WO2022016751A1 - 一种子宫内膜异位症分子诊疗制剂及其制备方法和应用 - Google Patents

一种子宫内膜异位症分子诊疗制剂及其制备方法和应用 Download PDF

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WO2022016751A1
WO2022016751A1 PCT/CN2020/129877 CN2020129877W WO2022016751A1 WO 2022016751 A1 WO2022016751 A1 WO 2022016751A1 CN 2020129877 W CN2020129877 W CN 2020129877W WO 2022016751 A1 WO2022016751 A1 WO 2022016751A1
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polypeptide
endometriosis
product obtained
modification
molecular diagnosis
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赵华山
张键
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Shenzhen Institute of Advanced Technology of CAS
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Definitions

  • the invention belongs to the field of medical cell biology, and relates to a molecular diagnosis and treatment preparation for endometriosis and a preparation method and application thereof.
  • Endometriosis is a common clinical gynecological intractable disease in which active endometrial tissue grows ectopic in a non-uterine environment.
  • pathogenesis of the disease is still unclear, there is still a lack of efficient and direct tools for the diagnosis and treatment of the disease.
  • Early detection is undoubtedly a prerequisite for the intervention and treatment of the disease.
  • the purpose of the present invention is to provide a molecular diagnosis and treatment preparation for endometriosis and its preparation method and application.
  • One aspect of the present invention provides a molecular diagnosis and treatment preparation for endometriosis, comprising: 1) an effector component, that is, a diagnostic compound and/or a drug for treating endometriosis; 2) a targeting component, that is, a target component To recognize the ability of the polypeptide;
  • the polypeptide includes one or more of the following sequences in combination, or a derivative of one or more of the following sequences in combination,
  • the polypeptide can be modified on a diagnostic and/or therapeutic carrier to achieve its specific recognition of the lesion tissue, thereby obtaining a disease intervention tool that can be used for diagnosis and treatment.
  • the derivative is the product obtained by the modification of the terminal or side chain of the polypeptide, or the product obtained by the labeling modification of the polypeptide by the fluorescent group, or the product obtained by the isotopic labeling of the polypeptide, or the polypeptide obtained by phosphorylation modification.
  • the modification of the terminal or side chain of the polypeptide includes but is not limited to N-terminal acetylation modification and C-terminal amination modification.
  • isotope used in isotopic labeling of the polypeptide includes, but is not limited to, 13C , and the modification is used for tracking purposes.
  • the phosphorylation modification of the polypeptide includes but is not limited to p-Ser, p-Thr, and p-Tyr.
  • polypeptide is labeled with biotin for the purpose of localization and detection, and the like.
  • polypeptide is modified with a photosensitizer to facilitate the preparation of a photosensitizer.
  • polypeptide is modified with azide, which is beneficial to the secondary ligation reaction.
  • polypeptide is modified with PEG for preparation of a drug carrier.
  • polypeptides can be synthesized independently by general organic chemistry laboratory conditions, or industrially synthesized by conventional commercial reagent companies, that is, the use of solid-phase method to synthesize polypeptides, and the condensation reaction between different amino acids on the resin to realize the synthesis of directional amino acid chains. .
  • the desired modification group is applied after the amino acid is linked.
  • the diagnostic compound includes a near-infrared region dye.
  • the near-infrared region dyes include but are not limited to Cy5, Cy7, and indocyanine green.
  • the near-infrared region dye is indocyanine green.
  • the drugs for treating endometriosis include therapeutic antibodies and existing therapeutic drugs for endometriosis.
  • the therapeutic drug for endometriosis is a drug with small molecular weight, suitable water solubility, and high biological safety and stability.
  • the therapeutic drug for endometriosis includes one or a combination of at least two of progestins, androgens, and gonadotropin-releasing hormone agonists;
  • the progestin drugs include puvera, progesterone, nemethon, and progesterone caproate;
  • the androgen drugs include danazol
  • the gonadotropin-releasing hormone agonist comprises goserelin.
