CN109925320A - Water-soluble fullerene is preparing the application in PI3K-AKT regulator - Google Patents
Water-soluble fullerene is preparing the application in PI3K-AKT regulator Download PDFInfo
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- CN109925320A CN109925320A CN201711376404.0A CN201711376404A CN109925320A CN 109925320 A CN109925320 A CN 109925320A CN 201711376404 A CN201711376404 A CN 201711376404A CN 109925320 A CN109925320 A CN 109925320A
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- fullerene
- water
- soluble
- pi3k
- embedded metal
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Abstract
The invention discloses a kind of water-soluble fullerenes to prepare the application in PI3K-AKT regulator, and the water-soluble fullerene structure includes at least one below: water-soluble modified empty fullerene, water-soluble modified embedded metal fullerene, the water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene composition, the pharmaceutical ester of the above three or the pharmaceutical salt of the above three.After water-soluble fullerene structure of the invention enters body, the expression and activation of adjustable PI3k and/or AKT；The PI3K of activation can generate second messenger PIP3 in conjunction with the signal protein AKT and PDK1 into the cell containing PH structural domain, promote PDK1 phosphorylation AKT Ser308 so as to cause AKT activation, the adjustable signaling molecule downstream of the AKT of activation, plays a role, treatment-related disease or obstacle.
Description
Technical field
The present invention relates to fullerene fields, and in particular to water-soluble fullerene structure is in preparation PI3K-AKT signal path tune
The application in agent is saved, water-soluble fullerene structure is related further specifically in preparation and treats the disease that PI3K-AKT signal path mediates
Application in drug.
Background technique
PI3K is a kind of endocellular phosphorus acyl inositol kinase, be made of adjusting subunit p85 and catalytic subunit p110 it is different
Dimer.PI3K is divided into I, II, III type according to the specific difference of its structure and substrate.Wherein III type PI3K is using PI as substrate,
For II type using PI and PIP as substrate, I type makes the inositol ring of substrate that phosphorylation occur using PI, PIP and PIP2 as substrate.
AKT is also referred to as protein kinase B, and which represent serine/threonine kinase subtribes.
Fullerene is another allotrope of the carbon in addition to graphite, diamond and agraphitic carbon.This substance
Refer to the cage structure being made of carbon atom, the most molecule of content is C60, followed by C70、C84, followed by content is opposite
Less C76、C78、C82Deng.Carbon cage inside additionally, due to fullerene is cavity structure, therefore its internal cavities can embed difference
Atom, ion or cluster, referred to as embedded fullerene, such as La@C60, indicate that La is embedded in C60Cage structure in ,@indicate
At, vivid expresses embedded meaning.
The information disclosed in the background technology section is intended only to increase the understanding to general background of the invention, without answering
When being considered as recognizing or imply that the information constitutes the prior art already known to those of ordinary skill in the art in any form.
Summary of the invention
One of the objects of the present invention is to provide water-soluble fullerene structures in preparation PI3K-AKT signal path regulator
In application.The second object of the present invention is that provide water-soluble fullerene structure is situated between in preparation treatment PI3K-AKT signal path
Application in the drug for the disease led.The third object of the present invention is to provide a kind of PI3K-AKT signal path regulator.This
The fourth purpose of invention is to provide the pharmaceutical composition and method of a kind of disease for treating the mediation of PI3K-AKT signal path.This
The fifth purpose of invention is to provide a kind of health care product of disease that improvement PI3K-AKT signal path mediates.
To achieve the above object, the present invention provides following technical schemes:
A kind of water-soluble fullerene structure is preparing the application in PI3K-AKT signal path regulator, described water-soluble rich
Strangle alkene structure include at least one below: water-soluble modified empty fullerene, water-soluble modified embedded metal fullerene,
The composition of the water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene, the above three
Pharmaceutical ester or the pharmaceutical salt of the above three.
The present invention also provides the diseases that a kind of water-soluble fullerene structure is mediated in preparation treatment PI3K-AKT signal path
Application in the drug of disease, the water-soluble fullerene structure includes at least one below: the water-soluble hollow fowler of modification
In alkene, water-soluble modified embedded metal fullerene, the water-soluble modified empty fullerene and the water-soluble modification
The pharmaceutical salt of the composition of engaged column fullerene, the pharmaceutical ester of the above three or the above three.
The present invention also provides a kind of PI3K-AKT signal path regulators, including at least one water solubility selected from the group below
Fullerene structure is as effective component: water-soluble modified empty fullerene, water-soluble modified embedded metal fullerene, described
The composition of water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene, the above three can medicine
Ester or the pharmaceutical salt of the above three, the PI3K-AKT signal path regulator further includes pharmaceutical carrier, dilute
Release at least one of agent or excipient.
The present invention also provides a kind of methods of disease for treating the mediation of PI3K-AKT signal path, including to suffering from
The subject for the disease that PI3K-AKT signal path mediates applies a effective amount of at least one water-soluble fullerene selected from the group below
Structure: water-soluble modified empty fullerene, water-soluble modified embedded metal fullerene, the water-soluble hollow richness of modification
Strangle the composition of alkene and the water-soluble modified embedded metal fullerene, the pharmaceutical ester of the above three or the above three
Pharmaceutical salt.
