CN108853515A - Preparation method and application, the pharmaceutical composition of small peptide hydrogel - Google Patents
Preparation method and application, the pharmaceutical composition of small peptide hydrogel Download PDFInfo
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- CN108853515A CN108853515A CN201810688226.3A CN201810688226A CN108853515A CN 108853515 A CN108853515 A CN 108853515A CN 201810688226 A CN201810688226 A CN 201810688226A CN 108853515 A CN108853515 A CN 108853515A
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- 238000006555 catalytic reaction Methods 0.000 claims abstract description 9
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical group OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims abstract description 9
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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Classifications
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- 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
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6903—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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- 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
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- 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
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- 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
- A61K49/0058—Antibodies
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- 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
- A61K49/0073—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 semi-solid, gel, hydrogel, ointment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention provides preparation method and application, the pharmaceutical composition of a kind of small peptide hydrogel, gained small peptide hydrogel has good target tumor inhibitory effect or living imaging effect.The preparation method of the small peptide hydrogel is, small peptide and antibody are mixed in aqueous solution, it assembles the small peptide and the antibody altogether and forms hydrogel, the small peptide can form hydrogel under enzymatic catalysis, and the antibody is the antibody for having targeting to tumour cell；The end-capping group of the small peptide is the group for having antitumous effect or living imaging effect to the tumour cell.Preferably, the group with antitumous effect is Chlorambucil, and the group with living imaging effect is Cy5.5.It is further preferred that the short peptide sequence is X-GDFDFpDY, wherein being Chlorambucil or Cy5.5 for X.Preferably, the antibody is antibody antiHER2.
Description
Technical field
The present invention relates to preparation method and application, the pharmaceutical compositions of a kind of small peptide hydrogel.
Background technique
The generation of cancer brings serious threat to the development of human health and social economy with development, and the whole world is annual
The number for dying of cancer is just being risen with very surprising speed.《The report of world's cancer》It has been shown that, the incidence rate of global cancer
It is swift and violent to increase.14,000,000 people by 2012 are increased to 19,000,000 people in 2035 by world's cancer number of patients, are arrived
The year two thousand fifty can reach 24,000,000 people.Therefore, it constantly explores and develops stronger anti-cancer therapies to contain tumour pair as early as possible
Grave danger of human health has become very urgent.
Mainly there are three kinds of chemotherapy, radiotherapy and operation excision for the treatment of cancer in traditional sense.Wherein chemotherapy master
If being based on some chemotherapeutics, such as Chlorambucil, taxol, camptothecine and adriamycin, they mainly pass through induction
Apoptosis simultaneously inhibits the growth of cell to kill tumour cell, but side effect is very strong.Radiotherapy is mainly exactly using one
A little with different energy electron rays carry out continual irradiation to malignant tumour, and then to kill cancer cell or inhibit cancer
The growth and diffusion of cell, but it lacks selectivity to tumor tissues, the injury of normal tissue also can not be ignored.Operation is controlled
There are very strong limitation, not every cancer patients to be treated by the way of operation excision for treatment.It performs the operation simultaneously
Excision again along with sequelae generation, in fact it could happen that influence ability to act, respiratory failure phenomena such as.
In the implementation of the present invention, the inventors discovered that having at least the following problems in the prior art：It needs to develop
The detection and treatment means of more safe and effective tumour.
Summary of the invention
Goal of the invention
It is an object of the present invention to provide a kind of preparation method of small peptide hydrogel, gained small peptide hydrogel has good
Target tumor inhibitory effect or living imaging effect, can be used for the diagnosis and treatment of tumour.
It is a further object to provide the small peptide hydrogels to prepare antineoplastic target drug or living imaging
Application in drug.
It is a further object to provide a kind of pharmaceutical compositions, can obtain the small peptide hydrogel.
Summary of the invention
According to the first aspect of the invention, the present invention provides a kind of preparation method of small peptide hydrogel,
Small peptide and antibody are mixed in aqueous solution, the small peptide and the antibody is made to be total to group under 2-6 DEG C of enzymatic catalysis
Dress forms hydrogel, and the small peptide can form hydrogel under enzymatic catalysis,
The antibody is the antibody for having targeting to tumour cell；
The end-capping group of the small peptide is the base for having antitumous effect or living imaging effect to the tumour cell
Group.
