WO2022016751A1 - Molecular diagnosis and treatment formulation for endometriosis, preparation method therefor and use thereof - Google Patents
Molecular diagnosis and treatment formulation for endometriosis, preparation method therefor and use thereof Download PDFInfo
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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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- Prior art keywords
- polypeptide
- endometriosis
- product obtained
- modification
- molecular diagnosis
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- 201000009273 Endometriosis Diseases 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 238000011282 treatment Methods 0.000 title claims abstract description 37
- 238000003745 diagnosis Methods 0.000 title claims abstract description 34
- 239000000203 mixture Substances 0.000 title abstract description 6
- 238000009472 formulation Methods 0.000 title abstract description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 63
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 62
- 229920001184 polypeptide Polymers 0.000 claims abstract description 61
- 239000003814 drug Substances 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 230000008685 targeting Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 230000004048 modification Effects 0.000 claims description 29
- 238000012986 modification Methods 0.000 claims description 29
- 239000012636 effector Substances 0.000 claims description 12
- 238000002372 labelling Methods 0.000 claims description 8
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 7
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 claims description 7
- 229960004657 indocyanine green Drugs 0.000 claims description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 6
- 239000000975 dye Substances 0.000 claims description 6
- -1 small molecule compound Chemical class 0.000 claims description 5
- 229940126585 therapeutic drug Drugs 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 claims description 4
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 claims description 4
- 239000003098 androgen Substances 0.000 claims description 4
- 238000007796 conventional method Methods 0.000 claims description 4
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims description 4
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 claims description 4
- 230000026731 phosphorylation Effects 0.000 claims description 4
- 238000006366 phosphorylation reaction Methods 0.000 claims description 4
- 239000003504 photosensitizing agent Substances 0.000 claims description 4
- 239000000583 progesterone congener Substances 0.000 claims description 4
- 239000000556 agonist Substances 0.000 claims description 3
- 150000001540 azides Chemical class 0.000 claims description 3
- 229960002685 biotin Drugs 0.000 claims description 3
- 235000020958 biotin Nutrition 0.000 claims description 3
- 239000011616 biotin Substances 0.000 claims description 3
- 210000004899 c-terminal region Anatomy 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 2
- 108010069236 Goserelin Proteins 0.000 claims description 2
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 claims description 2
- 229960000766 danazol Drugs 0.000 claims description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007850 fluorescent dye Substances 0.000 claims description 2
- 229960002913 goserelin Drugs 0.000 claims description 2
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 claims description 2
- USRGIUJOYOXOQJ-GBXIJSLDSA-N phosphothreonine Chemical compound OP(=O)(O)O[C@H](C)[C@H](N)C(O)=O USRGIUJOYOXOQJ-GBXIJSLDSA-N 0.000 claims description 2
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000186 progesterone Substances 0.000 claims description 2
- 229960003387 progesterone Drugs 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000001948 isotopic labelling Methods 0.000 claims 1
- 230000000638 stimulation Effects 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 238000010171 animal model Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000002357 endometrial effect Effects 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
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- 238000001514 detection method Methods 0.000 description 3
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- 238000001727 in vivo Methods 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PPXUUPXQWDQNGO-UHFFFAOYSA-N 2-azidoacetic acid Chemical group OC(=O)CN=[N+]=[N-] PPXUUPXQWDQNGO-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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Classifications
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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.
Abstract
Provided are a molecular diagnosis and treatment formulation, a preparation method therefor and use thereof. The formulation comprises: (1) an effect component, i.e. a diagnostic compound and/or a drug for treating endometriosis; and (2) a targeting component, i.e. a polypeptide having targeting recognition capability. The polypeptide comprises a polypeptide which is one or a combination of more of the following sequences or a derivative of the polypeptide which is one or a combination of more of the following sequences: SEQ ID No.1, SEQ ID No.2, SEQ ID No.3, SEQ ID No.4, SEQ ID No.5 and SEQ ID No.6. Said formulation is suitable for the diagnosis and/or treatment of endometriosis diseases in human, and can also be used as a research tool for an experimental animal for endometriosis.
Description
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。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.