The present invention also provides a kind of pharmaceutical compositions of disease for treating the mediation of PI3K-AKT signal path comprising extremely
A kind of few water-soluble fullerene structure selected from the group below is as effective component: water-soluble modified empty fullerene, water-soluble
Modified embedded metal fullerene, the water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene
Composition, the pharmaceutical ester of the above three or the pharmaceutical salt of the above three, described pharmaceutical composition further includes can medicine
At least one of carrier, diluent or excipient.
The present invention also provides a kind of health care products of disease that improvement PI3K-AKT signal path mediates comprising at least one
Kind water-soluble fullerene structure selected from the group below is as effective component: water-soluble modified empty fullerene, water-soluble modification
The group of embedded metal fullerene, the water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene
Object, the pharmaceutical ester of the above three or the pharmaceutical salt of the above three are closed, the health care product further includes being suitable for health care product
At least one of carrier, diluent or excipient.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the water-soluble modified empty fullerene includes selected from the group below one or more: (1) in empty fullerene ontology
Carbon cage outer surface is modified with the modification empty fullerene of hydrophilic radical；(2) the carbon cage outer surface of empty fullerene ontology is hydrophilic
Property biological micromolecule package modification empty fullerene；(3) empty fullerene ontology is by the carrier material with biocompatibility
The modification empty fullerene of load and formation；(4) empty fullerene for the water-soluble supramolecular system being self-assembly of.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the water-soluble modified embedded metal fullerene includes selected from the group below one or more: (1) in embedded metal fowler
The carbon cage outer surface of alkene ontology is modified with the modification embedded metal fullerene of hydrophilic radical；(2) embedded metal fullerene ontology
The modification embedded metal fullerene that carbon cage outer surface is wrapped up by hydrophily biological micromolecule；(3) embedded metal fullerene ontology quilt
The modification embedded metal fullerene of carrier material load with biocompatibility and formation；(4) water solubility being self-assembly of
The embedded metal fullerene of supramolecular system.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, empty fullerene ontology includes that one or more general formulas are C2mThe cage structure being made of carbon atom, 20≤m≤60,
Optional 30≤m≤60, further alternative m are 30 or 35 or 42.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, embedded metal fullerene ontology includes M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nWith
MxA3-xN@C2nOne of or it is a variety of, in which: M, A represent metallic element and M, A are selected from Sc, Y and lanthanide element
Any one, 20≤n≤60, optional 30≤n≤60, n be 41 or 30 or 35；0≤x≤3.N represents nitrogen, and C is represented
Carbon, S represent element sulphur, and lanthanide element includes La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb
And Lu.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the hydrophilic radical includes one of hydroxyl, carboxyl, sulfydryl, amino or hydrophilic amino-acid residue or a variety of.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the general formula of the water-soluble modified empty fullerene is C2a(OH)b；20≤a≤60, optional 30≤a≤60, into one
Walking optional a is 30 or 35 or 42；0 <b≤50, optional 0 <b≤30,10≤b≤30,20≤b≤30, further alternative b
=13,20,22,24 or 26.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the general formula of the water-soluble modified embedded metal fullerene is metallofullerene- (OH)c；
Metallofullerene represents embedded metal fullerene ontology, 0 < c≤50, optional 0 < c≤30,10≤c≤30,20≤c
≤ 30, further alternative c=13,20,22,24 or 26.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the general formula of the water-soluble modified embedded metal fullerene is M@C2d(OH)e；M is selected from rare earth metal, optional rare earth
Metal is Gd or La；20≤d≤60, further alternative 30≤d≤60, d are 41 or 30 or 35；0 < e≤50, optional 0 < e
≤ 30,10≤e≤30,20≤e≤30, also optional e=13,20,22,24 or 26.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, water-soluble modified empty fullerene is C70(OH)24；Water-soluble modified embedded metal fullerene is Gd@C82(OH)26。
C in above structure general formula2a(OH)b、metallofullerene-(OH)cWith formula M@C2d(OH)eIndicate that hydroxyl connects
It is connected on empty fullerene ontology or embedded metal fullerene ontology.B in general formula, c, e are by detecting the system being calculated
Count average value.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the hydrophily biological micromolecule includes at least one of amino acid and peptide chain.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the carrier material with biocompatibility includes at least one of liposome and cell membrane carrier.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the water-soluble modified empty fullerene is by carrying out water-soluble modified acquisition to empty fullerene ontology；Institute
Stating water-soluble modified embedded metal fullerene is by carrying out water-soluble modified acquisition to embedded metal fullerene ontology.
