CN113952467A - Endometriosis molecular diagnosis and treatment preparation and preparation method and application thereof - Google Patents
Endometriosis molecular diagnosis and treatment preparation and preparation method and application thereof Download PDFInfo
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- CN113952467A CN113952467A CN202010706564.2A CN202010706564A CN113952467A CN 113952467 A CN113952467 A CN 113952467A CN 202010706564 A CN202010706564 A CN 202010706564A CN 113952467 A CN113952467 A CN 113952467A
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- A61K47/60—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K49/0013—Luminescence
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- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
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- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
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- A—HUMAN NECESSITIES
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
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- C—CHEMISTRY; METALLURGY
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Abstract
The invention discloses a molecular diagnosis and treatment preparation for endometriosis and a preparation method and application thereof. The preparation comprises the following components: 1) an effector component, i.e. a diagnostic compound and/or a drug for the treatment of endometriosis; 2) a targeting module, i.e., a polypeptide with target recognition ability; the polypeptide comprises one or more combined polypeptides in the following sequences or derivatives of one or more combined polypeptides in 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. The invention is suitable for the diagnosis and/or treatment of human endometriosis diseases, and can also be used as a research tool for endometriosis model experimental animals.
Description
Technical Field
The invention belongs to the field of medical cytobiology, and relates to an endometriosis molecular diagnosis and treatment preparation as well as a preparation method and application thereof.
Background
Endometriosis is a clinically common gynecological problem with ectopic growth of active endometrial tissues in a non-uterine environment. At present, the pathogenesis of the disease is not clear, so that a high-efficiency direct tool means is lacked for diagnosing and treating the disease, early detection is undoubtedly the prerequisite for intervention and treatment of the disease, and a reagent or a medicament with diagnostic value and therapeutic value is transported to an endometriosis focus in the simplest way by utilizing a polypeptide with target recognition capability and the like, so that the diagnosis, intervention and treatment idea is very valuable.
Disclosure of Invention
In order to solve the problems in the background art, the invention aims to provide an endometriosis molecular diagnosis and treatment preparation, and a preparation method and application thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a molecular diagnosis and treatment preparation for endometriosis, which comprises the following components: 1) an effector component, i.e. a diagnostic compound and/or a drug for the treatment of endometriosis; 2) a targeting module, i.e., a polypeptide with target recognition ability;
the polypeptide comprises the polypeptide of one or more of the following sequences in combination, or the derivative of the polypeptide of one or more of the following sequences in combination,
the polypeptide is modified on a diagnosis and/or treatment carrier to realize the specific recognition of the polypeptide on lesion tissues, so that a disease intervention tool for diagnosis and treatment is obtained.
Further, the derivative is a product obtained by modifying the tail end or the side chain of the polypeptide, or a product obtained by modifying the polypeptide with a fluorescent group, or a product obtained by isotopic labeling of the polypeptide, or a product obtained by phosphorylating and modifying the polypeptide, or a product obtained by cyclizing and modifying the polypeptide based on a disulfide bond, or a product obtained by labeling the polypeptide with biotin, or a product obtained by modifying the polypeptide with a photosensitizer, or a product obtained by modifying the polypeptide with azide, or a product obtained by modifying the polypeptide with PEG, or a product obtained by modifying the polypeptide with methylation, or a product obtained by modifying the polypeptide with a fluorescence quenching group, or a product obtained by modifying the polypeptide with a protein coupling, or a product obtained by modifying the polypeptide with a small molecular compound.
Further, the polypeptide is subjected to terminal or side chain modification including but not limited to N-terminal acetylation modification and C-terminal amination modification.
Further, fluorescent dyes used in the labeled modification of the fluorescent group of the polypeptide include, but are not limited to, FITC, Rhodamine, Cy3, Cy5, Cy5.5, Cy7, which are modified for fluorescent detection purposes.
Further, isotopes used in isotopic labeling of said polypeptides include, but are not limited to13C, the modification is used for tracking purposes.
Further, phosphorylation modifications performed by the polypeptide include, but are not limited to, p-Ser, p-Thr, p-Tyr.
Further, the polypeptide is labeled with biotin for localization detection purposes and the like.
Further, the polypeptide is photosensitizer modified to facilitate the preparation of photosensitive formulations.
Further, the polypeptide is subjected to azide modification, which is beneficial to secondary ligation reaction.
Further, the polypeptide is modified by PEG and is used for preparing a drug carrier.
The polypeptide can be autonomously synthesized by general organic chemical laboratory conditions, and can also be industrially synthesized by conventional commercial reagent companies, namely, the polypeptide is synthesized by a solid phase method, and the synthesis of the directional amino acid chain is realized by the condensation reaction between different amino acids on resin. The derivative of the polypeptide then applies the desired modifying group after the amino acids have been linked.
Further, the diagnostic compound includes a near infrared dye.
Further, the near infrared region dyes include, but are not limited to, Cy5, Cy7, indocyanine green.