  • Another aspect of the present invention provides a method for preparing a molecular diagnosis and treatment preparation for endometriosis.
  • the effector component and the targeting component are connected and assembled by conventional methods to obtain a molecular diagnosis and treatment preparation for endometriosis; the The molar ratio of the effector component and the targeting component is 1:0 ⁇ 1:1, excluding 1:0, preferably 1:0.5 ⁇ 1:1.
  • a kind of preparation method of endometriosis molecular diagnosis and treatment preparation comprises the following steps:
  • connection and assembly are carried out by conventional methods (such as EDC method, etc.), and the molar ratio of effector components and targeting components is 1:0 ⁇ 1:1 (excluding 1:0), preferably 1:0.5 ⁇ 1:1.
  • the effector component is also a polypeptide substance, a conventional polypeptide synthesis method can be used, and a suitable polypeptide linker structure is used between the two components to directly synthesize a complete diagnostic preparation. It is generally stored at 4°C for future use or ready-to-use.
  • the molecular diagnosis and treatment preparation for endometriosis provided by the present invention can be used for the diagnosis of endometriosis.
  • FIG. 1 is an effect diagram of in vivo imaging of indocyanine green in an embodiment of the present invention.
  • the present invention uses SEQ The polypeptide sequence described in ID No. 1 is exemplified.
  • Example 1 SEQ Preparation of the polypeptide sequence described in ID No. 1
  • the effector component was selected from indocyanine green dye, which was purchased from a commercial chemical reagent company, and was modified with a DBCO linker, so as to facilitate subsequent connection with the polypeptide sequence.
  • the polypeptide sequence prepared in Example 1 was selected. Mix the effector component and the targeting component at a molar ratio of 1:0.5, and store them at 4 °C after thorough mixing.