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。Endometriosis is a common clinical gynecological intractable disease in which active endometrial tissue grows ectopic in a non-uterine environment. Up to now, since the 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. , it is a valuable diagnostic intervention and treatment idea to transport reagents or drugs with diagnostic value and therapeutic value to the endometriosis lesions in the simplest way.
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。In order to solve the problems raised in the above background technology, the purpose of the present invention is to provide a molecular diagnosis and treatment preparation for endometriosis and its preparation method and application.
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；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;
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，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,
EDVKDINFDTKEKFLAGCLIVSFHEGKCSEQ ID No.1EDVKDINFDTKEKFLAGCLIVSFHEGKCSEQ ID No.1
GKKTQELKNIRTNSELLKEWIIAAFHEGKCSEQ ID No.2GKKTQELKNIRTNSELLKEWIIAAFHEGKCSEQ ID No.2
LKPSHEKKNDDNGKKLCKACSEQ ID No.3LKPSHEKKNDDNGKKLCKACSEQ ID No.3
EDVKDINFDTKEKFLAGCLIVSFHEGKSEQ ID No.4EDVKDINFDTKEKFLAGCLIVSFHEGKSEQ ID No.4
GKKTQELKNIRTNSELLKEWIIAAFHEGKSEQ ID No.5GKKTQELKNIRTNSELLKEWIIAAFHEGKSEQ ID No.5
LKPSHEKKNDDNGKKLCKA
SEQ ID No.6。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。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.
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。Further, 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 product of the peptide, or the product obtained by cyclization modification of the polypeptide based on disulfide bonds, or the product obtained by the labeling of the polypeptide with biotin, or the product obtained by the modification of the polypeptide by a photosensitizer, or the product obtained by the azide modification of the polypeptide, or The product obtained by PEG modification of polypeptide, or the product obtained by methylation modification of polypeptide, or the product obtained by modification of polypeptide by fluorescence quenching group, or the product obtained by polypeptide modified by protein coupling, or the product obtained by polypeptide modified by small molecule compounds product obtained.
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。Further, 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.
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。Further, the fluorescent dyes used in the labeling and modification of the fluorophore of the polypeptide include but are not limited to FITC, Rhodamine, Cy3, Cy5, Cy5.5, Cy7, and the modification is used for the purpose of fluorescence detection.
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。
Further, the isotope used in isotopic labeling of the polypeptide includes, but is not limited to, 13C , and the modification is used for tracking purposes.
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。Further, the phosphorylation modification of the polypeptide includes but is not limited to p-Ser, p-Thr, and 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。Further, the polypeptide is labeled with biotin for the purpose of localization and detection, and the like.
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。Further, the polypeptide is modified with a photosensitizer to facilitate the preparation of a photosensitizer.
进一步地，所述多肽进行叠氮修饰，有利于次级的连接反应。Further, the polypeptide is modified with azide, which is beneficial to the secondary ligation reaction.
进一步地，所述多肽进行PEG修饰，用于药物载体制备。Further, the polypeptide is modified with PEG for preparation of a drug carrier.
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。The 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. . For derivatives of polypeptides, the desired modification group is applied after the amino acid is linked.
进一步地，所述诊断化合物包括近红外区染料。Further, the diagnostic compound includes a near-infrared region dye.
进一步地，所述近红外区染料包括但不限于Cy5，Cy7，吲哚菁绿。Further, the near-infrared region dyes include but are not limited to Cy5, Cy7, and indocyanine green.
进一步地，所述近红外区染料为吲哚菁绿。Further, the near-infrared region dye is indocyanine green.
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。Further, the drugs for treating endometriosis include therapeutic antibodies and existing therapeutic drugs for endometriosis.
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。Further, the therapeutic drug for endometriosis is a drug with small molecular weight, suitable water solubility, and high biological safety and stability.
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；Further, the therapeutic drug for endometriosis includes one or a combination of at least two of progestins, androgens, and gonadotropin-releasing hormone agonists;
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；Preferably, the progestin drugs include puvera, progesterone, nemethon, and progesterone caproate;
优选地，所述雄激素类药物包括丹那唑；Preferably, the androgen drugs include danazol;
优选地，所述促性腺激素释放激素激动剂包括戈舍瑞林。Preferably, the gonadotropin-releasing hormone agonist comprises goserelin.
