydrazide, photosensitive biotin and biotin-dUTP.
  • the modification of the photosensitizer can be used to prepare photosensitizers.
  • azide modification can be used in secondary connection reactions.
  • the PEG modification can be used to prepare drug carriers.
  • the isotopes used in the isotopic labeling are selected from one or more combinations of 13 C, 14 C, 15 N, 2 H, 3 H, 18 O, 34 S, and 36 S.
  • Another aspect of the present invention provides the use of the derivatives of the above polypeptides in the preparation of drugs or detection reagents capable of crossing the blood-brain barrier and targeting brain tumors.
  • Another aspect of the present invention provides a brain tumor targeting carrier, the surface of which is modified with the above-mentioned polypeptide of the present invention.
  • the carrier is selected from liposomes and nanoparticles.
  • the carrier is loaded with active ingredients.
  • the blood-brain barrier-mediated polypeptide can be synthesized independently under general chemical laboratory conditions, or it can be synthesized industrially by a commercial reagent company.
  • the polypeptide is synthesized by a solid-phase method, and different amino acids on the resin are oriented to synthesize amino acid chains through condensation reactions. .
  • Derivatives of polypeptides are labeled with modifying groups after the amino acids are connected.
  • Another aspect of the present invention provides a brain tumor-targeting drug, which is a conjugate of the above-mentioned polypeptide or its derivative and an active ingredient.
  • the polypeptide and its derivatives can be combined with diagnostic and/or therapeutic carriers through organic chemical methods to exert their application value on the basis of mediating the function of crossing the blood-brain barrier.
  • polypeptide probe targeting brain tumors is the above-mentioned polypeptide or its derivatives, which is prepared by coupling with a fluorescent dye through an organic chemical reaction.
  • the fluorescent dye is a dye with a fluorescent group in the near-infrared region, preferably, the dye with a fluorescent group in the near-infrared region is selected from Cy5, Cy7, and ICG.
  • the brain tumor is selected from glioma, medulloblastoma, ependymoma, brain metastases, meningioma, sella tumor, acoustic neuroma, epidermoid cyst, dermoid cyst.
  • the brain tumor is in the cerebral cortex.
  • the mediating polypeptide provided by the present invention can independently cross the blood-brain barrier and target brain tumors.
  • the mediator polypeptide provided by the present invention can be used as a modified polypeptide to enhance the targeting and therapeutic properties of drugs or drug carriers for brain tumors.
  • the mediating polypeptide provided by the present invention is easy to synthesize and modify, and the cost is low, so it has broad application prospects.
  • the multiple derivatives and candidate polypeptides provided by the present invention provide a wide range of preparation strategies for diagnostic and therapeutic compounds or drugs for their practical applications.
  • the present invention is suitable for drug-mediated applications in the human brain, and is also suitable as a research tool for brain disease modeling experimental animals.
  • Fig. 1 is an effect diagram of brain tumor targeting in Example 3 of the present invention. The figure shows the distribution and results of the fluorescent signal in the brains of the four groups of mice in Example 3.
  • Embodiment 1 Preparation of polypeptide sequence
  • polypeptide sequence is as follows:
  • polypeptides are synthesized by conventional solid-phase synthesis or liquid-phase synthesis methods.
  • the solid-phase synthetic peptide method is used to react from the amino acid at the C-terminal to the N-terminal.
  • the amino acid linkage is completed one by one, and then precipitated and centrifuged with excess ether, and the crude peptide is purified by HPLC. Afterwards, mass spectrometry was performed, and freeze-dried in liquid nitrogen for further use.
  • SEQ ID NO.1 is a mouse metabolite
  • SEQ ID NO. ID NO.2 is mouse osteocalcin
  • SEQ ID NO.3 is human metabolin
  • SEQ ID NO.3 is human metabolite ID NO.4 is human osteocalcin.
  • Embodiment 2 the preparation of polypeptide probe
  • This embodiment provides a polypeptide probe, using the polypeptide prepared in Example 1, and combining it with ICG through an organic chemical reaction.
  • the probe is prepared by linking the polypeptide with ICG by click chemistry method, and the linker is the universal DBCO.