  • mice Male female mice were taken, sterilized and anesthetized, anteroposterior endometrial tissue was taken, cut into small pieces (2 mm ⁇ 2 mm), fixed and inoculated near the mesenteric blood vessels, and the wounds were sutured, and the mice rested and had free access to food and water for one month. After the vesicles grow, the modeling can be considered successful.
  • the diagnosis and treatment preparation prepared in Example 2 was injected into the tail vein of the successful model mice, and 24 hours later, the mice were subjected to respiratory anesthesia, and then placed in a small animal imager, and the fluorescence was observed in vivo under respiratory anesthesia.
  • the excitation wavelength of the fluorescence signal is between 600-900 nanometers.
  • the molecular diagnosis and treatment preparation for endometriosis provided by the present application can be used for the purpose of diagnosis and treatment of endometriosis.

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Abstract

提供了一种子宫内膜异位症分子诊疗制剂及其制备方法和应用。制剂包括：1)效应组件，即诊断化合物和/或治疗子宫内膜异位症的药物；2)靶向组件，即具有靶向识别能力的多肽；所述多肽包括以下序列中的一条或多条组合的多肽，或以下序列中的一条或多条组合的多肽的衍生物，SEQ ID No.1，SEQ ID No.2，SEQ ID No.3，SEQ ID No.4，SEQ ID No.5，SEQ ID No.6。适用于人类子宫内膜异位症疾病的诊断和/或治疗，也可作为子宫内膜异位症造模实验动物的研究工具。

Description

一种子宫内膜异位症分子诊疗制剂及其制备方法和应用 技术领域
本发明属于医学细胞生物学领域，涉及一种子宫内膜异位症分子诊疗制剂及其制备方法和应用。
 背景技术
子宫内膜异位症是临床上常见的一种有活性子宫内膜组织在非子宫环境中异位生长的妇科疑难杂症。截止目前，由于该疾病的发病机制尚不明晰，因此，对该疾病的诊断治疗还缺乏高效直接的工具手段，早期发现无疑是该病干预治疗的先决条件，利用具有靶向识别能力的多肽等，将具有诊断价值和治疗价值的试剂或药物，以最简单的方式运送到子宫内膜异位病灶处，是一种很有价值的诊断干预治疗思路。
 技术问题
为了解决上述背景技术中所提出的问题，本发明的目的在于提供一种子宫内膜异位症分子诊疗制剂及其制备方法和应用。
 技术解决方案
本发明一方面提供了一种子宫内膜异位症分子诊疗制剂，包括：1）效应组件，即诊断化合物和/或治疗子宫内膜异位症的药物；2）靶向组件，即具有靶向识别能力的多肽；
所述多肽包括以下序列中的一条或多条组合的多肽，或以下序列中的一条或多条组合的多肽的衍生物，
EDVKDINFDTKEKFLAGCLIVSFHEGKCSEQ ID No.1
GKKTQELKNIRTNSELLKEWIIAAFHEGKCSEQ ID No.2
LKPSHEKKNDDNGKKLCKACSEQ ID No.3
EDVKDINFDTKEKFLAGCLIVSFHEGKSEQ ID No.4
GKKTQELKNIRTNSELLKEWIIAAFHEGKSEQ ID No.5
LKPSHEKKNDDNGKKLCKA SEQ ID No.6。
所述的多肽通过修饰于诊断和/或治疗载体上实现其对病灶组织的特异识别，从而得到可用于诊疗的疾病干预工具。