" small peptide " is term commonly used in the art, refers to the short-chain peptide being made of 3-9 amino acid residue.
Whether the present invention examines the formation of hydrogel by the method for inversion bottle commonly used in the art.
There are many methods of kind for small peptide self assembly plastic, most common to include, heating-cooling, ionic strength regulation, pH tune
Control, photocatalysis and enzymatic etc..For enzyme as natural products existing for nature, it is many unique and not to have in terms of being catalyzed plastic
Analogous advantage, such as：Mild condition, 37 DEG C be enzyme play catalytic effect optimum temperature, under conditions of 37 DEG C, enzyme with
Catalytic effect can be played after Binding Capacity rapidly, and the fluctuation of temperature will affect the catalytic effect of enzyme, have in practical applications
When in order to slow down Catalysis Rate, 2-6 DEG C (such as 4 DEG C) can be selected as reaction condition；Followed by high efficiency, the hair of enzymatic effect
Wave speed quickly, a certain amount of substrate may convert rapidly under a small amount of enzyme existence condition；Third is that specificity, a kind of enzyme can only be made
For a kind of specific substrate, after small peptide of the present invention has restriction enzyme site, it is desirable to must have specific enzyme as cutting
Agent.As common sense in the field, the small peptide has good water solubility first, and small peptide of the present invention and antibody antiHER2 can
To be evenly dispersed in very much in PBS solution system.In 2/1000ths small peptide concentration and 10-15%wt antibody concentration than lower addition alkali
Acid phosphatase can form total assemble nanometer fiber after 2-6 DEG C of (such as 4 DEG C) condition catalysis overnight.This enzymatic plastic (EISA)
Method simple practical, ingredient are controllable, have effectively facilitated the total assembling of small peptide and antibody.Inversion can be passed through by being formed by hydrogel
The method of bottle judges, even if still maintaining good stability under the conditions of 37 DEG C.Take supernatant to find after centrifugation almost without
The presence of antibody, antibody is all gathered in lower sediment fiber, it was demonstrated that effective assembling altogether.
Preferably,
The group with antitumous effect is Chlorambucil (being referred to as CRB-HA below),
The group with living imaging effect is Cy5.5.
It is further preferred that
The short peptide sequence is X-GDFDFpDY, wherein being CRB-HA or Cy5.5 for X.The small peptide can be used well known
The synthesis of Fmoc- solid phase synthesis process.
Preferably,
The antibody is antibody antiHER2.
Preferably, the quality of the antibody is the 10%-15% of the small peptide.The concentration of small peptide is not generally low in hydrogel
It is too low to be unfavorable for assembling plastic in 2mg/mL (usually 2-10mg/mL), exceed very much in waste.
According to the second aspect of the invention, it is anti-in preparation that the present invention provides the resulting small peptide hydrogels of the preparation method
Application in tumor-targeting drug or living imaging drug.The anticarcinogen that the dosage of the small peptide is generally connected according to end-capping group
It determines, specifically determines the dosage of the small peptide according to the safe dose of anticarcinogen.
According to the third aspect of the invention we, the present invention provides a kind of pharmaceutical compositions, including
Small peptide and antibody,
The antibody is the antibody for having targeting to tumour cell；
The end-capping group of the small peptide is the base for having antitumous effect or living imaging effect to the tumour cell
Group.
Preferably,
The group with antitumous effect is CRB-HA,
The group with living imaging effect is Cy5.5.
It is further preferred that it is characterized in that,
The short peptide sequence is X-GDFDFpDY, wherein being CRB-HA or Cy5.5 for X.
Preferably,
The antibody is antibody antiHER2.
