WO2022016752A1 - Endometriosis lesion-targeted nano-delivery system, and preparation method therefor and use thereof - Google Patents
Endometriosis lesion-targeted nano-delivery system, and preparation method therefor and use thereof Download PDFInfo
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- WO2022016752A1 WO2022016752A1 PCT/CN2020/129878 CN2020129878W WO2022016752A1 WO 2022016752 A1 WO2022016752 A1 WO 2022016752A1 CN 2020129878 W CN2020129878 W CN 2020129878W WO 2022016752 A1 WO2022016752 A1 WO 2022016752A1
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- Prior art keywords
- polypeptide
- delivery system
- endometriosis
- product obtained
- modification
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- 201000009273 Endometriosis Diseases 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
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- 238000012986 modification Methods 0.000 claims abstract description 29
- 239000002105 nanoparticle Substances 0.000 claims abstract description 23
- 230000008685 targeting Effects 0.000 claims abstract description 20
- 230000003902 lesion Effects 0.000 claims abstract description 18
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- 150000002632 lipids Chemical class 0.000 claims abstract description 5
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound 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 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 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
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- -1 small molecule compound Chemical class 0.000 claims description 4
- 238000009210 therapy by ultrasound Methods 0.000 claims description 4
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims description 4
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- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 claims description 3
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- 239000007850 fluorescent dye Substances 0.000 claims description 3
- 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 3
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 claims description 3
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- 150000004032 porphyrins Chemical class 0.000 claims description 3
- 239000000186 progesterone Substances 0.000 claims description 3
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- 239000000583 progesterone congener Substances 0.000 claims description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- 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
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- 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
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- 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
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- 229950000801 hydroxyprogesterone caproate Drugs 0.000 claims description 2
- 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 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
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- 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
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- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Definitions
- the invention belongs to the field of nanometer medical cell biology, and relates to an endometriosis lesion targeting nanometer delivery system and a preparation method and application thereof.
- Endometriosis is the abnormal growth and survival of active endometrial cells outside the lining of the uterus, leading to the disease. Its pathogenesis has not yet been elucidated, and there are many hypotheses, such as endocrine factors, inflammation, immunity, new blood vessels, genetic factors, stem cell theory and so on.
- the theory of "peripheral blood flow" endometriosis implantation is currently recognized as the main reason for the formation of abdominal endometriosis. Endometrial cells pass through peritoneal cells, especially the peritoneal extracellular matrix, to complete adhesion, invasion, and angiogenesis, forming ectopic lesions and causing various disease symptoms. It can be seen that early diagnosis and treatment of the disease is the key. Therefore, developing a delivery system with targeted delivery function has important application value for the diagnosis and treatment of this disease.
- the purpose of the present invention is to provide a targeted nano-delivery system for endometriosis lesions and a preparation method and application thereof.
- One aspect of the present invention provides an endometriosis lesion targeting nano-delivery system, comprising a hydrophobic inner core located in the center, a lipid monolayer surrounding the hydrophobic inner core, and a hydrophilic targeting polypeptide layer, the The hydrophilic targeting polypeptide layer is exposed outside the lipid monolayer, and the targeting polypeptide in the hydrophilic targeting polypeptide layer includes one or more combination polypeptides in the following sequences, or one of the following sequences Derivatives of polypeptides or combinations of them,
- 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 and modification of the polypeptide by the fluorescent group, or the product obtained by the isotope 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.
- 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.
- polypeptide isotopically labeled isotopically used include, but are not limited to 13 C, the modified 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 under general organic chemistry laboratory conditions, or industrially synthesized by conventional commercial reagent companies, that is, using solid-phase method to synthesize polypeptides and condensation reactions 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 particle size of the targeted nano-delivery system for endometriosis lesions is 10-1000 nanometers.
- a target delivery material is also included, and the target delivery material is wrapped by the hydrophobic inner core.
- the target delivery material includes one or a combination of at least two of a diagnostic compound and a drug for the treatment of endometriosis.
- the diagnostic compound includes one or a combination of at least two of quantum dots, rare earth nanoparticles, metal nanocrystal clusters, cyanines, rhodamines, aromatic acids, porphyrins, and BODIPY fluorescent materials;
- the diagnostic compound is a cyanine; more preferably, the cyanine comprises indocyanine green.
- the medicines for the treatment of endometriosis include 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 preparation method of the aforementioned endometriosis lesion-targeted nano-delivery system, comprising the following steps:
- Nanoparticles are formed after ultrasonic treatment and blowing out the organic solvent with nitrogen;
- Nanoparticles are formed after ultrasonic treatment and blowing out the organic solvent with nitrogen;
- the molecule with amphoteric properties is a polymer-modified lipid molecule
- the polymer comprises polyethylene glycol
- the lipid molecule comprises one or a combination of at least two of stearic acid, lecithin, and triacylglycerol.
- the targeting polypeptides and nanoparticles can be obtained by organic chemical methods, such as aminocarboxylation, click chemistry, etc. (specifically, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. hydrochloride method) to achieve the assembly of intact nanoparticles.
