CN108969536A - Application of the water-soluble fullerene structure in the drug of preparation treatment obesity - Google Patents
Application of the water-soluble fullerene structure in the drug of preparation treatment obesity Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/44—Elemental carbon, e.g. charcoal, carbon black
Abstract
The invention discloses application of the water-soluble fullerene structure in the drug of preparation treatment obesity, and the water-soluble fullerene structure includes the composition of water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and the water-soluble embedded metal fullerene, the pharmaceutical ester of the above three or the pharmaceutical salt in the above three.Above-mentioned water-soluble fullerene structure as effective component can efficiently treat obesity, improve fat metabolism, reduce the content of white adipose.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of water-soluble fullerene structure treats the drug of obesity in preparation
In application.
Background technique
Obesity is a kind of common metabolic syndrome.When the human body consumes more calories than it consumes, extra heat
Amount is stored in fat cell as a triglyceride, is increased intracorporal Fat Accumulation, is finally developed into obesity.Obesity
1. percentage composition (F) that diagnostic criteria presses body fat calculates, the adult male F=15% of general Normal-weight, women F=
22%, if male F > 25%, women F > 30%, diagnosable is obesity；2. according to body mass index BMI (weight/height2It is single
Position kg/m2) judge, suggest by WHO: BMI=18.5-24.9 be it is normal, 25-29.9 be it is overweight, > 30 is obesity；③
Waistline (WC) male > 94cm, female > 80cm are obesity.
According to the Crack cause of obesity, three types can be classified as: simple obesity, secondary fat and drug
Property it is fat, wherein simple obesity is divided into constitutional obesity again and crosses feeding habits obesity.In recent decades, with the city in China
Change development, living standards of the people are also faced with nervous allegro work while continuous improvement.Dietary structure variation and shortage
It takes exercise so that China's population of being obese quicklys increase.If taking measures to be treated not in time, obesity will increase patient's hypertension,
The risk of the metabolism class disease such as atherosclerosis, diabetes, fatty liver, seriously affects the good health and a long life of the mankind.
The caged Spectra of Carbon Clusters that fullerene is made of different number of carbon atoms is except graphite, diamond and unformed
Another allotrope of carbon except carbon.The most fullerene molecule of content is C60, followed by C70、C84, followed by contain
Measure relatively small number of C76、C78、C82Deng.Carbon cage inside additionally, due to fullerene is cavity structure, therefore its internal cavities can be interior
Embedding not homoatomic, ion or cluster are referred to as embedded fullerene, such as Gd C82, indicate that Gd is embedded in C82Cage structure
In ,@indicates at, and vivid expresses embedded meaning.Fullerene structure is because its unique molecular structure determines its uniqueness
Physicochemical properties.
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
The purpose of the present invention is to provide a kind of water-soluble fullerenes, water-soluble embedded metal fullerene, water solubility
Fullerene and the composition of water-soluble embedded metal fullerene, the corresponding pharmaceutical ester of the above three or the above three couple
Application of the pharmaceutical salt answered in the drug of preparation treatment obesity.Another object of the present invention is to provide one kind to include
The pharmaceutical composition of the treatment obesity of above-mentioned water-soluble fullerene structure.A further object of the present invention is to provide a kind of uses
The method of above-mentioned water-soluble fullerene structure treatment obesity.Above-mentioned water-soluble fullerene structure as effective component can be high
The treatment of effect ground is fat, improves fat metabolism, reduces the content of white adipose.
In order to realize purpose, the present invention provides following technical schemes:
A kind of water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and the water
Pharmaceutical salt in the composition of the embedded metal fullerene of dissolubility, the pharmaceutical ester of the above three or the above three is being made
Application in the drug of standby treatment obesity.
The present invention also provides a kind of methods for treating obesity, including applying effective quantity to the subject with obesity
At least one effective component selected from the group below: water-soluble fullerene, water-soluble embedded metal fullerene, the water solubility
Fullerene and the composition of the water-soluble embedded metal fullerene, the pharmaceutical ester of the above three, the above three
Pharmaceutical salt.