Great development has been obtained in the hydrogel that small peptide is formed at present, they are in cancer diagnosis and treatment, cell
Dimensional culture, drug delivery and immunological regulation etc. show great potentiality.The research of inventor early period finds fragrance
The small peptide (such as tetrapeptide) of group end capping can usually form good hydrogel under enzymatic catalysis and (be fallen by commonly used in the art
The method for setting bottle is examined).The antibodies on tumor cell of some clinical applications has targeting, such as monoclonal antibody is (such as
AntiHER2 it) is played an important role in terms of the diagnosing and treating of tumour.Antibody antiHER2 is the antibody for HER2+,
It can be with efficient targeting to the surface of HER2+ tumour cell.The present invention is short by the group CRB-HA sealing end with anticancer effect
After peptide and antibody simple physical mixed method, total assembling is carried out under enzyme catalysis, the total assemble nanometer fiber of formation is not only
Targeting Effect with antibody, while can also effectively tumour is tracked and be inhibited, this for tumour diagnosis and control
Treatment effect has great meaning.
The present invention effectively combines the antitumous effect that enzymatic is total to assembling, the targeting of antibody and anticancer small peptide one
It rises, provides valuable means for the detection and treatment of tumour.
Detailed description of the invention
Fig. 1：Assembling forms nanofiber schematic diagram altogether under alkaline phosphatase enzyme effect for CRB small peptide and antibody；
Fig. 2：Treatment effect of the total assembly of CRB small peptide and 10 or 15%wt antibody for the NCI-N87 tumour of HER2+
Fruit；
Fig. 3：Diagnosis effect of the total assembly of Cy5.5 small peptide and 10 or 15%wt antibody for the NCI-N87 tumour of HER2+
(A represents independent small peptide group to fruit, and B represents small peptide and antibody, and assembling group, C do not represent small peptide and 10wt% antibody assembling group altogether, D altogether
Represent small peptide and 15wt% antibody assembling group altogether).
Specific embodiment
The present invention is further described with embodiment below, but the embodiment is only used for the present invention rather than limits this hair
It is bright.
In following embodiment, whether examining the formation of hydrogel by the method for inversion bottle commonly used in the art.
Involved preparation source is as follows in following embodiment：
2-Cl-Trt resin, Tianjin Nankai Hecheng S&T Co., Ltd., active 1.2mmol/mL；
N,N-diisopropylethylamine (indicates with DIEPA) below, sigma aldrich company (Sigma-Aldrich),
Purity 99%；
Trifluoroacetic acid (indicates with TFA) below, sigma aldrich company (Sigma-Aldrich), purity 99%；
Tri isopropyl silane (indicates with TIS) below, sigma aldrich company (Sigma-Aldrich), purity
99%；
Alkaline phosphatase (ALP), lark prestige Science and Technology Ltd.；
Chlorambucil (CRB-HA), lark prestige Science and Technology Ltd., purity 99%；
Cy5.5 (fluorescent dye), Tianjin Skien think Science and Technology Ltd., purity 98%；
Culture medium, RMPI 1640 match silent winged generation that science and technology (ThermoFisher Scientific), sterile；
Fetal calf serum matches silent winged generation that science and technology (ThermoFisher Scientific), sterile；
Benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (being indicated below with HBTU), it is biochemical purchased from gill
(Shanghai) Co., Ltd., purity 98%；
D amino acids, gill biochemistry (Shanghai) Co., Ltd., purity 98%；
Cancer cell NCI-N87 is gastric carcinoma cells, is purchased from Tianjin Su Lai Biotechnology Co., Ltd, and presses following step
Rapid culture：
1) water-bath is warming up to 37 DEG C in advance, and by culture medium, serum, dual anti-etc. to be put into ultraviolet light irradiation half in super-clean bench small
When sufficiently to sterilize；
2) the cancer cell NCI-N87 frozen is taken out from liquid nitrogen container, is immediately placed in 37 DEG C of water-bath and is thawed, later rapidly
It is transferred in super-clean bench：Celliferous solution is carefully transferred in the centrifuge tube containing 1mL culture medium with pipettor,
1000rpm is centrifuged 3 minutes, abandons supernatant, is transferred to containing the dual anti-culture medium resuspension of 10% fetal calf serum and 1% containing culture
In the culture dish of base, 37 DEG C are then placed in, gas concentration lwevel 5%；
3) next day observes cell state, carries out following experiment after passing on if good.