  • ICG with activating functional groups include amino NH 2 , carboxyl COOH, activated lipid NHS, maleimide MAL, mercapto SH, azide N 3 , alkyne ALK, and then prepared with Example 1 Peptide coupling to obtain cross-blood-brain barrier peptide ICG probes.
  • human U87 glioblastoma was transplanted into the cerebral cortex of the mouse through a brain locator, and after 3 days, the peptide ICG probe (including SEQ ID NO.1) prepared in Example 2 was injected into the tail vein, Scrambled peptide probe, ICG solution (2mM) and PBS were injected in 100 microliters per mouse, and detected under the small animal imager 24 hours later.
  • the mediator polypeptide provided by the present application can be used for the purpose of targeting brain tumors.

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Abstract

本发明公开了一种靶向脑瘤的多肽及其衍生物和应用，属于生物医药领域。具体公开了多肽在制备脑瘤靶向药物或检测试剂中的用途，所述多肽选自代谢素或骨钙素；还公开了其衍生物，所述的衍生物为多肽经过末端或侧链的修饰后所得到的产物。该类多肽分子可跨血脑屏障进入脑组织内，结合于脑瘤区域，为脑部肿瘤疾病的诊疗提供了一种特异的靶向投递手段。

Description

一种靶向脑瘤的多肽及其衍生物和应用 技术领域
本发明属于医学生物学领域，涉及一种靶向脑瘤的多肽及其衍生物和应用。
 背景技术
脑部肿瘤的诊断治疗中，由于血脑屏障存在，使得相应的药物，在全身给药的过程中，大大损耗，能够到达脑肿瘤部位的药物非常有限，影响了脑肿瘤疾病的诊断和治疗。因此，寻找能够介导药物靶向到达肿瘤病灶的工具分子就非常有价值了。然而，截至目前，既能跨过血脑屏障又能靶向肿瘤病灶的相关介导配体的选择还非常有限。相对于巨大了临床需求，这方面的研究进展还很缓慢，可用的候选配体也很欠缺。
 技术问题
脑部肿瘤的诊断治疗中，由于血脑屏障存在，使得相应的药物，在全身给药的过程中，大大损耗，能够到达脑肿瘤部位的药物非常有限，影响了脑肿瘤疾病的诊断和治疗。因此，寻找能够介导药物靶向到达肿瘤病灶的工具分子就非常有价值了。然而，截至目前，既能跨过血脑屏障又能靶向肿瘤病灶的相关介导配体的选择还非常有限。相对于巨大了临床需求，这方面的研究进展还很缓慢，可用的候选配体也很欠缺。
 技术解决方案
就上述背景技术中所提出的瓶颈问题，本发明的目的在于提供一种脑瘤靶向多肽及其衍生物和应用。
本发明一方面提供了一种多肽在制备靶向脑瘤的药物或检测试剂中的用途；
所述多肽选自代谢素（Metabolitin）或骨钙素（Osteocalcin）。
进一步地，代谢素选自如SEQ ID NO.1或SEQ ID NO.3所示的多肽，
YLGASVPSPDPLEPT                         SEQ ID No.1；
YLYQWLGAPVPYPDPLEPR              SEQ ID No.3。
进一步地，骨钙素选自如SEQ ID NO.2或SEQ ID NO.4所示的多肽，
YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4。
本发明另一方面提供了一种靶向脑瘤的多肽的衍生物，所述的衍生物为上述多肽经过末端或侧链的修饰后所得产物或经过同位素标记修饰得到的产物；
所述修饰所得产物选自经过荧光基团修饰得到的产物，或经过磷酸化修饰得到的产物，或基于二硫键的环化修饰得到的产物，或经过生物素标记修饰得到的产物，或经过光敏剂修饰得到的产物，或叠氮修饰得到的产物，或经过PEG修饰得到的产物，或经过甲基化修饰得到的产物，或经过荧光淬灭基团修饰得到的产物，或经过蛋白偶联修饰得到的产物，或经过小分子化合物修饰得到的产物；