Above-mentioned application, method, PI3K-AKT signal path regulator, pharmaceutical composition or health care product are in another embodiment party
In formula, the water-soluble modified method is any one of following methods:
(1) method of surface modification hydroxyl are as follows: by empty fullerene ontology and/or embedded metal fullerene ontology, dioxygen
Water and aqueous slkali, which are mixed and reacted to empty fullerene ontology and/or embedded metal fullerene ontology, all to be dissolved, by institute
Reaction solution filtering is obtained, filtrate washing collects precipitating later and then dialyses, obtains water soluble hydroxy derivative corresponding with ontology.
Optionally, the method for surface modification hydroxyl are as follows: the hydrogen peroxide and quality hundred that mass percentage is 1-30% by (a)
The sodium hydrate aqueous solution and/or potassium hydroxide aqueous solution that point content is 10-80% are that 1-10:1 is mixed to get according to volume ratio
20-500mg empty fullerene ontology and/or embedded metal fullerene ontology is added in mixed liquor in every 10-200ml mixed liquor
(such as: C60 solid or C70 solid or Gd@C82 solid), stirring is all dissolved to solid under conditions of 50-80 DEG C, is filtered, and is protected
Reserved filtrate；(b) ethyl alcohol that excessive concentration is 85%-100% is added in the filtrate to wash, and collects precipitating, by institute
It states precipitating and is dissolved in water, obtain solution；(c) solution for obtaining (b) step carries out dialysis treatment (optional dialysis to the solution
Room temperature conductivity less than 1 μ s/cm；Optionally, the molecular cut off Mw=3500 of bag filter used in dialysing).Into one
Further include the steps that freeze-drying after walking optional dialysis treatment, to obtain corresponding solid.
It is further alternative, the method for surface modification hydroxyl are as follows: the hydrogen peroxide that mass percentage is 20-30% by (a)
The sodium hydrate aqueous solution for being 10-20% with mass percentage and/or potassium hydroxide aqueous solution are 1-4:1 mixed according to volume ratio
Conjunction obtains mixed liquor, and 20-150mg empty fullerene ontology and/or embedded metal fullerene are added in every 10-20ml mixed liquor
Ontology (such as: C60 solid or C70 solid or Gd@C82 solid), stirring is all dissolved to solid under conditions of 50-60 DEG C, mistake
Filter retains filtrate；(b) ethyl alcohol that excessive concentration is 85%-100% is added in the filtrate to wash, and collects precipitating,
The precipitating is dissolved in water, obtains solution；(c) solution for obtaining (b) step carries out dialysis treatment.
(2) method of surface modification amino are as follows: by above-mentioned steps sodium hydrate aqueous solution and/or potassium hydroxide it is water-soluble
Liquid is substituted for ammonium hydroxide.
(3) method of physics cladding are as follows: by empty fullerene ontology and/or embedded metal fullerene ontology and poly- second two
At least one of alcohol, polyvinylpyrrolidone and cyclodextrin mix and carry out ball milling or ultrasound etc. and can be obtained by and ontology phase
The water-soluble fullerene structure for the cladding answered, such as the empty fullerene of coated with polyethylene glycol and/or embedding for coated with polyethylene glycol
Metal fullerene, the empty fullerene of polyvinylpyrrolidone cladding and/or the embedded metal of polyvinylpyrrolidone cladding are rich
Strangle alkene.
In another embodiment, the PI3K-AKT signal is logical for drug or aforementioned pharmaceutical compositions in above-mentioned application
The disease that road mediates includes: at least one of glycolipid metabolism disease, hypertension, Apoptosis autophagy；Optionally, the glycolipid
Metabolic disease includes at least one of diabetes and diabetic complication, such as diabetic nephropathy, diabetic eye diseases etc..
Drug, above-mentioned PI3K-AKT signal path regulator or aforementioned pharmaceutical compositions in above-mentioned application is another real
It applies in mode, the drug, the PI3K-AKT signal path regulator or the pharmaceutical composition can be tablet, pill, powder, ingot
Agent, sachet, cachet, elixir, suspending agent, emulsion, solution, syrup, aerosol, ointment, soft hard gelatin capsule, bolt
The preparation of agent, aseptic injectable solution or aseptic packaging powder-injection.Effective component is prepared into drug or pharmaceutical composition in the present invention
Object makes its quick-release, sustained release or sustained release effective component after being applied to subject, such as: effective component can be mixed with carrier
It closes, diluted with carrier or encapsulates in the carrier.
Drug, above-mentioned PI3K-AKT signal path regulator or aforementioned pharmaceutical compositions in above-mentioned application is another real
Apply in mode, be suitable for as carrier, excipient and diluent some examples include lactose, it is dextrose, sucrose, sorbierite, sweet
Reveal alcohol, starch, resin, Arabic gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicates, microcrystalline cellulose, poly- second
Alkene pyrrolidone, cellulose, aqueous syrup (water syrup), methylcellulose, methylparaben and propyl ester, talcum powder, tristearin
Sour magnesium and liquid paraffin.
Drug, above-mentioned PI3K-AKT signal path regulator or aforementioned pharmaceutical compositions in above-mentioned application is another real
It applies in mode, the drug, the PI3K/AKT regulator or pharmaceutical composition can also also comprise lubricant, wetting agent, emulsification
With the auxiliary agents such as suspending agent, preservative, sweetener or corrigent.