- organic chemical methods such as aminocarboxylation, click chemistry, etc. (specifically, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. hydrochloride method) to achieve the assembly of intact nanoparticles.
- the molar ratio of the nanoparticle and the targeting polypeptide is 1:0 ⁇ 1:1, excluding 1:0, preferably 1:0.5 ⁇ 1:1.
- Another aspect of the present invention provides an application of any of the aforementioned endometriosis lesion-targeted nano-delivery systems in the preparation of drugs for diagnosing and/or treating endometriosis.
- the nano-delivery system provided by the present invention can be used for the purpose of diagnosing endometriosis.
- the nano-delivery system provided by the present invention can be used as a treatment tool for endometriosis.
- the nano-delivery system provided by the present invention has a relatively simple preparation process and low cost, so it has a good market prospect.
- the present invention utilizes nanoparticle encapsulation technology, combined with the surface modification of polypeptides with targeting ability, can specifically identify endometriosis lesions, thereby providing an efficient drug delivery system for the diagnosis and treatment of such patients . Since the nanoparticle encapsulation technology can deliver suitable diagnostic reagents or therapeutic drugs to the lesion site, it can realize its role as a diagnostic and therapeutic tool.
- the invention is suitable for the diagnosis and treatment of human endometriosis disease, and is also suitable for basic application transformation research of endometriosis modeling experimental animals.
- FIG. 1 is a graph showing the detection result of a small animal imager at a lesion site 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
- polypeptide sequence is industrially synthesized by a specialized polypeptide preparation company.
- the amino acid at the C-terminus was linked to the N-terminus.
- the crude peptide was purified by HPLC. , mass spectrometry analysis, liquid nitrogen quick freeze drying for use.
- Distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG) and distearoylphosphatidylethanolamine-polyethylene glycol-dibenzocyclooctyne (DSPE-PEG-DBCO) were first dissolved in tetrahydrofuran , add the fluorescent dye after mixing evenly, and add the mixture dropwise to the water under ultrasonic conditions. After a clear solution was formed, it was transferred to a cell disrupter (frequency set to 20%) for 5 min of sonication, and nitrogen was purged for 5 min to remove tetrahydrofuran to form nanoparticles.
- a cell disrupter frequency set to 20%
- Example 1 The polypeptide sequence prepared in Example 1 was selected and modified on the surface of the nanoparticles prepared in Example 2. Nanoparticles and peptides were linked by a classic click chemistry method, the molar ratio of nanoparticles and peptides was 1:0.5, and incubated overnight at 4°C for later use.
- mice Male C57 female mice aged 7-8 weeks were purchased. After anesthesia, the uterine tissue was taken from one side of the anteroposterior uterus, and 2 square mm of endometrial tissue was excised. The ectopic inoculation was performed on the abdominal mesentery, and then the abdominal wall muscles and skin were sutured and integrated. The surgical operation was fully sterilized, and the mice were kept at rest for more than one month.
- Example 5 Imaging observation of material taken from ectopic endometrial tissue lesions
- Example 4 For the endometriosis mouse model prepared in Example 4, after resting for 1-2 months, after the formation of ectopic lesions, the endometriosis prepared in Example 3 was injected into the tail vein. After 24 hours, the ectopic endometrial tissue was observed in a small animal imager, and specific fluorescence signals were seen at the lesion site (as shown in Figure 1).
- the targeted nano-delivery system for endometriosis lesions provided by the present application can be used for the purpose of diagnosis and treatment of endometriosis.
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Abstract
Description
Claims (10)
- 一种子宫内膜异位症病灶靶向纳米投递系统,其特征在于,包括位于中心的疏水内核、包绕所述疏水内核的脂质单分子层和亲水靶向多肽层,所述亲水靶向多肽层暴露在所述脂质单分子层外,所述亲水靶向多肽层中所述靶向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, An endometriosis lesion-targeted nano-delivery system, characterized in that it comprises a hydrophobic inner core at the center, a lipid monolayer surrounding the hydrophobic inner core, and a hydrophilic targeting polypeptide layer, and the hydrophilic The targeting polypeptide layer is exposed outside the lipid monolayer, and the targeting polypeptide in the hydrophilic targeting polypeptide layer comprises one or more of the following sequences in combination, or one or more of the following sequences Derivatives of the polypeptides of the 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病灶靶向纳米投递系统,其特征在于,所述子宫内膜异位症病灶靶向纳米投递系统的粒径为10~1000纳米。The endometriosis lesion targeted nano-delivery system according to claim 1, wherein the particle size of the endometriosis lesion-targeted nano-delivery system is 10-1000 nanometers.