Further, the near infrared region dye is indocyanine green.
Further, the drug for treating endometriosis includes a therapeutic antibody, and a therapeutic drug for endometriosis which is currently available.
Furthermore, the therapeutic drug for endometriosis is a drug which has a small molecular weight, appropriate water solubility, and high biosafety and stability.
Further, the treatment medicament for endometriosis comprises one or a combination of at least two of progestogen medicament, androgen medicament and gonadotropin releasing hormone agonist;
preferably, the progestogen drugs include previtamin, progesterone, entamedone, progesterone caproate;
preferably, the androgen medication comprises danazol;
preferably, the gonadotropin releasing hormone agonist comprises goserelin.
The invention provides a preparation method of the endometriosis molecular diagnosis and treatment preparation, which comprises the steps of connecting and assembling an effect component and a targeting component by a conventional method to obtain the endometriosis molecular diagnosis and treatment preparation; the molar ratio of the effector component to the targeting component is 1: 0-1: 1, excluding 1: 0, preferably 1: 0.5-1: 1.
further, the preparation method of the endometriosis molecular diagnosis and treatment preparation comprises the following steps:
a) preparing an effect component: preparing a diagnostic compound and/or a medicament for the treatment of endometriosis;
b) preparation of targeting module: preparing the polypeptide by a conventional method, or a modified polypeptide derivative;
c) the effector component and the targeting component are connected: the connection assembly is carried out by a conventional method (such as an EDC method and the like), and the molar ratio of the effector component to the targeting component is 1: 0-1: 1 (excluding 1: 0), preferably 1: 0.5-1: 1. if the effect component is also polypeptide substance, the complete diagnosis and treatment preparation can be directly synthesized by using a proper polypeptide linker structure between the two components by using a conventional polypeptide synthesis method. Generally, the mixture is stored at 4 ℃ for standby or prepared as before.
The endometriosis molecular diagnosis and treatment preparation is applied to preparation of medicines for diagnosing and/or treating endometriosis.
The invention has the beneficial effects that:
(1) the molecular diagnosis and treatment preparation for endometriosis provided by the invention can be used for diagnosing endometriosis.
(2) The molecular diagnosis and treatment preparation for endometriosis provided by the invention can be used for treating endometriosis.
(3) The endometriosis molecular diagnosis and treatment preparation provided by the invention has the characteristics of simple synthesis process and low cost because the whole size is maintained at the level of a small molecular compound, and is favorable for commercialized application.
(4) The compound or the medicine with diagnostic or therapeutic effect is added with the targeting molecule which specifically recognizes the ectopic endometrial tissue, so that the compound or the medicine with diagnostic value or therapeutic value is targeted and administered to the specifically recognized focal tissue. The molecular diagnosis and treatment preparation for endometriosis is a modified small molecular compound, so that the stability is high and the in vivo transportation is facilitated. The invention is suitable for diagnosing and treating human endometriosis diseases, and can also be used as a research tool for endometriosis modeling experimental animals.
Drawings
Fig. 1 is a graph of the in-vivo imaging effect of indocyanine green in the example of the present invention.
Detailed Description
For a better understanding of the present invention, the following examples are given to illustrate the present invention, but the present invention is not limited to the following examples.
The invention takes the polypeptide sequence of SEQ ID No.1 as an example.
Example 1: preparation of the polypeptide sequence of SEQ ID No.1
The polypeptide sequence is industrially synthesized by a specialized polypeptide preparation company.
The method is based on solid phase synthesis of resin, polypeptide molecules are synthesized from C end to N end through condensation reaction between amino acids, and modification is carried out by using azidoacetic acid.
Example 2: preparation of molecular diagnosis and treatment preparation for endometriosis
The effector component was selected from indocyanine green dye, available from commercial chemicals, and was selected to be modified with DBCO linker for subsequent attachment to the polypeptide sequence. Targeting module part, the polypeptide sequence prepared in example 1 was selected. The effector component and the targeting component are arranged in a mode of 1: mixing at 0.5 mol ratio, mixing, and storing at 4 deg.C.
Example 3: preparation of mouse animal model with endometriosis
Taking an adult female mouse, after disinfection and anesthesia, taking an orthotopic endometrial tissue, cutting into small pieces (2 mm X2 mm), fixedly inoculating the small pieces near an mesenteric blood vessel, suturing a wound, then statically culturing the mouse, freely taking drinking water, and after one month, growing vesicles to consider that molding is successful.
Example 4: fluorescent signal detection under small animal imager
The diagnosis and treatment preparation prepared in the example 2 is injected into the tail vein of the successfully molded mouse, after 24 hours, the mouse is subjected to respiratory anesthesia, then the mouse is placed in a small animal imager, and a fluorescence signal is observed in a living body under the respiratory anesthesia state, wherein the excitation wavelength of fluorescence is between 600 and 900 nanometers.