进一步地，所述的衍生物为多肽进行末端或侧链的修饰得到的产物，或多肽进行荧光基团的标记修饰得到的产物，或多肽进行同位素标记得到的产物，或多肽进行磷酸化修饰得到的产物，或多肽进行基于二硫键的环化修饰得到的产物，或多肽进行生物素的标记得到的产物，或多肽进行光敏剂修饰得到的产物，或多肽进行叠氮修饰得到的产物，或多肽进行PEG修饰得到的产物，或多肽进行甲基化修饰得到的产物，或多肽进行荧光淬灭基团修饰得到的产物，或多肽进行蛋白偶联修饰得到的产物，或多肽进行小分子化合物修饰得到的产物。
进一步地，所述多肽进行末端或侧链的修饰包括但不限于N端乙酰化修饰，C端的胺化修饰。
进一步地，所述多肽进行荧光基团的标记修饰中所用的荧光染料包括但不限于FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7，该修饰以便用于荧光检测目的。
进一步地，所述多肽进行同位素标记中所用的同位素包括但不限于 13C，该修饰用于追踪目的。
进一步地，所述多肽进行的磷酸化修饰包括但不限于p-Ser、p-Thr、p-Tyr。
进一步地，所述多肽进行生物素的标记，用于定位检测目的等。
进一步地，所述多肽进行光敏剂修饰，以便于制备光敏感制剂。
进一步地，所述多肽进行叠氮修饰，有利于次级的连接反应。
进一步地，所述多肽进行PEG修饰，用于药物载体制备。
所述的多肽可通过一般有机化学实验室条件自主合成，也可以通过常规的商业化试剂公司工业合成，即利用固相法合成多肽，在树脂上不同氨基酸之间缩合反应实现定向氨基酸链的合成。多肽的衍生物则在氨基酸完成连接后，施加所需的修饰基团。
进一步地，所述诊断化合物包括近红外区染料。
进一步地，所述近红外区染料包括但不限于Cy5，Cy7，吲哚菁绿。
进一步地，所述近红外区染料为吲哚菁绿。
进一步地，所述治疗子宫内膜异位症的药物包括治疗性抗体、目前已有的针对子宫内膜异位症的治疗药物。
进一步地，所述针对子宫内膜异位症的治疗药物为小分子量，具有适宜的水溶性，且生物安全性和稳定性高的药物。
进一步地，所述针对子宫内膜异位症的治疗药物包括孕激素类药物、雄激素类药物、促性腺激素释放激素激动剂中的一种或至少两种的组合；
优选地，所述孕激素类药物包括普维拉、黄体酮、内美通、己酸孕酮；
优选地，所述雄激素类药物包括丹那唑；
优选地，所述促性腺激素释放激素激动剂包括戈舍瑞林。
本发明另一方面提供了一种子宫内膜异位症分子诊疗制剂的制备方法，将效应组件和靶向组件通过常规方法进行连接装配，即得到子宫内膜异位症分子诊疗制剂；所述效应组件和靶向组件的摩尔比为1：0~1：1，不包括1：0，优选为1：0.5~1：1。
进一步地，一种子宫内膜异位症分子诊疗制剂的制备方法，包括以下步骤：
a) 效应组件准备：准备诊断化合物和/或治疗子宫内膜异位症的药物；
b) 靶向组件准备：常规方法制备多肽，或修饰的多肽衍生物；
c) 效应组件和靶向组件连接：通过常规方法进行连接装配（如EDC法等），效应组件和靶向组件的摩尔比为1：0~1：1（不包括1：0），优选为1：0.5~1：1。如果效应组件也为多肽类物质，可用常规多肽合成方法，两组件之间用适宜的多肽连接子结构，直接合成完整的诊疗制剂。一般置于4℃保存备用或现用现配。
上述任一所述的子宫内膜异位症分子诊疗制剂在制备诊断和/或治疗子宫内膜异位症的药物中的应用。
 有益效果
（1）本发明提供的子宫内膜异位症分子诊疗制剂，可用于子宫内膜异位症的诊断。
（2）本发明提供的子宫内膜异位症分子诊疗制剂，可用于子宫内膜异位症的治疗。
（3）本发明提供的子宫内膜异位症分子诊疗制剂，由于其整体的大小维持在小分子化合物水平，因此其合成具有过程简单及成本低廉的特点，有利于其商品化的应用。
（4）通过将具有诊断或治疗作用的化合物或药物，加以特异的识别异位子宫内膜组织的靶向分子，实现对特异识别病灶组织的靶向给予具有诊断价值或治疗价值的化合物或药物。由于该子宫内膜异位症分子诊疗制剂为修饰的小分子化合物，因此稳定性高且有利于体内转运。本发明适用于人类子宫内膜异位症疾病的诊断治疗，也可作为子宫内膜异位症造模实验动物的研究工具。
 附图说明
图1为本发明实施例中吲哚菁绿的活体成像效果图。
 本发明的实施方式
为了更好地理解本发明的内容，下面结合具体实施方法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。
本发明以SEQ ID No.1所述多肽序列为例。
实施例1：SEQ ID No.1所述多肽序列的制备
所述多肽序列由专门的多肽制备公司工业合成。
基于树脂的固相法合成，从C端向N端通过氨基酸之间的缩合反应合成多肽分子，并施以叠氮乙酸修饰。
实施例2：子宫内膜异位症分子诊疗制剂的制备
效应组件选取吲哚菁绿染料，购自商业化化学试剂公司，选择由DBCO连接子修饰的，以便于接下来与多肽序列连接。靶向组件部分，选取实施例1制备得到的多肽序列。将效应组件和靶向组件按1：0.5摩尔比混合，充分混匀后，置于4 ℃保存。