The present invention also provides a kind of pharmaceutical composition for treating obesity, including it is at least one it is selected from the group below effectively at
Point: water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and described water-soluble embedded
The composition of metal fullerene, the pharmaceutical ester of the above three, the above three officinal salt, further include pharmaceutical load
At least one of body, diluent and excipient.
In another embodiment, the water-soluble fullerene includes choosing for above-mentioned application, method or pharmaceutical composition
From one or more fullerenes of the following group: (1) surface modification has the fullerene of hydrophilic radical；(2) by hydrophily biological micromolecule
The fullerene of package；(3) fullerene loaded by the carrier material with biocompatibility；(4) water solubility being self-assembly of
Supramolecular system fullerene.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the water-soluble embedded metal fowler
Alkene includes one or more embedded metal fullerenes selected from the group below: (1) surface modification has the embedded metal fowler of hydrophilic radical
Alkene；(2) the embedded metal fullerene wrapped up by hydrophily biological micromolecule；(3) it is born by the carrier material with biocompatibility
The embedded metal fullerene of load；(4) the water-soluble supramolecular system embedded metal fullerene being self-assembly of.
In another embodiment, the fullerene includes one or more for above-mentioned application, method or pharmaceutical composition
General formula is C2mThe cage structure being made of carbon atom, 30≤m≤60, such as；C60, C70, C84Deng.
In another embodiment, the embedded metal fullerene includes M@for above-mentioned application, method or pharmaceutical composition
C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nOne of or it is a variety of, in which: M, A
It represents metallic element and M, A is selected from any one in Sc, Y and lanthanide element, 30≤n≤60；0≤x≤3.Example
Such as: Gd@C82.N represents nitrogen, and C represents carbon, and S represents element sulphur, lanthanide element include La, Ce, Pr, Nd, Pm,
Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
In another embodiment, the hydrophilic radical includes hydroxyl, carboxylic for above-mentioned application, method or pharmaceutical composition
One of base, sulfydryl, amino, water-soluble amino acids residue are a variety of.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the general formula of the water-soluble fullerene
For C2a(OH)b(Amino Acid)c, Amino Acid represents water-soluble amino acids residue；30≤a≤60, optional a be 30 or
35；0 <b < 50, optional 0 <b < 30, also optional b=13,20,24 etc.；0≤c < 20, optional c=2-15, also optional c
=6.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the water solubility embedded metal fullerene
General formula be M@C2d(OH)e(Amino Acid)f, Amino Acid represents water-soluble amino acids residue；M is selected from rare earth metal,
Optional rare earth metal is Gd, La etc.；30≤d≤60, optional d are 41 or 30 or 35；0 < e < 50, optional 0 < e < 30, also
Optional e=13,20,24 etc.；0≤f < 20, optional f=2-15, also optional f=6.
In another embodiment, the water-soluble amino acids residue refers to for above-mentioned application, method or pharmaceutical composition
Water-soluble amino acids are modifying fullerene and/or when embedded metal fullerene, lose remaining after a part of amino acid molecular
Incomplete amino acid, it may be assumed that amino acid residue is a part of amino acid molecular, is incomplete amino acid.Lack amino
Any one of acid molecule part is all amino acid residue, such as: losing the hydrogen in amino acid on amino, lose in amino acid
Hydrogen or hydroxyl on carboxyl etc..Optionally, the water-soluble amino acids residue is alanine residue, glycine residue, serine
At least one of residue, arginine residues, lysine residue and tianmenine residue.
In another embodiment, the hydrophily biological micromolecule includes for above-mentioned application, method or pharmaceutical composition
At least one of amino acid and peptide chain.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the carrier with biocompatibility
Material includes at least one of liposome and cell membrane carrier.