所述多肽选自代谢素（Metabolitin）或骨钙素（Osteocalcin）。
进一步地，代谢素选自如SEQ ID NO.1或SEQ ID NO.3所示的多肽，
YLGASVPSPDPLEPT                         SEQ ID No.1；
YLYQWLGAPVPYPDPLEPR              SEQ ID No.3。
进一步地，骨钙素选自如SEQ ID NO.2或SEQ ID NO.4所示的多肽，
YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4。
进一步地，所述末端的修饰选自多肽N端乙酰化修饰和C端的胺化修饰。
进一步地，所述侧链的修饰选自多肽中氨基酸侧链R基上的修饰。
进一步地，所述荧光基团的修饰中所用的荧光染料选自FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7、ICG，该修饰可用于荧光检测。
进一步地，所述磷酸化修饰选自p-Ser、p-Thr、p-Tyr中的一种或多种的组合。
进一步地，所述生物素的标记，所述生物素选自D-生物素、生物素酰肼、光敏生物素和生物素-dUTP。
进一步地，所述光敏剂修饰，可用于制备光敏感制剂。
进一步地，所述叠氮修饰，可用于次级的连接反应。
进一步地，所述PEG修饰，可用于制备药物载体。
进一步地，所述同位素标记中所用的同位素选自 13C、 14C、 15N、 2H、 3H、 18O、 34S、 36S中的一种或多种的组合。
本发明另一个方面提供了上述多肽的衍生物在制备能够跨血脑屏障靶向脑瘤的药物或检测试剂中的用途。
本发明另一个方面提供了一种脑瘤靶向的载体，所述载体表面修饰有本发明上述多肽。
进一步地，所述载体选自脂质体、纳米粒。
进一步地，所述载体中负载活性成分。
所述的跨血脑屏障介导多肽可通过一般化学实验室条件自主合成，也可以由商业化试剂公司工业合成，采用固相法合成多肽，在树脂上不同氨基酸，经过缩合反应定向合成氨基酸链。多肽的衍生物，是在氨基酸完成连接后，再标记上修饰基团。
本发明再一方面提供了一种靶向脑瘤的药物，所述药物为上述多肽或其衍生物与活性成分的偶联物。所述的多肽及其衍生物可通过有机化学方法结合于诊断和/或治疗载体上发挥介导跨血脑屏障的功能基础上的应用价值。
本发明再一方面提供了一种靶向脑瘤的多肽探针，所述多肽探针为上述多肽或其衍生物，与荧光染料通过有机化学反应偶联制得。
进一步地，所述荧光染料选择具有近红外区荧光基团的染料，优选地，所述具有近红外区荧光基团的染料选自Cy5、Cy7、ICG。
在本发明中，所述的脑瘤选自胶质瘤、髓母细胞瘤、室管膜瘤、脑转移瘤、脑膜瘤、蝶鞍区肿瘤、听神经瘤、表皮样囊肿、皮样囊肿。
进一步地，所述的脑瘤在大脑皮层内。
 有益效果
本发明的有益效果：
（1）本发明提供的介导多肽，可以自主跨越血脑屏障，靶向脑瘤。
（2）本发明提供的介导多肽，可作为修饰多肽以增强药物或药物载体对脑瘤的靶向性和治疗性。
（3）本发明提供的介导多肽，其易于合成修饰，成本低廉，因此应用前景广泛。
（4）本发明提供的多元的衍生物备选多肽，为其实际应用提供了广泛的诊疗化合物或药物的制备策略。
（5）本发明提供的多肽分子由于序列的特异性，本发明适用于人类脑部药物介导的应用，也适用于作为脑疾病造模实验动物中的研究工具。
 附图说明
图1为本发明实施例3中靶向脑瘤效果图。图中显示实施例3中4组小鼠脑部荧光信号分布和结果。
 本发明的实施方式
为了更好地理解本发明的内容，下面结合具体实施案例，对本发明内容作进一步说明，但本发明的保护内容不局限以下实施例。
实施例1：多肽序列的制备
采用人工合成的方法合成跨血脑屏障多肽序列，
所述多肽序列如下所述：
YLGASVPSPDPLEPT                         SEQ ID No.1；
YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
YLYQWLGAPVPYPDPLEPR              SEQ ID No.3；
YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4。