Involved equipment is as follows in following embodiment：
High performance liquid chromatograph (German Lumtech, HPLC)
Transmission electron microscope (Tecnai G2 F20 system)；
Freeze drier (Cologne Ya Tai, Beijing, LGJ-1-50)；
Digital Nuclear Magnetic Resonance (German Bruker, Bruker 400M).
Prepare embodiment 1
Antitumor small peptide and antibody are total to the preparation of assembly
(1) D configuration small peptide CRB-HA-G is synthesized with Fmoc- solid phase synthesis processDFDFpDY, structural formula are as follows：
Specific step is as follows：
1) it is swollen：1mmol 2-Cl-Trt resin is weighed in synthesis in solid state device, then be added 15mL methylene chloride (with
Under be referred to as DCM), be placed on shaking table and rock 15min, be swollen 2-Cl-Trt resin sufficiently；
2) DCM is removed from the synthesis in solid state device equipped with 2-Cl-Trt resin with ear washing bulb clean；
3) the fmoc-protected amino acid of 1.5mmol is dissolved in the anhydrous DCM of 10mL, the DIEPA of 3mmol is added, fills
It is transferred in above-mentioned solid phase synthesizer after dividing dissolution, reacts 1.5h at room temperature；
4) it closes：The reaction solution in synthesis in solid state device is removed with ear washing bulb, is then washed with the anhydrous DCM of 10mL, 1min/
It is secondary, it washes 3-5 times altogether, addition volume ratio is anhydrous DCM: methanol: DIEPA=8.5: 2: 1 confining liquid 10mL is closed at room temperature
15min；
5) it washes：The reaction solution in synthesis in solid state device is removed with ear washing bulb, is first washed with anhydrous DCM, each DCM dosage
10mL 1min/ times, is washed 3-5 times altogether, then is washed with n,N-Dimethylformamide (being indicated below with DMF), each DMF dosage
10mL 1min/ times, is washed 3-5 times altogether, and DMF of the 10mL containing percent by volume for 20% piperidines is added, cuts protecting group Fmoc
Then 35min is washed with DMF, each DMF dosage 10mL 1min/ times, is washed 3-5 times altogether, carries out next step reaction；
6) second fmoc-protected amino acid 2mmol, HBTU 2mmol, DIEPA 4mmol and 10ml DMF being added,
It is added in solid phase reactor after completely dissolution, reacts 2h；
7) DMF is washed, and each DMF dosage 10mL 1min/ times, is washed 3-5 times altogether；Then piperidines cuts protecting group Fmoc
Then 35min is washed with DMF, repeat that amino acid is added, add until by end-capping group；
8) DMF and DCM are washed respectively, and each dosage is 10mL, 1min/ times, are cut after washing respectively 3-5 times, by 95%
TFA, 2.5%TIS, 2.5%H2O percent by volume composition solution 10mL be added in above-mentioned solid phase synthesizer, product from
Cut on 2-cl-Trt resin, vacuum is spin-dried for being concentrated, settled after removing solvent with ether, obtain crude product, yield about 80-90% it
Between.It is lyophilized again with HPLC separating-purifying later, obtains sterling.
Its structural characterization data are as follows：
1H NMR (400MHz, DMSO-d6) δ 8.04-7.93 (m, 1H), 7.40-7.11 (m, 6H), 7.08 (d, J=
8.3Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 6.65 (d, J=8.3Hz, 1H), 4.61-4.37 (m, 1H), 3.52 (dd, J=
16.8,5.3Hz, 1H), 3.46-3.39 (m, 1H), 3.03 (d, J=11.0Hz, 1H), 2.97-2.90 (m, 1H), 2.43 (dd, J
=15.5,8.0Hz, 1H), 2.08 (t, J=7.3Hz, 1H), 1.69 (dd, J=14.5,7.3Hz, 1H)
(2) 2mg D configuration small peptide CRB-HA-G is takenDFDFpDY is placed in the vial of 4mL, and 0.2mg or 0.3mg is added
Antibody, add PBS solution (pH=7.4) polishing to total volume be 1mL, its pH value is adjusted to the sodium carbonate liquor of 1M
7.4, mix well and room temperature ultrasound make it completely dissolved, be added 1U/mL alkaline phosphatase be placed on 4 DEG C under the conditions of overnight
Storage, can be obtained small peptide and antibody is total to the nanofiber of assembly.