Drug, above-mentioned PI3K-AKT signal path regulator or aforementioned pharmaceutical compositions in above-mentioned application is another real
Apply in mode, when the drug, the PI3K/AKT regulator or described pharmaceutical composition in liquid form in the presence of, effectively at
The concentration divided in the drug or described pharmaceutical composition is 0.01-100mg/mL, is optionally 0.01-10mg/mL,
0.01-20mg/mL, 0.01-30mg/mL, 0.01-40mg/mL, 0.01-50mg/mL, 50-100mg/mL；When the drug or
Described pharmaceutical composition in solid form in the presence of, concentration of the effective component in the drug or described pharmaceutical composition is
0.01-100mg/g is optionally 0.01-10mg/g, 0.01-20mg/g, 0.01-30mg/g, 0.01-40mg/g, 0.01-
50mg/g, 50-100mg/g.
In another embodiment, described subject is a human or animal for the above method, and animal can be mammal, such as
Mouse, cavy, rat, dog, rabbit, monkey etc..
In another embodiment, the administration dosage of the effective component is 1mg/kg/d-100mg/kg/ to the above method
D is optionally 1-50mg/kg/d, 1-20mg/kg/d, 1-10mg/kg/d, 10-100mg/kg/d apply the course for the treatment of can for 5 days-
30 days, it can take or take for a long time in short term according to the state of an illness；The method of application of effective component can be oral, intravenous injection or abdominal cavity
Administration.
Term used herein " PI3K-AKT signal path regulator " refers to the table of adjustable PI3K and/or AKT
The product for reaching and/or activating both may include positive adjusting or may include inversely adjusting, such as: both may include that up-regulation promotes
Expression, the activation of PI3K and/or AKT, may also comprise and lower the expression for inhibiting PI3K and/or AKT, activation.
Term used herein " treatment " includes its generally accepted meaning, which includes preventing, prevention, pressing down
The development of symptom produced by making, improve and slow down, stop or reversing or expected lesion.As such, the present invention cover it is therapeutic and
Preventative application.
Term used herein " effective component ", " effective component water-soluble fullerene structure " or " water-soluble fullerene
Structure " refers to water-soluble modified empty fullerene, water-soluble modified embedded metal fullerene, described water-soluble changes
The composition of property empty fullerene and the water-soluble modified embedded metal fullerene, the above three pharmaceutical ester or with
The pharmaceutical salt of upper three.
Term used herein " effective quantity " refer to effective component through it is single or multiple be applied to patient and to diagnosing or
The patient treated provides the amount or dosage of intended effect.Effective quantity can be by the diagnostician that is participated in as those skilled in the art
By known technology and under similar situation, resulting observation result determines member.Determining the effective of applied effective component
When amount or dosage, the diagnostician participated in is considered as many factors, and the factor includes but is not limited to: the kind of mammal
Belong to；Volume, age and general health；Related disease specific；The disease involves in degree or severity；Individual patient
Response；The particular compound applied；Mode of administration；The bioavailability characteristics of applied preparation；Selected dosage regimen；
The use of concomitant drugs therapy；And other relevant situations.
Term used herein " empty fullerene ontology " refers to not former by water-soluble modified empty fullerene
Material.
Term used herein " embedded metal fullerene ontology " refers to not by water-soluble modified embedded metal
Fullerene raw material.
Compared with prior art, the invention has the following beneficial effects:
After water-soluble fullerene structure of the invention enters body, the expression and activation of adjustable PI3K and/or AKT；
The PI3K of activation can generate second messenger PIP3 in conjunction with the signal protein AKT and PDK1 into the cell containing PH structural domain, promote
PDK1 phosphorylation AKT Ser308 is played and is made so as to cause AKT activation, the adjustable signaling molecule downstream of the AKT of activation
With treatment-related disease or obstacle.
Water-soluble fullerene structure of the invention can improve pancreas by promoting expression and the activation of PI3K and/or AKT
Insulin resistance.
Detailed description of the invention
Figure 1A is the C that embodiment 1 is prepared70(OH)nThermogravimetric analysis and differential thermogravimetric curve.Figure 1B is embodiment 1
The Gd@C being prepared82(OH)nThermogravimetric analysis and differential thermogravimetric curve.
The mRNA expression that Fig. 2 is PI3K in mouse muscle in embodiment 2, it may be assumed that express the PI3K mRNA of blank group
Level is set as 1.
The mRNA expression that Fig. 3 is AKT in mouse muscle in embodiment 2, it may be assumed that the AKT mRNA of blank group is expressed into water
It is flat to be set as 1.
The protein expression level that Fig. 4 is AKT and pAKT in each group mouse muscle in embodiment 2.
Fig. 5 is the albumen relative expression levels of mouse muscle pAKT/AKT in embodiment 2, it may be assumed that by the pAKT/ of blank group
AKT expressing quantity ratio is set as 1.