Method, the method for package, the method for load and the method for self assembly of above-mentioned modification can be according to prior art public affairs
The method opened carries out.It is listed below:
(1) method of physics cladding can by least one of raw material fullerene and raw material embedded metal fullerene with it is poly-
At least one of ethylene glycol, polyvinylpyrrolidone and cyclodextrin mix and carry out ball milling or ultrasound etc. and can be obtained by with it is former
The water-soluble fullerene structure coated accordingly is expected, such as the fullerene of coated with polyethylene glycol and/or embedding for coated with polyethylene glycol
Metal fullerene, the fullerene of polyvinylpyrrolidone cladding and/or the embedded metal fullerene of polyvinylpyrrolidone cladding.
(2) when the number in water-soluble fullerene structure containing amino acid residue is 0 (i.e. Fullerol), can be turned by phase
The reactive liquid solution (XingG et al, J.Phys.Chem.B., 2004 (108): 11473-11479) or richness that shifting catalyst participates in
Alkene/embedded metal fullerene ontology is strangled directly to react to obtain with aqueous slkali.Optionally, the embedded gold of water-soluble fullerene/water solubility
The preparation method for belonging to fullerene includes: (a) by aqueous hydrogen peroxide solution (optional, aqueous hydrogen peroxide solution mass percentage
For 1-30%) and sodium hydroxide solution/potassium hydroxide solution (optional, sodium hydroxide solution/potassium hydroxide solution quality hundred
Dividing content is 10-80%) and mixing (it is optional, according to aqueous hydrogen peroxide solution and sodium hydroxide solution/potassium hydroxide solution body
Long-pending ratio is that 1-10:1 is mixed), fullerene ontology/embedded metal fullerene ontology is added in mixed liquor (optionally, in every 10-
20-500mg fullerene ontology/embedded metal fullerene ontology is added in 200ml mixed liquor), it is reacted at 50-80 DEG C of temperature
(optional, the reaction is to be stirred to react 4-24h；Optionally, speed of agitator 1000r/min), filtering retains filtrate.(b)
Excessive ethyl alcohol (optional, the concentration of alcohol is 85%-100%) is added in the filtrate, by centrifugation (it is optional, from
Heart revolving speed is 10000r/min, centrifugation time 1-10min) precipitating is collected afterwards, the precipitating is dissolved in water, obtains solution.(c)
The solution that (b) step is obtained carries out dialysis treatment, optionally, dialyse to the solution room temperature conductivity less than 1 μ s/
cm；Optionally, the solution after the dialysis is freeze-dried, to obtain hydroxylating fullerene solid/hydroxylating
Embedded metal fullerene solid.
(3) when the number in water-soluble fullerene structure containing amino acid residue is not 0, (a) uses water soluble amino
Sour and NaOH/KOH preparation water soluble amino acid-base solution (optional, the mass ratio of water-soluble amino acids and NaOH/KOH are 1:
1-10 is also optionally 1:2 or 1:1-8；Optionally, the mass fraction of NaOH/KOH can be 10 in water soluble amino acid-base solution
~50%, it is also optional for 14% or 10~30%)；(b) according to amino acid and fullerene ontology/embedded metal fullerene ontology
Molar ratio is 1-1000:1, is optionally 50-1000:1,100-1000:1,200-1000:1, by amino acid-base solution and fowler
Alkene ontology/embedded metal fullerene ontology is mixed；(c) by 40-80 DEG C of said mixture reaction (optional, the reaction
To be stirred to react 1-7 hours), it is filtered to remove unreacted a small amount of solid powder；(d) filtrate dialysis removes small molecular weight impurity, mistake
After filter, obtained dark brown solution is water-soluble fullerene/embedded metal fullerene of amino acid modification of the invention.It can
It selects, the molecular cut off Mw=3500 for used bag filter of dialysing, the hole of miillpore filter used in the filtering after dialysis
Diameter 200-220nm.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the water-soluble amino acids be alanine,
At least one of glycine, serine, arginine, lysine and tianmenine.