Experimental result：It takes supernatant precipitating to run gel electrophoresis after above-mentioned system (0.3mg antibody) centrifugation, is carried out with standard items
Compare, find supernatant almost without the presence of antibody, antibody is all gathered in lower sediment fiber, it was demonstrated that effectively group altogether
Dress.
Prepare embodiment 2
Cy5.5 small peptide and antibody are total to the preparation of assembly
(1) D configuration small peptide Cy5.5-G is synthesized with Fmoc- solid phase synthesis processDFDFpDY, structural formula are as follows：
Specific steps are as described in preparation embodiment 1, end-capping group Cy5.5.
Its structural characterization data are as follows：
1H NMR(400MHz,DMSO)δ11.32(s,1H),9.19(s,1H),8.56–8.30(m,2H),8.20–7.96
(m, 3H), 7.86 (d, J=8.3Hz, 1H), 7.51-7.30 (m, 3H), 7.26-7.01 (m, 11H), 6.89 (t, J=6.3Hz,
2H), 6.65 (d, J=8.3Hz, 2H), 4.62-4.35 (m, 3H), 3.83-3.41 (m, 4H), 2.98 (dd, J=9.7,4.0Hz,
1H), 2.78-2.56 (m, 3H), 2.33 (t, J=11.5Hz, 1H), 1.35 (d, J=5.8Hz, 3H)
(2) 1mg Cy5.5-G is takenDFDFpDY is placed in the vial of 4mL, and the antibody of 0.2mg or 0.3mg is added,
It is 1mL that PBS solution (pH=7.4) polishing, which is added, to total volume, its pH value is adjusted to 7.4 with the sodium carbonate liquor of 1M, is filled
Point mix and room temperature ultrasound make it completely dissolved, be added 1U/mL alkaline phosphatase be placed on 4 DEG C under the conditions of store overnight,
Small peptide can be obtained and antibody is total to the nanofiber of assembly.
Experimental result：It takes supernatant precipitating to run gel electrophoresis after above-mentioned system (0.3mg antibody) centrifugation, is carried out with standard items
Compare, find supernatant almost without the presence of antibody, antibody is all gathered in lower sediment fiber, it was demonstrated that effectively group altogether
Dress.
Compare preparation example 1
Take 2mg D configuration small peptide CRB-HA-GDFDFpDY is placed in the vial of 4mL, adds PBS solution (pH=7.4)
Polishing is 1mL to total volume, its pH value is adjusted to 7.4 with the sodium carbonate liquor of 1M, mixes well and room temperature ultrasound makes it
Be completely dissolved, be added 1U/mL alkaline phosphatase be placed on 4 DEG C under the conditions of store overnight, obtain the water only containing anticancer small peptide
Gel.
Compare preparation example 2
(1) 2mg D configuration small peptide CRB-HA-G is takenDFDFpDY is placed in the vial of 4mL, adds PBS solution (pH=
7.4) polishing is 1mL to total volume, its pH value is adjusted to 7.4 with the sodium carbonate liquor of 1M, mixes well and room temperature is ultrasonic
Make it completely dissolved, be added 1U/mL alkaline phosphatase be placed on 4 DEG C under the conditions of store overnight, obtain only containing anticancer small peptide
Hydrogel.
(2) antibody of 0.3mg is added in the above system, mixes before administration, obtains what small peptide did not assembled altogether with antibody
System.
Compare preparation example 3
Sterile 1 × PBS, as experimental comparison group.