Fig. 6 is the change of blood sugar of each group mouse in insulin resistant experiment.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In attached drawing, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is
A part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art
Every other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.Unless
Separately have it is other explicitly indicate that, otherwise in entire disclosure and claims, term " includes " or its transformation such as "comprising" or
" including " etc. will be understood to comprise stated element or component, and not exclude other elements or other compositions
Part.
It should not necessarily be construed as in this application as exemplary illustrated any embodiment preferred or advantageous over other embodiments.
In addition, in order to better illustrate the present invention, numerous details is given in specific embodiment below.
It will be appreciated by those skilled in the art that without certain details, the present invention equally be can be implemented.In some instances, for
Method well known to those skilled in the art, means, element are not described in detail, in order to highlight purport of the invention.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.Following realities
Experimental method used in example etc. is applied, is routine experiment method unless otherwise specified.The raw materials used Gd@C of following embodiment82
Solid powder purchase is taken in the fresh material Science and Technology Ltd. in Xiamen good fortune, molecular weight 1141, purity 99.1%.Following embodiment institute
It is taken in the fresh material Science and Technology Ltd. with the purchase of raw material C70 solid powder in Xiamen good fortune, molecular weight 840, purity 99%.
The preparation of embodiment 1, water-soluble fullerene structure
Weigh 100mg C70Solid powder, the hydrogen peroxide of 7ml 30% and the sodium hydrate aqueous solution of 3ml 10%, by three
It is reacted under conditions of 50 DEG C after person's mixing, until C70Solid powder filters after all dissolving；By gained filtered fluid excess ethyl alcohol
Washing is to remove excessive H2O2The colourless liquid in upper layer is removed afterwards with NaOH and by centrifugation (revolving speed: 10000r/min, time: 4min)
The precipitating of collection is dissolved in ultrapure water and obtains clear solution by body, using M.W.=3500 bag filter by the clear solution super
It dialyses in pure water, room temperature is dialysed to the conductivity of ultrapure water less than 1 μ s/cm, and empty fullerene hydroxylating is obtained after freeze-drying
Derivative C70(OH)nSolid.
Weigh 100mg Gd@C82Solid powder, the hydrogen peroxide of 7ml 30% and the sodium hydrate aqueous solution of 3ml 10%, will
It is reacted under conditions of 50 DEG C after three's mixing, until Gd@C82Solid powder filters after all dissolving；Gained filtered fluid is excessive
Ethanol washing is to remove excessive H2O2With NaOH and by centrifugation (revolving speed: 10000r/min, time: 4min) afterwards remove upper layer without
The precipitating of collection is dissolved in ultrapure water and obtains clear solution by color liquid, using M.W.=3500 bag filter by the clear solution
It dialyses in ultrapure water, room temperature is dialysed to the conductivity of ultrapure water less than 1 μ s/cm, and embedded metal fowler is obtained after freeze-drying
Alkene hydroxylation derivative Gd@C82(OH)n。
To the above-mentioned C being prepared70(OH)nIt carries out elemental analysis (Flash EA 1112), and combines thermogravimetric and difference quotient heat
Its connect hydroxyl value of interpretation of result again.In the result of elemental analysis, the C70(OH)nIn, C content 37.85%, H content
It is 1.51%, N content < 0.3%.From Figure 1A thermogravimetric analysis it is found that C70(OH)nThe water for containing 3.7% in solid powder, in conjunction with element
The ratio of H content and C content in analysis can calculate 24 hydroxyls of carbon cage surface modification, so C70(OH)nAverage formula
For C70(OH)24。
To the above-mentioned Gd@C being prepared82(OH)nCarry out elemental analysis, and combine thermogravimetric and the interpretation of result of difference quotient thermogravimetric its
Connect hydroxyl value.In the result of elemental analysis, the Gd@C82(OH)nIn, C content 36.95%, H content 2.36%, N
Content 0%.From Figure 1B thermogravimetric analysis it is found that Gd@C82(OH)nThe water for containing 12.6% in solid powder, contains in conjunction with H in elemental analysis
The ratio of amount and C content, can calculate 26 hydroxyls of carbon cage surface modification.So Gd@C82(OH)nAverage formula be Gd@
C82(OH)26.The partial size of soluble derivative, Gd@C are measured by dynamic light scattering (DLS)82(OH)nThe partial size of material is about
145.2nm, can be to biological internal injection.
Embodiment 2, water-soluble embedded metal fullerene Gd@C82(OH)nAdjust PI3K and/or AKT
PI3K-AKT signal path is the primary signal pathways of insulin.Insulin first with the insulin of cell surface by
Body combines, and activates the tyrosine kinase of its β subunit, then activates PI3K to believe by the activation of insulin receptor substrate albumen
Number, the PI3K of activation generates second messenger PIP3 in conjunction with the signal protein AKT and PDK1 into the cell containing PH structural domain, promotes
The Ser308 of PDK1 phosphorylation AKT causes AKT to activate.AKT after activation can activate or inhibit downstream by phosphorylation
A series of substrates such as Bad, cas9, GSK etc. be transferred to and migrate etc. to adjust the Proliferation, Differentiation of cell, to influence
Disease relevant to AKT adjusting.It, can be to intracellular glucose transporter after the PI3K of cells activated by insulin promotes AKT to activate
Vesica generates metathesis, on the other hand promotes Glycogen synthesis by adjusting glycogen synthase kinase.That is a system such as PI3K and AKT
Column signal participates in mediating the adjusting of glycolipid metabolism.