In another embodiment, the treatment obesity includes: 1) to make body for above-mentioned application, method or pharmaceutical composition
Tend to again normal；2) the body fats contents such as subcutaneous fat, perirenal fat, gonadal fat are reduced.
In another embodiment, the drug or pharmaceutical composition can be piece for said medicine or aforementioned pharmaceutical compositions
It is agent, pill, powder, pastille, sachet, cachet, elixir, suspending agent, emulsion, solution, syrup, aerosol, ointment, soft
With the preparation of hard gelatin capsule, suppository, aseptic injectable solution or aseptic packaging powder-injection.Effective component is prepared into the present invention
Method known to a person of ordinary skill in the art can be used to prepare during the preparation process in the method for drug or pharmaceutical composition, 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, be used
Carrier dilution or encapsulating are in the carrier.Carrier, excipient and diluent are either serve as the carrier of effective component, excipient
And diluent, it is also possible to serve as the carrier of medium, excipient and diluent.
Drug or aforementioned pharmaceutical compositions in above-mentioned application in another embodiment, suitable carrier, excipient
It can be solid, semisolid or fluent material with diluent, such as: lactose, dextrose, sucrose, sorbierite, mannitol, starch, tree
Rouge, Arabic gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, fibre
Tie up element, aqueous syrup (water syrup), methylcellulose, methylparaben and propyl ester, talcum powder, magnesium stearate or liquid stone
Wax.
Drug or aforementioned pharmaceutical compositions in above-mentioned application in another embodiment, the drug or pharmaceutical composition
Lubricant, wetting agent, emulsification and suspending agent, preservative, sweetener or corrigent can also be also comprised.
Aforementioned pharmaceutical compositions in another embodiment, when the drug or described pharmaceutical composition in liquid form
In the presence of, concentration of the effective component in the drug or described pharmaceutical composition is 0.01-100mg/mL, is optionally
0.01-3mg/mL, 0.01-5mg/mL, 0.01-10mg/mL, 0.01-20mg/mL, 0.01-30mg/mL, 0.01-40mg/mL,
0.01-50mg/mL；When the drug or described pharmaceutical composition in solid form in the presence of, effective component in the drug or
Concentration in described pharmaceutical composition is 0.01-100mg/g, is optionally 0.01-3mg/g, 0.01-5mg/g, 0.01-10mg/
G, 0.01-20mg/g, 0.01-30mg/g, 0.01-40mg/g.
The above method in another embodiment, the subject be mammal, as mouse, cavy, rat, dog,
Rabbit, monkey and people etc..
In another embodiment, the administration dosage of the effective component is 1mg/kg/d-100mg/kg/ to the above method
D is optionally 1-20mg/kg/d, 1-10mg/kg/d etc., and the application course for the treatment of can be -30 days 5 days, can be taken in short term according to the state of an illness
Or it takes for a long time；The method of application of effective component can be oral, intravenous injection or intraperitoneal administration.
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 fullerene, water-soluble embedded metal fullerene, water-soluble fullerene and water-soluble interior
At least one of the composition of engaged column fullerene, the pharmaceutical ester of the above three and pharmaceutical salt of the above 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 " raw material fullerene ", " fullerene ", " fullerene ontology " are each meant not by water-soluble
Property modified fullerene.
Term used herein " raw material embedded metal fullerene ", " embedded metal fullerene ", " embedded metal fullerene
Ontology " is each meant not by water-soluble modified embedded metal fullerene.
The disclosure of all ranges should be considered as the disclosure to subranges and all point values all in range in the present invention.Example
Such as: the disclosure of 1-1000 should be considered as also disclosing 1-200, the ranges such as 200-300, at the same also disclose 200,300,400,
500, the point values such as 600,700,800,900 and 100.
It is described for convenience in the present invention, has used "/" symbol, meaning is at least one therein, such as " fullerene sheet
Body/embedded metal fullerene ontology " indicates at least one of fullerene ontology and embedded metal fullerene ontology.