采用常规的固相合成或液相合成的方法合成上述多肽。其中利用固相合成多肽法为从C端的氨基酸向N端反应，经过树脂活化、氨基酸链接、洗脱保护、检测等步骤，逐个完成氨基酸链接，然后用过量乙醚沉淀离心，对粗肽经过HPLC纯化后，质谱分析，在液氮中速冷冻干备用。
其中SEQ ID NO.1为鼠源代谢素，SEQ ID NO.2为鼠源骨钙素，SEQ ID NO.3为人源代谢素，SEQ ID NO.4为人源骨钙素。
实施例2：多肽探针的制备
本实施例提供一种多肽探针，采用实施例1制备的多肽，将其与ICG通过有机化学反应结合。
具体方法为购买或合成，本实施例中，通过点击化学方法将多肽与ICG连接完成探针制备，其中的连接子为通用的DBCO。具有活化功能基团的ICG，活化功能基团包含氨基NH 2、羧基COOH、活化脂NHS、马来酰亚胺MAL、巯基SH、叠氮N 3、炔烃ALK，然后与实施例1制备的多肽偶联，获得跨血脑屏障多肽ICG探针。
实施例3：脑瘤小鼠造模及靶向能力检测
使用成年小鼠，通过脑定位仪，将人U87胶质细胞瘤，移植于小鼠大脑皮层部位，3天后，尾静脉注射实施例2制备的多肽ICG探针（含SEQ ID NO.1）、乱序多肽探针，ICG溶液（2mM）以及PBS，每只小鼠注射100微升，24小时后，在小动物成像仪下检测。
实验结果见图1，通过对比4组结果可知，在脑瘤部位多肽探针组（A组）有特异信号，而其他三组（S组：乱序多肽探针；N组：ICG溶液组；PBS组）均未显示在脑部有荧光信号。以上实验结果可知，本发明的多肽探针能够实现跨血脑屏障靶向脑瘤的作用。
综上，本申请提供的介导多肽可用于脑瘤靶向的目的。
以上所述仅为本发明的具体实施方式，不是全部的实施方式，本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换，均为本发明的权利要求所涵盖。

Claims (10)

  1. 一种多肽在制备靶向脑瘤的药物或检测试剂中的用途；其特征在于，
    所述多肽选自代谢素（Metabolitin）或骨钙素（Osteocalcin）；
    优选地，代谢素选自如SEQ ID NO.1或SEQ ID NO.3所示的多肽，
    YLGASVPSPDPLEPT                         SEQ ID No.1；
    YLYQWLGAPVPYPDPLEPR              SEQ ID No.3；
    优选地，骨钙素选自如SEQ ID NO.2或SEQ ID NO.4所示的多肽，
    YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
    YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4。
  2. 根据权利要求1所述的用途，其特征在于，
    所述的脑瘤选自胶质瘤、髓母细胞瘤、室管膜瘤、脑转移瘤、脑膜瘤、蝶鞍区肿瘤、听神经瘤、表皮样囊肿、皮样囊肿；
    优选地，所述的脑瘤在大脑皮层内。
  3. 一种自主跨越血脑屏障且靶向脑瘤的多肽衍生物，其特征在于，
    所述的多肽衍生物为多肽经过末端或侧链的修饰后所得产物或经过同位素标记修饰得到的产物；
    所述修饰所得产物选自经过荧光基团修饰得到的产物，或经过磷酸化修饰得到的产物，或基于二硫键的环化修饰得到的产物，或经过生物素标记修饰得到的产物，或经过光敏剂修饰得到的产物，或叠氮修饰得到的产物，或经过PEG修饰得到的产物，或经过甲基化修饰得到的产物，或经过荧光淬灭基团修饰得到的产物，或经过蛋白偶联修饰得到的产物，或经过小分子化合物修饰得到的产物；
    所述多肽选自代谢素（Metabolitin）或骨钙素（Osteocalcin）；
    优选地，代谢素选自如SEQ ID NO.1或SEQ ID NO.3所示的多肽，
    YLGASVPSPDPLEPT                         SEQ ID No.1；
    YLYQWLGAPVPYPDPLEPR              SEQ ID No.3；
    优选地，骨钙素选自如SEQ ID NO.2或SEQ ID NO.4所示的多肽，
    YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
    YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4。
  4. 根据权利要求3所述的自主跨越血脑屏障且靶向脑瘤的多肽衍生物，其特征在于，所述末端的修饰选自多肽N端乙酰化修饰和C端的胺化修饰；
    所述侧链的修饰选自多肽中氨基酸侧链R基上的修饰；