(1) experimental method
Experimental animal is db/db diabetic mice, Nanjing zootype center is purchased from, quoted from Jackson Lab, the U.S..
This mouse is widely applied diabetes B animal model, is that leptin receptor gene defect causes development after obesity to be glycosuria
The mouse model of disease, the spontaneous mutation of leptin receptor (leptinreceptor, Lepr) can cause eat, quench one's thirst, diuresis etc.
Symptom.There is hyperglycemia at 4~8 weeks in db/db mouse.
Experimental animal grouping: experimental animal is randomly divided into 4 groups, every group 6；A group takes the mouse of 6 db/m non-diabetics to make
For blank group, drug treatment is the application physiological saline isometric with drug used in C group；B group takes 6 db/db mouse conducts
Model group, drug treatment are the application physiological saline isometric with drug used in C group；C group takes 6 db/db mouse as Gd@
C82(OH)nExperimental group, drug treatment are the Gd@C that application is prepared according to the method for embodiment 182(OH)n；D group is inhibitor
Group, inhibitor group mouse is in addition to according to Gd@C82(OH)nExperimental mice applies Gd@C82(OH)nMethod apply Gd@C82(OH)n
In addition, AKT inhibitor MK2206,30mg/kg/ is administered orally in 1h and 1h before dissection respectively before carrying out insulin resistance and testing
It is secondary.The physiological saline or Gd@C of A-D group82(OH)nIt is all made of the mode of intraperitoneal administration, the week old of each group mouse, which enters the 10th week, to be opened
Begin to be administered, be administered once daily, Gd@C82(OH)nDosage be 10mg/kg/d, successive administration two weeks.
Insulin resistance experiment is carried out after two weeks in the treatment of above 4 groups of mouse: being started to test after fasting 3h, be originated in experiment
That is fasting blood-glucose is surveyed when 0min, is then A-D group mouse peritoneal insulin injection 1U/kg, and surveys blood 15,30,60min respectively
Sugar.
Insulin resistance is completed to test and dissect each group mouse after allowing mouse to restore 2 days.
Take A-C group 50-100mg musculature (take musculature be because research insulin resistance concern main phase
Closing organ is the organ that insulin works, rather than the organ of excreting insulin), first plus Triol is ground, is centrifuged,
Chlorination imitates/Triol oscillation, centrifugation, and water intaking is added to isopropanol/Trizol shaking, is centrifuged, washs the mRNA extracted.It is right
MRNA carries out reverse transcription into cDNA, finally carries out PCR amplification, so that the mRNA expression of PI3K and AKT is detected, as a result as schemed
Shown in 2 and Fig. 3.
Separately the musculature of the 50-100mg of A-D group is taken to add 1ml lysate, be homogenized, supernatant liquor is removed in centrifugation, quantitative, electricity
Swimming takes glue, and transferring film, closing, in conjunction with primary antibody and secondary antibody, washing, development imaging obtains the WB band of AKT, as a result as shown in Figure 4
(wherein AKT item has trailing phenomenon).
(2)Gd@C82(OH)nAdjust the experimental result of the content of PI3K and/or AKT
As shown in Fig. 2, mRNA expression (the i.e. opposite mRNA of mRNA expression here that Fig. 2 is PI3K in muscle
PI3K mrna expression amount/naive mice PI3K mRNA of expression quantity, opposite mrna expression amount=each group mouse is expressed
Amount).The PI3K mRNA content of the model group mouse of fullerene treatment is not carried out with diabetes but compared to naive mice
The decline of PI3K mRNA content, but the content of the PI3K mRNA of the mouse after water-soluble fullerene structure treatment increases, and says
Bright water-soluble fullerene structure can promote the generation of PI3K mRNA, to promote the generation of PI3K, go forward side by side a step section PI3K
The physiological change that relevant downstream signal and signal generate.
(mRNA expression here is opposite mrna expression amount to the mRNA expression that Fig. 3 is AKT in muscle, relatively
Mrna expression amount=each group mouse AKT mrna expression amount/naive mice AKT mrna expression amount).With blank group phase
Than not carrying out with diabetes but Gd@C82(OH)nThere are insulin resistance, insulin letters for the model group db/db mouse for the treatment of
Number access abnormal expression, AKT mRNA content is decreased obviously, but the AKT of the mouse after water-soluble fullerene structure treatment
MRNA content is obviously improved, suitable with blank group.Fig. 4 is the protein expression water of AKT and phosphorylation AKT (pAKT) in mouse muscle
It is flat, by protein band this it appears that compared to the blank group, the content of the AKT and pAKT of model group db/db mouse are all drops
Low, but pass through Gd@C82(OH)nThe expression for treating rear AKT and pAKT all increased.And the mouse of inhibitor group presses down through AKT
After preparation processing, the content of AKT and pAKT are reduced.Fig. 3 and Fig. 4 proves that water-soluble fullerene structure can promote the expression of AKT；
Fig. 5 shows yet Relative Expression values (pAKT/AKT Relative Expression values=each group mouse pAKT/ of each group mouse of pAKT/AKT
The pAKT/AKT value of AKT value ÷ naive mice), wherein the ratio of pAKT/AKT improves in the muscle of experimental mice, explanation
Water-soluble fullerene structure can promote the activation of AKT, and take the mouse of AKT inhibitor, pAKT/AKT in muscle
Ratio does not significantly improve.