Compare preparation example 4
Take 1mg D configuration small peptide Cy5.5-GDFDFpDY is placed in the vial of 1mL, adds PBS solution (pH=7.4)
Polishing is 1mL to total volume, its pH value is adjusted to 7.4 with the sodium carbonate liquor of 1M, mixes well and room temperature ultrasound makes it
Be completely dissolved, be added 1U/mL alkaline phosphatase be placed on 4 DEG C under the conditions of store overnight, obtain only containing fluorophor small peptide
System is used in small animal living body imaging later.
Compare preparation example 5
(1) 1mg D configuration small peptide Cy5.5-G is takenDFDFpDY is placed in the vial of 1mL, adds PBS solution (pH=
7.4) polishing is 1mL to total volume, its pH value is adjusted to 7.4 with the sodium carbonate liquor of 1M, mixes well and room temperature is ultrasonic
Make it completely dissolved, be added 1U/mL alkaline phosphatase be placed on 4 DEG C under the conditions of store overnight, only contained fluorophor
Small peptide aquogel system is used in small animal living body imaging later.
(2) antibody of 0.3mg is added in the above system, mixes before administration, obtains what small peptide did not assembled altogether with antibody
System.
Application Example 1
Oncotherapy is implemented
(1) foundation of the culture of cell and mouse tumor model
The NCI-N87 tumour cell of HER2+ is aseptically cultivated, culture medium is RMPI 1640, and quantity reaches laggard
Row digestion, centrifugation, PBS cleaning and etc. be prepared into the cell suspension of 5,000,000/100 μ L.The mouse that growth week old is 6-8 weeks is taken,
Subcutaneous implantation cancer cell is carried out with left side oxter, quantity is 5,000,000/mouse, and volume is 100 μ L.
(2) drug treatment
It is long to 30-50mm to tumor size3When mouse is randomly divided into five groups, every group has 5 mouse, is denoted as respectively
PBS group (comparison preparation example 3), independent small peptide group (comparison preparation example 1), small peptide and antibody not altogether assembling group (comparison preparation example 2),
Small peptide and 10%wt antibody assembling group altogether, small peptide and 15%wt antibody assembling group altogether.It is denoted as 1 day, is taken with injection time first time
Prepare in embodiment 1, comparison preparation example 1, comparison preparation example 2 and comparison preparation example 3 it is obtained it is different organize other hydrogel or
Hydrogel is diluted 5 times according to safe dose and is dispersed as after viscous solution respectively with every 100 microlitres of mouse of dosage pair by solution
Mouse carries out tail vein injection.Later respectively on day 4, the 7th day, the 19th day, same dose of tail vein note is carried out within the 13rd day
Penetrate treatment.
(3) tumor size monitors
From starting first day of administration, we are just tracked and monitor to the size of mouse tumor.Use vernier caliper
The length and width of every mouse tumor are measured respectively, and the calculation formula of volume is V=ab2/ 2 (wherein a represents the length of tumour, b generation
The width of table tumour).Mouse tumor size is once recorded, while monitoring the variation of mouse weight within every two days.
(4) interpretation of result
From the result in Fig. 2, we, which be can analyze, finds out：Wherein ordinate gross tumor volume represents different groups of other tumours
Volume size, this directly reflects our the other tumor inhibitory effects of different treatment groups；Abscissa represents entire therapeutic process
Duration；Black arrow is directed toward corresponding different time points and represents the time point of drug treatment；The not curve of isolabeling
Represent different treatment groups.By curvilinear trend it will be seen that by after treatment and tracking in 21 days, PBS pairs
Reach 944.3mm according to the tumor average volume of group3, the tumour relative volume of independent small peptide group is 598.2mm3, small peptide and antibody are not
The tumour relative volume of total assembling group is 552.3mm3, the tumour relative volume of small peptide and 10%wt antibody assembling group altogether is
68.4mm3, the tumour relative volume of small peptide and 15%wt antibody assembling group altogether is 23.5mm3.Relative to PBS group, independent small peptide
Group, small peptide and antibody not assembling group, small peptide and 10%wt antibody assembling group, small peptide and 15%wt antibody assembling group altogether altogether altogether it is swollen
Tumor percent by volume is respectively 63.35%, 58.49%, 7.24% and 2.49%, and relative inhibition is respectively 36.65%,
41.51%, 92.76% and 97.51%.It can thus be seen that the total assembly of small peptide and antibody has good suppression to tumour
Effect processed, but individually small peptide or assembly is not total to without so apparent inhibitory effect.Analyze reason：AntiHER2 is anti-
Body is the antibody that the tumour cell of a kind of couple of HER2+ has special targeting, and the present invention is because enzymatic is total to assembling process, by small peptide
It is closely fitted together altogether with antibody, so that the anticancer small peptide of Targeting Effect is not provided with Targeting Effect originally, drug is more
Ground is gathered in tumor locus, has reached more cellular uptake effects, therefore better tumor inhibitory effect may be implemented.This
Imagine next to be distributed in vivo in tracking implementation in our small peptide and has obtained sufficient confirmation.