- 根据权利要求1所述的子宫内膜异位症病灶靶向纳米投递系统,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 endometriosis lesion-targeted nano-delivery system according to claim 1, wherein the derivative is a product obtained by modifying a terminal or side chain of a polypeptide, or a polypeptide is labeled with a fluorescent group The product obtained by modification, or the product obtained by isotope labeling of the polypeptide, or the product obtained by phosphorylation modification of the polypeptide, or the product obtained by the cyclization modification of the polypeptide based on disulfide bonds, or the product obtained by labeling the polypeptide with biotin, Or the product obtained by the polypeptide modified with photosensitizer, or the product obtained by the polypeptide modified by azide, or the product obtained by the polypeptide modified by PEG, or the product obtained by the polypeptide modified by methylation, or the polypeptide obtained by the fluorescence quenching group modification The product of the peptide, or the product obtained by the modification of the polypeptide by protein coupling, or the product obtained by the modification of the polypeptide 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病灶靶向纳米投递系统,其特征在于,还包括目标投递物,所述目标投递物被所述疏水内核包裹。The endometriosis lesion-targeted nano-delivery system according to claim 1, further comprising a target delivery material, wherein the target delivery material is encapsulated by the hydrophobic inner core.
- 根据权利要求4所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述目标投递物包括诊断化合物、治疗子宫内膜异位症的药物中的一种或至少两种的组合。The endometriosis lesion-targeted nano-delivery system according to claim 4, wherein the target delivery material comprises one or at least two of a diagnostic compound and a drug for the treatment of endometriosis The combination.
- 根据权利要求5所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述诊断化合物包括量子点、稀土纳米粒子、金属纳米晶簇、菁类、罗丹明类、芳酸类、卟啉类、BODIPY类荧光材料中的一种或至少两种的组合;The endometriosis lesion-targeted nano-delivery system according to claim 5, wherein the diagnostic compounds comprise quantum dots, rare earth nanoparticles, metal nanocrystal clusters, cyanines, rhodamines, aromatic acids One or a combination of at least two of the fluorescent materials, porphyrins, porphyrins, and BODIPYs;优选地,所述诊断化合物为菁类;更优选地,所述菁类包括吲哚菁绿。Preferably, the diagnostic compound is a cyanine; more preferably, the cyanine comprises indocyanine green.
- 根据权利要求5所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述治疗子宫内膜异位症的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 endometriosis lesion-targeted nano-delivery system according to claim 5, wherein the drugs for treating endometriosis include progesterone drugs, androgen drugs, gonadotropin-releasing drugs one or a combination of at least two 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.
- 权利要求1-7任一项所述的子宫内膜异位症病灶靶向纳米投递系统的制备方法,其特征在于,包括以下步骤:The preparation method of the endometriosis lesion-targeted nano-delivery system according to any one of claims 1-7, characterized in that, comprising the following steps:a) 将具有两性性质的分子在有机溶剂中混匀;a) Mix the molecules with amphoteric properties in an organic solvent;b) 将上述混合物,在超声环境下逐滴加入水中,形成新的混合液体;b) Add the above mixture dropwise to water in an ultrasonic environment to form a new mixed liquid;c)经过超声处理,和氮气吹打出去有机溶剂后形成纳米颗粒;c) Nanoparticles are formed after ultrasonic treatment and blowing out the organic solvent with nitrogen;d)将纳米颗粒和靶向多肽反应实现连接后得到所述子宫内膜异位症病灶靶向纳米投递系统;d) obtaining the endometriosis lesion targeted nano-delivery system after the nanoparticle and the targeting polypeptide are reacted and connected;或a) 将具有两性性质的分子在有机溶剂中混匀;or a) mixing molecules with amphoteric properties in an organic solvent;b) 加入所需量的目标投递物,再次混匀;b) Add the required amount of the target deliverable and mix again;c) 将上述混合物,在超声环境下逐滴加入水中,形成新的混合液体;c) Add the above mixture dropwise to water in an ultrasonic environment to form a new mixed liquid;d)经过超声处理,和氮气吹打出去有机溶剂后形成纳米颗粒;d) Nanoparticles are formed after ultrasonic treatment and blowing out the organic solvent with nitrogen;e)将纳米颗粒和靶向多肽反应实现连接后得到所述子宫内膜异位症病灶靶向纳米投递系统;e) After the nanoparticle and the targeting polypeptide are reacted and connected, the endometriosis lesion-targeted nano-delivery system is obtained;所述具有两性性质的分子为聚合物修饰的脂类分子;The molecule with amphoteric properties is a polymer-modified lipid molecule;优选地,所述聚合物包括聚乙二醇;Preferably, the polymer comprises polyethylene glycol;优选地,所述脂类分子包括硬脂酸、卵磷脂、三酰甘油中的一种或至少两种的组合。Preferably, the lipid molecule comprises one or a combination of at least two of stearic acid, lecithin, and triacylglycerol.
- 根据权利要求8所述的制备方法,其特征在于,所述纳米颗粒和靶向多肽的摩尔比例为1:0~1:1,不包括1:0,优选为1:0.5~1:1。The preparation method according to claim 8, wherein the molar ratio of the nanoparticles and the targeting polypeptide is 1:0~1:1, excluding 1:0, preferably 1:0.5~1:1.
- 权利要求1-7任一项所述的子宫内膜异位症病灶靶向纳米投递系统在制备诊断和/或治疗子宫内膜异位症的药物中的应用。Application of the targeted nano-delivery system for endometriosis lesions according to any one of claims 1-7 in the preparation of medicines for diagnosis and/or treatment of endometriosis.
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