(3) water-soluble embedded metal fullerene Gd@C82(OH)nImprove insulin resistance.
Such as the variation that Fig. 6 is blood glucose in insulin resistant experiment.Through Gd@C82(OH)nDiabetic mice injection after treating
Blood sugar concentration declines after insulin, and insulin resistance is obviously improved, but has taken the mouse insulin injection of AKT inhibitor
Afterwards, blood glucose not decreased significantly, in conjunction in Figure 4 and 5 in inhibitor group mouse muscle pAKT and AKT expression decline, explanation
Water-soluble fullerene structure is to improve insulin resistant by promoting the activation of AKT.
The present invention is using db diabetic mice as model, with water-soluble embedded metal fullerene Gd@C82(OH)nFor, it grinds
The effect that water-soluble fullerene structure adjusts, activates PI3K and AKT is studied carefully, and in the relevant disease of PI3K and/or AKT or barrier
Application in hindering.
The aforementioned description to specific exemplary embodiment of the invention is in order to illustrate and illustration purpose.These descriptions
It is not wishing to limit the invention to disclosed precise forms, and it will be apparent that according to the above instruction, can much be changed
And variation.The purpose of selecting and describing the exemplary embodiment is that explaining specific principle of the invention and its actually answering
With so that those skilled in the art can be realized and utilize a variety of different exemplary implementation schemes of the invention and
Various chooses and changes.The scope of the present invention is intended to be limited by claims and its equivalents.
Claims (10)
1. a kind of water-soluble fullerene structure is preparing the application in PI3K-AKT signal path regulator, the water solubility fowler
Alkene structure includes at least one below: water-soluble modified empty fullerene, water-soluble modified embedded metal fullerene, institute
State the composition of water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene, the above three can
The pharmaceutical salt of medicinal ester or the above three.
2. a kind of application of water-soluble fullerene structure in the drug for the disease that preparation treatment PI3K-AKT signal path mediates,
The water-soluble fullerene structure includes at least one below: in water-soluble modified empty fullerene, water-soluble modification
The combination of engaged column fullerene, the water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene
The pharmaceutical salt of object, the pharmaceutical ester of the above three or the above three.
3. a kind of pharmaceutical composition for the disease for treating the mediation of PI3K-AKT signal path, including at least one water selected from the group below
Dissolubility fullerene structure is as effective component: water-soluble modified empty fullerene, water-soluble modified embedded metal fullerene,
The composition of the water-soluble modified empty fullerene and the water-soluble modified embedded metal fullerene, the above three
Pharmaceutical ester or the pharmaceutical salt of the above three, described pharmaceutical composition further include pharmaceutical carrier, diluent or tax
At least one of shape agent.
4. water-soluble fullerene structure according to claim 1 is preparing the application in PI3K-AKT signal path regulator
Or water-soluble fullerene structure as claimed in claim 2 is in the drug for the disease that preparation treatment PI3K-AKT signal path mediates
Application or pharmaceutical composition as claimed in claim 3, it is characterised in that:
The water-soluble modified empty fullerene includes selected from the group below one or more: (1) in empty fullerene ontology
Carbon cage outer surface is modified with the modification empty fullerene of hydrophilic radical；(2) the carbon cage outer surface of empty fullerene ontology is hydrophilic
Property biological micromolecule package modification empty fullerene；(3) empty fullerene ontology is by the carrier material with biocompatibility
The modification empty fullerene of load and formation；(4) empty fullerene for the water-soluble supramolecular system being self-assembly of；
The water-soluble modified embedded metal fullerene includes selected from the group below one or more: (1) in embedded metal fowler
The carbon cage outer surface of alkene ontology is modified with the modification embedded metal fullerene of hydrophilic radical；(2) embedded metal fullerene ontology
The modification embedded metal fullerene that carbon cage outer surface is wrapped up by hydrophily biological micromolecule；(3) embedded metal fullerene ontology quilt
The modification embedded metal fullerene of carrier material load with biocompatibility and formation；(4) water solubility being self-assembly of
The embedded metal fullerene of supramolecular system.