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。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.
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：Further, a kind of preparation method of endometriosis molecular diagnosis and treatment preparation, comprises the following steps:
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；a) Preparation of effector components: preparation of diagnostic compounds and/or drugs for the treatment of endometriosis;
b) 靶向组件准备：常规方法制备多肽，或修饰的多肽衍生物；b) Preparation of targeting components: prepare polypeptides or modified polypeptide derivatives by conventional methods;
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。c) Connection of effector components and targeting components: The 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. If 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.
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。Application of any of the above-mentioned molecular diagnosis and treatment preparations for endometriosis in the preparation of medicines for diagnosing and/or treating endometriosis.
（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。(1) The molecular diagnosis and treatment preparation for endometriosis provided by the present invention can be used for the diagnosis of endometriosis.
（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。(2) The molecular diagnosis and treatment preparation for endometriosis provided by the present invention can be used for the treatment of endometriosis.
（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。(3) The molecular diagnosis and treatment preparation for endometriosis provided by the present invention, because its overall size is maintained at the level of small molecular compounds, its synthesis has the characteristics of simple process and low cost, which is beneficial to its commercial application.
（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。(4) By adding a compound or drug with a diagnostic or therapeutic effect to a targeting molecule that specifically recognizes ectopic endometrial tissue, a compound or drug with diagnostic or therapeutic value can be given to the target of specific identification of the lesion tissue. . Because the endometriosis molecular diagnosis and treatment preparation is a modified small molecule compound, it has high stability and is favorable for in vivo transport. The invention is suitable for diagnosis and treatment of human endometriosis disease, and can also be used as a research tool for endometriosis modeling experimental animals.
图1为本发明实施例中吲哚菁绿的活体成像效果图。FIG. 1 is an effect diagram of in vivo imaging of indocyanine green in an embodiment of the present invention.
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。In order to better understand the content of the present invention, the content of the present invention will be further described below in conjunction with specific implementation methods, but the protection content of the present invention is not limited to the following examples.
本发明以SEQ
ID No.1所述多肽序列为例。The present invention uses SEQ
The polypeptide sequence described in ID No. 1 is exemplified.
实施例1：SEQ
ID No.1所述多肽序列的制备Example 1: SEQ
Preparation of the polypeptide sequence described in ID No. 1
所述多肽序列由专门的多肽制备公司工业合成。The polypeptide sequence is industrially synthesized by a specialized polypeptide preparation company.
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。Based on resin-based solid-phase synthesis, polypeptide molecules are synthesized from the C-terminal to the N-terminal through the condensation reaction between amino acids, and modified with azidoacetic acid.
实施例2：子宫内膜异位症分子诊疗制剂的制备Example 2: Preparation of Endometriosis Molecular Diagnosis and Treatment Preparation
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。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. For the targeting component part, 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.
实施例3：子宫内膜异位症小鼠动物模型制备Example 3: Preparation of Endometriosis Mouse Animal Model
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。Adult 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.
实施例4：小动物成像仪下荧光信号检测Example 4: Fluorescence signal detection under small animal imager
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。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.
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。The specific recognition of ectopic endometrial tissue based on the targeting component, as well as the long-wavelength imaging properties of indocyanine green (as shown in Figure 1), allow this formulation to be used for endometriosis lesions. Imaging diagnosis, so as to achieve the purpose of early diagnosis.
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。In conclusion, 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.
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。The above descriptions are only specific embodiments of the present invention, not all of the embodiments. Any equivalent transformations to the technical solutions of the present invention that are taken by those of ordinary skill in the art by reading the description of the present invention are covered by the claims of the present invention. .