Application Example 2
Small peptide is distributed tracking in vivo to be implemented
Cy5.5 is a kind of common near-infrared fluorescent group, is had a wide range of applications in terms of small animal living body imaging.This
Invention selects it as living imaging group.
(1) foundation of the culture of cell and mouse tumor model
The NCI-N87 tumour cell of HER2+ is aseptically cultivated, culture medium is RMPI 1640, and quantity reaches laggard
Row digestion, centrifugation, PBS cleaning and etc. be prepared into the cell suspension of 10,000,000/100 μ L.Taking growth week old is 6-8 weeks small
Mouse carries out subcutaneous implantation cancer cell with left side oxter, and quantity is 10,000,000/mouse, and volume is 100 μ L.
(2) mouse is administered
It is long to about 200mm to tumor size3When mouse is randomly divided into 4 groups, every group has 3 mouse, is denoted as list respectively
Assembling group, small peptide do not assemble altogether with 15%wt antibody altogether for assembling group, small peptide and 10%wt antibody altogether for only small peptide group, small peptide and antibody
Group.Injection take preparation embodiment 2 and comparison preparation example 4, comparison preparation example 5 made from difference system, dilute 5 times after break up after at
Tail vein injection is carried out to mouse with every 100 microlitres of mouse of dosage respectively after viscous solution.We utilize small animal living body
Imaging system, 48 hours distribution situations after tracking in drug injection to Mice Body.It wherein mainly include drug in tumor locus
Distribution and the distribution in major organs, such as the heart, liver, spleen, stomach, kidney etc..
(3) interpretation of result
According to the result of Fig. 3, it has been found that when 4 hours, small peptide is all distributed in whole body but without apparent
Aggregation, only the total assembly of small peptide and various concentration antibody is some more in tumor locus distribution；But when circulation time reaches
When by 8 hours, individual small peptide group almost fall by metabolism, no matter in tumour or each organ all without dividing
Cloth, untotal assembling group situation is similar with independent small peptide group, does not also appear in the aggregation of tumor locus, but small peptide and antibody
There is the situation similar with 4 hours in assembly altogether；When be recycled to 12 it is small when, discovery assembly it is obviously rich in tumor locus
Collection, is only also distributed in kidney；When 24 hours and 48 hours, being only enriched in tumor locus is occurring in assembly
The phenomenon that, this assembly for having turned out us has good Targeting Effect, can effectively be enriched in tumour portion after 12h
Position, why also demonstrate our anticancer peptide has good inhibition tumor growth effect.
Claims (10)
1. a kind of preparation method of small peptide hydrogel, which is characterized in that
Small peptide and antibody are mixed in aqueous solution, the small peptide and the antibody is made to assemble shape altogether under 2-6 DEG C of enzymatic catalysis
At hydrogel, the small peptide can form hydrogel under enzymatic catalysis,
The antibody is the antibody for having targeting to tumour cell；
The end-capping group of the small peptide is the group for having antitumous effect or living imaging effect to the tumour cell.
2. preparation method as described in claim 1, which is characterized in that
The group with antitumous effect is Chlorambucil,
The group with living imaging effect is Cy5.5.
3. preparation method as claimed in claim 2, which is characterized in that
The short peptide sequence is X-GDFDFpDY, wherein being Chlorambucil or Cy5.5 for X.