5. water-soluble fullerene structure according to claim 4 is preparing the application in PI3K-AKT signal path regulator
Or water-soluble fullerene structure as claimed in claim 4 is in the drug for the disease that preparation treatment PI3K-AKT signal path mediates
Application or pharmaceutical composition as claimed in claim 4, it is characterised in that:
Empty fullerene ontology includes that one or more general formulas are C2mThe cage structure being made of carbon atom, 20≤m≤60 can
30≤m≤60 of choosing, further alternative m are 30 or 35 or 42；
Embedded metal fullerene ontology includes M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nWith
MxA3-xN@C2nOne of or it is a variety of, in which: M, A represent metallic element and M, A are selected from Sc, Y and lanthanide element
Any one, 20≤n≤60, optional 30≤n≤60, n be 41 or 30 or 35；0≤x≤3.
6. water-soluble fullerene structure according to claim 4 is preparing the application in PI3K-AKT signal path regulator
Or water-soluble fullerene structure as claimed in claim 4 is in the drug for the disease that preparation treatment PI3K-AKT signal path mediates
Application or pharmaceutical composition as claimed in claim 4, it is characterised in that: the hydrophilic radical include hydroxyl, carboxyl, sulfydryl,
One of amino or hydrophilic amino-acid residue are a variety of.
7. water-soluble fullerene structure according to claim 1 is preparing the application in PI3K-AKT signal path regulator
Or water-soluble fullerene structure as claimed in claim 2 is in the drug for the disease that preparation treatment PI3K-AKT signal path mediates
Application or pharmaceutical composition as claimed in claim 3, it is characterised in that:
The general formula of the water-soluble modified empty fullerene is C2a(OH)b；20≤a≤60, optional 30≤a≤60, into one
Walking optional a is 30 or 35 or 42；0 <b≤50, optional 0 <b≤30,10≤b≤30,20≤b≤30, further alternative b
=13,20,22,24 or 26；
The general formula of the water-soluble modified embedded metal fullerene is metallofullerene- (OH)c；
Metallofullerene represents embedded metal fullerene ontology, 0 < c≤50, optional 0 < c≤30,10≤c≤30,20≤c
≤ 30, further alternative c=13,20,22,24 or 26.
8. water-soluble fullerene structure according to claim 7 is preparing the application in PI3K-AKT signal path regulator
Or water-soluble fullerene structure as claimed in claim 7 is in the drug for the disease that preparation treatment PI3K-AKT signal path mediates
Application or pharmaceutical composition as claimed in claim 7, it is characterised in that: the water-soluble modified embedded metal fullerene
General formula is M@C2d(OH)e；M is selected from rare earth metal, and optional rare earth metal is Gd or La；20≤d≤60, further alternative 30
≤ d≤60, d are 41 or 30 or 35；0 < e≤50, optional 0 < e≤30,10≤e≤30,20≤e≤30, also optional e=
13,20,22,24 or 26.
9. water-soluble fullerene structure according to claim 1 is preparing the application in PI3K-AKT signal path regulator
Or water-soluble fullerene structure as claimed in claim 2 is in the drug for the disease that preparation treatment PI3K-AKT signal path mediates
Application or pharmaceutical composition as claimed in claim 3, it is characterised in that: the water-soluble modified empty fullerene is to pass through
Water-soluble modified acquisition is carried out to empty fullerene ontology；The water-soluble modified embedded metal fullerene is by internal
Engaged column fullerene ontology carries out water-soluble modified acquisition；
Optionally, described water-soluble modified for surface modification hydroxyl, the method for surface modification hydroxyl are as follows: by empty fullerene ontology
And/or embedded metal fullerene ontology, hydrogen peroxide and aqueous slkali mix and are reacted to empty fullerene ontology and/or embedded
Metal fullerene ontology all dissolves, and gained reaction solution is filtered, filtrate washing, collects precipitating later and then dialyses, obtain with
The corresponding water soluble hydroxy derivative of ontology；
It is further alternative, the method for surface modification hydroxyl are as follows: the hydrogen peroxide and quality that mass percentage is 1-30% by (a)
The sodium hydrate aqueous solution and/or potassium hydroxide aqueous solution that percentage composition is 10-80% are that 1-10:1 is mixed according to volume ratio
To mixed liquor, 20-500mg empty fullerene ontology and/or embedded metal fullerene sheet are added in every 10-200ml mixed liquor
Body, stirring is all dissolved to solid under conditions of 50-80 DEG C, and filtering retains filtrate；(b) filtrate is added excessive
Concentration is that the ethyl alcohol of 85%-100% is washed, and collects precipitating, and the precipitating is dissolved in water, obtains solution；(c) by (b)
The solution that step obtains carries out dialysis treatment.
10. the disease that water-soluble fullerene structure according to claim 2 is mediated in preparation treatment PI3K-AKT signal path
Application or pharmaceutical composition as claimed in claim 3 in the drug of disease, it is characterised in that: what PI3K-AKT signal path mediated
Disease includes: at least one of glycolipid metabolism disease, hypertension, Apoptosis autophagy；Optionally, the glycolipid metabolism disease
Including diabetes and diabetic complication.
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| CN116656012A (en) * | 2022-02-18 | 2023-08-29 | 广东粤港澳大湾区国家纳米科技创新研究院 | Water-soluble fullerene compound and preparation method and application thereof |
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