Claims (10)
- 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； 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 recognition component capable peptides;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，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,EDVKDINFDTKEKFLAGCLIVSFHEGKCSEQ ID No.1EDVKDINFDTKEKFLAGCLIVSFHEGKCSEQ ID No.1GKKTQELKNIRTNSELLKEWIIAAFHEGKCSEQ ID No.2GKKTQELKNIRTNSELLKEWIIAAFHEGKCSEQ ID No.2LKPSHEKKNDDNGKKLCKACSEQ ID No.3LKPSHEKKNDDNGKKLCKACSEQ ID No.3EDVKDINFDTKEKFLAGCLIVSFHEGKSEQ ID No.4EDVKDINFDTKEKFLAGCLIVSFHEGKSEQ ID No.4GKKTQELKNIRTNSELLKEWIIAAFHEGKSEQ ID No.5GKKTQELKNIRTNSELLKEWIIAAFHEGKSEQ ID No.5LKPSHEKKNDDNGKKLCKA SEQ ID No.6。LKPSHEKKNDDNGKKLCKA SEQ ID No. 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；The molecular diagnosis and treatment preparation for endometriosis according to claim 1, wherein the derivative is a product obtained by modifying a terminal or side chain of a polypeptide, or a product obtained by modifying a polypeptide by labeling a fluorescent group. The product, or the product obtained by isotope labeling of the polypeptide, or the product obtained by the phosphorylation modification of the polypeptide, or the product obtained by the cyclization modification of the polypeptide based on the disulfide bond, or the product obtained by the labeling of the polypeptide with biotin, or the product obtained by the polypeptide The product obtained by modification of photosensitizer, or the product obtained by azide modification of polypeptide, or the product obtained by PEG modification of polypeptide, or the product obtained by methylation modification of polypeptide, or the product obtained by modification of polypeptide by fluorescence quenching group, Or the product obtained by the polypeptide modified by protein coupling, or the product obtained by the polypeptide modified by the small molecule compound;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；Preferably, the modification of the terminal or side chain of the polypeptide includes N-terminal acetylation modification and C-terminal amination modification;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；Preferably, the fluorescent dyes used in the labeling and modification of the fluorescent group of the polypeptide include 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； Preferably, the polypeptide isotopically labeled isotopically used include 13 C;优选地，所述多肽进行的磷酸化修饰包括p-Ser、p-Thr、p-Tyr。Preferably, the phosphorylation modification of the polypeptide includes p-Ser, p-Thr, and p-Tyr.
- 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。The molecular diagnosis and treatment preparation for endometriosis according to claim 1, wherein the diagnostic compound comprises a near-infrared region dye.
- 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。The molecular diagnosis and treatment preparation for endometriosis according to claim 3, wherein the near-infrared region dyes comprise Cy5, Cy7, and indocyanine green.
- 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。The molecular diagnosis and treatment preparation for endometriosis according to claim 4, wherein the near-infrared region dye is indocyanine green.
- 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。The molecular diagnosis and treatment preparation for endometriosis according to claim 1, wherein the drugs for treating endometriosis include therapeutic antibodies, existing treatments for endometriosis drug.
- 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。The molecular diagnosis and treatment preparation for endometriosis according to claim 6, wherein the therapeutic drug for endometriosis is of small molecular weight, has suitable water solubility, and is biologically safe and stable high drug.
- 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；The molecular diagnosis and treatment preparation for endometriosis according to claim 7, wherein the therapeutic drugs for endometriosis include progestin drugs, androgen drugs, gonadotropin-releasing hormone stimulation one or a combination of at least two of the agents;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；Preferably, the progestin drugs include puvera, progesterone, nemethon, and progesterone caproate;优选地，所述雄激素类药物包括丹那唑；Preferably, the androgen drugs include danazol;优选地，所述促性腺激素释放激素激动剂包括戈舍瑞林。Preferably, the gonadotropin-releasing hormone agonist comprises goserelin.
- 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。A preparation method of a molecular diagnosis and treatment preparation for endometriosis, characterized in that, 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 effector component and The molar ratio of the targeting components is 1:0~1:1, excluding 1:0, preferably 1:0.5~1:1.
- 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。Application of the molecular diagnosis and treatment preparation for endometriosis according to any one of claims 1 to 8 in the preparation of a medicament for diagnosing and/or treating endometriosis.
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