4. preparation method as claimed in any one of claims 1-3, which is characterized in that
The antibody is antibody antiHER2.
5. preparation method as claimed in claim 4, which is characterized in that the quality of the antibody is the 10%- of the small peptide
15%.
6. small peptide hydrogel obtained by any one of claim 1-5 preparation method is preparing antineoplastic target drug or living imaging
Application in drug.
7. a kind of pharmaceutical composition, which is characterized in that including
Small peptide and antibody,
The antibody is the antibody for having targeting to tumour cell；
The end-capping group of the small peptide is the group for having antitumous effect or living imaging effect to the tumour cell.
8. pharmaceutical composition as claimed in claim 7, which is characterized in that
The group with antitumous effect is Chlorambucil,
The group with living imaging effect is Cy5.5.
9. pharmaceutical composition as claimed in claim 8, which is characterized in that
The short peptide sequence is X-GDFDFpDY, wherein being Chlorambucil or Cy5.5 for X.
10. pharmaceutical composition as claimed in any one of claims 7-9, which is characterized in that
The antibody is antibody antiHER2.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110755634A (en) * | 2019-10-11 | 2020-02-07 | 江苏恒泰生物科技有限公司 | Anti-tumor nano-drug and preparation method thereof |
| CN110790822A (en) * | 2019-11-21 | 2020-02-14 | 南开大学 | Polypeptide derivative capable of simulating biological activity of platelet-derived factor, nanofiber and application of polypeptide derivative and nanofiber |
| WO2020211504A1 (en) * | 2019-04-18 | 2020-10-22 | 福州大学 | Polypeptide hydrogel and preparation method therefor |
| CN112358529A (en) * | 2020-11-12 | 2021-02-12 | 南开大学 | Polypeptide, derivative and hydrogel thereof, and application of polypeptide, derivative and hydrogel in preparation of medicine for preventing and/or treating type I diabetes |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312810A (en) * | 2017-07-11 | 2017-11-03 | 南开大学 | The preparation of enzymatic Chlorambucil polypeptide hydrogel and anti-cancer applications |
-
2018
- 2018-06-28 CN CN201810688226.3A patent/CN108853515B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312810A (en) * | 2017-07-11 | 2017-11-03 | 南开大学 | The preparation of enzymatic Chlorambucil polypeptide hydrogel and anti-cancer applications |
Non-Patent Citations (2)
| Title |
|---|
| CHUNHUI LIANG ET AL.: ""Supramolecular Nanofibers of Drug-Peptide Amphiphile and Affibody Suppress HER2+ Tumor Growth"", 《ADVANCED HEALTHCARE MATERIALS》 * |
| HUAIMIN WANG ET AL.: ""Enzyme-Catalyzed Formation of Supramolecular Hydrogels as Promising Vaccine Adjuvants"", 《ADVANCED FUNCTIONAL MATERIALS》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020211504A1 (en) * | 2019-04-18 | 2020-10-22 | 福州大学 | Polypeptide hydrogel and preparation method therefor |
| CN110755634A (en) * | 2019-10-11 | 2020-02-07 | 江苏恒泰生物科技有限公司 | Anti-tumor nano-drug and preparation method thereof |
| CN110755634B (en) * | 2019-10-11 | 2022-11-29 | 江苏恒泰生物科技有限公司 | Anti-tumor nano-medicament and preparation method thereof |
| CN110790822A (en) * | 2019-11-21 | 2020-02-14 | 南开大学 | Polypeptide derivative capable of simulating biological activity of platelet-derived factor, nanofiber and application of polypeptide derivative and nanofiber |
| CN110790822B (en) * | 2019-11-21 | 2021-04-06 | 南开大学 | Polypeptide derivative capable of simulating biological activity of platelet-derived factor, nanofiber and application of polypeptide derivative and nanofiber |
| CN112358529A (en) * | 2020-11-12 | 2021-02-12 | 南开大学 | Polypeptide, derivative and hydrogel thereof, and application of polypeptide, derivative and hydrogel in preparation of medicine for preventing and/or treating type I diabetes |
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