实施例3：子宫内膜异位症小鼠动物模型制备
取成年雌性小鼠，消毒麻醉后，取正位子宫内膜组织，切小块（2毫米X2毫米），固定接种于肠系膜血管附近，缝合伤口后，小鼠静养，自由采食饮水，一个月后有囊泡生长即可认为造模成功。
实施例4：小动物成像仪下荧光信号检测
对造模成功的小鼠尾静脉注射实施例2中所制备的诊疗制剂，24小时后，对小鼠进行呼吸麻醉，然后，置于小动物成像仪内，并保持呼吸麻醉状态下活体观察荧光信号，荧光的激发波长为600-900纳米之间。
基于靶向组件的特异性识别异位子宫内膜组织的特性，以及吲哚菁绿的长波长成像特性（如图1所示），可使此制剂能够应用于子宫内膜异位症病灶的成像诊断，从而实现早期诊断目的。
综上，本申请提供的子宫内膜异位症分子诊疗制剂可用于子宫内膜异位症的诊疗目的。
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. 一种子宫内膜异位症分子诊疗制剂，其特征在于，包括：1）效应组件，即诊断化合物和/或治疗子宫内膜异位症的药物；2）靶向组件，即具有靶向识别能力的多肽；
    所述多肽包括以下序列中的一条或多条组合的多肽，或以下序列中的一条或多条组合的多肽的衍生物，
    EDVKDINFDTKEKFLAGCLIVSFHEGKCSEQ ID No.1
    GKKTQELKNIRTNSELLKEWIIAAFHEGKCSEQ ID No.2
    LKPSHEKKNDDNGKKLCKACSEQ ID No.3
    EDVKDINFDTKEKFLAGCLIVSFHEGKSEQ ID No.4
    GKKTQELKNIRTNSELLKEWIIAAFHEGKSEQ ID No.5
    LKPSHEKKNDDNGKKLCKA SEQ ID No.6。
  2. 根据权利要求1所述的子宫内膜异位症分子诊疗制剂，其特征在于，所述的衍生物为多肽进行末端或侧链的修饰得到的产物，或多肽进行荧光基团的标记修饰得到的产物，或多肽进行同位素标记得到的产物，或多肽进行磷酸化修饰得到的产物，或多肽进行基于二硫键的环化修饰得到的产物，或多肽进行生物素的标记得到的产物，或多肽进行光敏剂修饰得到的产物，或多肽进行叠氮修饰得到的产物，或多肽进行PEG修饰得到的产物，或多肽进行甲基化修饰得到的产物，或多肽进行荧光淬灭基团修饰得到的产物，或多肽进行蛋白偶联修饰得到的产物，或多肽进行小分子化合物修饰得到的产物；
    优选地，所述多肽进行末端或侧链的修饰包括N端乙酰化修饰，C端的胺化修饰；
    优选地，所述多肽进行荧光基团的标记修饰中所用的荧光染料包括FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7；
    优选地，所述多肽进行同位素标记中所用的同位素包括 13C；
    优选地，所述多肽进行的磷酸化修饰包括p-Ser、p-Thr、p-Tyr。
  3. 根据权利要求1所述的子宫内膜异位症分子诊疗制剂，其特征在于，所述诊断化合物包括近红外区染料。
  4. 根据权利要求3所述的子宫内膜异位症分子诊疗制剂，其特征在于，所述近红外区染料包括Cy5，Cy7，吲哚菁绿。
  5. 根据权利要求4所述的子宫内膜异位症分子诊疗制剂，其特征在于，所述近红外区染料为吲哚菁绿。
  6. 根据权利要求1所述的子宫内膜异位症分子诊疗制剂，其特征在于，所述治疗子宫内膜异位症的药物包括治疗性抗体、目前已有的针对子宫内膜异位症的治疗药物。
  7. 根据权利要求6所述的子宫内膜异位症分子诊疗制剂，其特征在于，所述针对子宫内膜异位症的治疗药物为小分子量，具有适宜的水溶性，且生物安全性和稳定性高的药物。
  8. 根据权利要求7所述的子宫内膜异位症分子诊疗制剂，其特征在于，所述针对子宫内膜异位症的治疗药物包括孕激素类药物、雄激素类药物、促性腺激素释放激素激动剂中的一种或至少两种的组合；
    优选地，所述孕激素类药物包括普维拉、黄体酮、内美通、己酸孕酮；
    优选地，所述雄激素类药物包括丹那唑；
    优选地，所述促性腺激素释放激素激动剂包括戈舍瑞林。
  9. 一种子宫内膜异位症分子诊疗制剂的制备方法，其特征在于，将效应组件和靶向组件通过常规方法进行连接装配，即得到子宫内膜异位症分子诊疗制剂；所述效应组件和靶向组件的摩尔比为1：0~1：1，不包括1：0，优选为1：0.5~1：1。
  10. 权利要求1-8任一项所述的子宫内膜异位症分子诊疗制剂在制备诊断和/或治疗子宫内膜异位症的药物中的应用。
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