Based on the characteristic of the targeting component for specifically identifying the ectopic endometrial tissue and the long-wavelength imaging characteristic of indocyanine green (as shown in figure 1), the preparation can be applied to imaging diagnosis of endometriosis focus, so that the purpose of early diagnosis is achieved.
In conclusion, the molecular diagnosis and treatment preparation for endometriosis provided by the application can be used for the diagnosis and treatment purpose of endometriosis.
The above description is only a specific embodiment of the present invention, and not all embodiments, and any equivalent modifications of the technical solutions of the present invention, which are made by those skilled in the art through reading the present specification, are covered by the claims of the present invention.
SEQUENCE LISTING
<110> Shenzhen advanced technology research institute
<120> endometriosis molecular diagnosis and treatment preparation and preparation method and application thereof
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Claims (10)
1. An endometriosis molecular diagnosis and treatment preparation is characterized by comprising the following components: 1) an effector component, i.e. a diagnostic compound and/or a drug for the treatment of endometriosis; 2) a targeting module, i.e., a polypeptide with target recognition ability;
the polypeptide comprises the polypeptide of one or more of the following sequences in combination, or the derivative of the polypeptide of one or more of the following sequences in combination,
EDVKDINFDTKEKFLAGCLIVSFHEGKC SEQ ID No.1
GKKTQELKNIRTNSELLKEWIIAAFHEGKC SEQ ID No.2
LKPSHEKKNDDNGKKLCKAC SEQ ID No.3
EDVKDINFDTKEKFLAGCLIVSFHEGK SEQ ID No.4
GKKTQELKNIRTNSELLKEWIIAAFHEGK SEQ ID No.5
LKPSHEKKNDDNGKKLCKA SEQ ID No.6。
2. the molecular diagnostic and therapeutic agent for endometriosis according to claim 1, wherein said derivative is a product obtained by modifying a terminal or a side chain of a polypeptide, or the product obtained by the labeling modification of the fluorescent group of the polypeptide or the product obtained by the isotopic labeling of the polypeptide, or phosphorylation modification of the polypeptide, or disulfide bond-based cyclization modification of the polypeptide, or the product obtained by labeling the polypeptide with biotin or the product obtained by modifying the polypeptide with photosensitizer, or the product obtained by performing azide modification on the polypeptide, or the product obtained by performing PEG modification on the polypeptide, or a product obtained by performing methylation modification on the polypeptide, or a product obtained by performing fluorescence quenching group modification on the polypeptide, or a product obtained by modifying the polypeptide through protein coupling, or a product obtained by modifying the polypeptide through a small molecular compound;
preferably, the polypeptide is subjected to terminal or side chain modification including N-terminal acetylation modification and C-terminal amination modification;
preferably, fluorescent dyes used in the labeled modification of the fluorescent group of the polypeptide include FITC, Rhodamine, Cy3, Cy5, Cy5.5, Cy 7;
preferably, the polypeptideIsotopes used in carrying out isotopic labeling include13C;
Preferably, the phosphorylation modifications performed by the polypeptide include p-Ser, p-Thr, p-Tyr.
3. The endometriosis molecular diagnostic or therapeutic preparation according to claim 1, wherein said diagnostic compound comprises a dye in the near infrared region.
4. The molecular diagnostic and therapeutic preparation for endometriosis according to claim 3, wherein the dye in the near infrared region comprises Cy5, Cy7, indocyanine green.
5. The molecular diagnostic and therapeutic preparation for endometriosis according to claim 4, wherein the dye in the near infrared region is indocyanine green.
6. The molecular diagnostic and therapeutic agent for endometriosis according to claim 1, wherein the drug for endometriosis comprises a therapeutic antibody, a currently available therapeutic drug for endometriosis.
7. The molecular diagnostic and therapeutic agent for endometriosis according to claim 6, wherein the therapeutic agent for endometriosis is a drug having a small molecular weight, an appropriate water solubility, and high biosafety and stability.
8. The molecular diagnostic and therapeutic preparation for endometriosis according to claim 7, wherein the therapeutic drug for endometriosis comprises one or a combination of at least two of progestogen drugs, androgen drugs, gonadotropin releasing hormone agonists;
preferably, the progestogen drugs include previtamin, progesterone, entamedone, progesterone caproate;
preferably, the androgen medication comprises danazol;
preferably, the gonadotropin releasing hormone agonist comprises goserelin.
9. A preparation method of a molecular diagnosis and treatment preparation for endometriosis is characterized in that an effect component and a targeting component are connected and assembled by a conventional method to obtain the molecular diagnosis and treatment preparation for endometriosis; the molar ratio of the effector component to the targeting component is 1: 0-1: 1, excluding 1: 0, preferably 1: 0.5-1: 1.
10. use of a molecular diagnostic and therapeutic preparation according to any one of claims 1 to 8 for the preparation of a medicament for the diagnosis and/or treatment of endometriosis.
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