    所述荧光基团的修饰中所用的荧光染料选自FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7、ICG，该修饰可用于荧光检测；
    所述磷酸化修饰选自p-Ser、p-Thr、p-Tyr中的一种或多种的组合；
    所述生物素的标记，所述生物素选自D-生物素、生物素酰肼、光敏生物素和生物素-dUTP；
    所述光敏剂修饰，可用于制备光敏感制剂；
    所述叠氮修饰，可用于次级的连接反应；
    所述PEG修饰，可用于制备药物载体；
    所述同位素标记中所用的同位素选自 13C、 14C、 15N、 2H、 3H、 18O、 34S、 36S中的一种或多种的组合。
  5. 权利要求3或4所述的多肽衍生物在制备能够跨血脑屏障靶向脑瘤的药物或检测试剂中的用途。
  6. 根据权利要求5所述的所述的用途，所述脑瘤选自胶质瘤、髓母细胞瘤、室管膜瘤、脑转移瘤、脑膜瘤、蝶鞍区肿瘤、听神经瘤、表皮样囊肿、皮样囊肿；
    优选地，所述的脑瘤在大脑皮层内。
  7. 一种脑瘤靶向的载体，所述载体表面修饰有多肽；其特征在于，所述多肽选自代谢素（Metabolitin）或骨钙素（Osteocalcin）；
    优选地，代谢素选自如SEQ ID NO.1或SEQ ID NO.3所示的多肽，
    YLGASVPSPDPLEPT                         SEQ ID No.1；
    YLYQWLGAPVPYPDPLEPR              SEQ ID No.3；
    优选地，骨钙素选自如SEQ ID NO.2或SEQ ID NO.4所示的多肽，
    YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
    YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4。
  8. 根据权利要求7所述的载体，其特征在于，所述载体选自脂质体、纳米粒；
    优选地，所述载体中负载活性成分。
  9. 一种靶向脑瘤的多肽探针，其特征在于，所述多肽探针为多肽或其衍生物，与荧光染料通过有机化学反应偶联制得；
    所述多肽选自代谢素（Metabolitin）或骨钙素（Osteocalcin）；代谢素选自如SEQ ID NO.1或SEQ ID NO.3所示的多肽，
    YLGASVPSPDPLEPT                         SEQ ID No.1；
    YLYQWLGAPVPYPDPLEPR              SEQ ID No.3；
    骨钙素选自如SEQ ID NO.2或SEQ ID NO.4所示的多肽，
    YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
    YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4；
    优选地，所述荧光染料选择具有近红外区荧光基团的染料，更优选地，所述具有近红外区荧光基团的染料选自Cy5、Cy7、ICG。
  10. 一种靶向脑瘤的药物，所述药物为上述多肽或其衍生物与活性成分的偶联物；
    所述多肽选自代谢素（Metabolitin）或骨钙素（Osteocalcin）；代谢素选自如SEQ ID NO.1或SEQ ID NO.3所示的多肽，
    YLGASVPSPDPLEPT                         SEQ ID No.1；
    YLYQWLGAPVPYPDPLEPR              SEQ ID No.3；
    骨钙素选自如SEQ ID NO.2或SEQ ID NO.4所示的多肽，
    YLGASVPSPDPLEPTREQCELNPACDELSDQYGLKTAYKRIYGITI                  SEQ ID No.2；
    YLYQWLGAPVPYPDPLEPREVCELNPDCDELADHIGFQEAYRRFYGPV SEQ ID No.4；
    所述活性成分为抗肿瘤成分。
PCT/CN2022/137005 2021-12-07 2022-12-06 一种靶向脑瘤的多肽及其衍生物和应用 WO2023104048A1 (zh)

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