Compared with prior art, the invention has the following beneficial effects: in the present invention as the above-mentioned water-soluble of effective component
Property fullerene structure can efficiently treat obesity, improve fat metabolism, reduce white adipose such as perirenal adipose tissue, subcutaneous rouge
The content of fat tissue and gonadal fat tissue.
Detailed description of the invention
Fig. 1 is 1Gd of embodiment of the present invention@C82(OH)13(NHCH2CH2COOH)6Thermogravimetric analysis thermogravimetric and difference quotient thermogravimetric are bent
Line.
Fig. 2 is 1Gd of embodiment of the present invention@C82(OH)13(NHCH2CH2COOH)6Infrared spectrogram.
Fig. 3 is electron spin nuclear magnetic resonance (ESR) figure of GF material in embodiment 3.
Fig. 4 is the changes of weight curve of each group mouse during drug treatment in embodiment 4, and the curve of top half is model
The curve of group and treatment group, is followed successively by model group, treatment group -0.375mM, treatment group -0.75mM and treatment group-from top to bottom
The curve of 1.5mM, lower half portion are blank group, and curve from top to bottom is followed successively by blank+physiological saline group, blank+GF group.
Fig. 5 is the weight gain figure of each group mouse in embodiment 4 after drug treatment start and ending, in which: N.S. is indicated
Physiological saline, GF indicate Gd@C82(OH)13(NHCH2CH2COOH)6, i.e., from left to right each group is respectively as follows: blank+physiological saline
Group, blank+GF group, model group, treatment group -0.375mM, treatment group -0.75mM and treatment group -1.5mM.
Fig. 6 is the statistical chart of each group mouse main portions fat content after drug treatment in embodiment 4, wherein: N.S. table
Show that physiological saline, GF indicate Gd@C82(OH)13(NHCH2CH2COOH)6, i.e., from left to right each group is respectively as follows: blank+physiological saline
Group, blank+GF group, model group, treatment group -0.375mM, treatment group -0.75mM and treatment group -1.5mM.In each group, from
It is left-to-right to respectively represent perirenal adipose tissue, subcutaneus adipose tissue and gonadal fat tissue.
Specific embodiment
With reference to the accompanying drawing, specific embodiments of the present invention will be described in detail, it is to be understood that guarantor of the invention
Shield range is not limited by the specific implementation.
Experimental method used in following embodiments is conventional method unless otherwise specified.Institute in following embodiments
Material, reagent etc., are commercially available unless otherwise specified.
The preparation for the embedded metal fullerene structure that embodiment 1, water-soluble amino acids are modified
10mg Gd@C82Solid is added in single port bottle, and the Beta-alanine alkali soluble that 6mlNaOH mass fraction is 14% is added
(molar ratio of amino acid and sodium hydroxide is specially 1:2 to liquid；Beta-alanine and Gd@C82Molar ratio be 1000:1), at 50 DEG C
It is vigorously stirred 1.5h, black solid, which gradually dissolves, generates dark brown solution.It is filtered to remove unreacted a small amount of solid powder, filtrate
Using ethanol washing, the dialysis of Mw=3500 bag filter removes small molecular weight impurity, uses the palm fibre obtained after 220nm filtering with microporous membrane
Dark solution is the embedded metal fullerene structure of water-soluble amino acids modification of the invention.
Embodiment 2
Gd@C is used to embodiment 182The embedded metal fullerene structure for the water-soluble amino acids modification being prepared carries out
Elemental analysis and thermogravimetric curve analysis, the results are shown in Table 1 for elemental analysis, and thermogravimetric curve is analyzed as shown in Figure 1:
The elemental analysis result of the embedded metal fullerene structure of 1 Beta-alanine of table modification
According to thermogravimetric curve analysis it can be concluded that containing in the embedded metal fullerene structure of water-soluble amino acids modification
10.9% water is about 13 H by calculating2O molecule further speculates in conjunction with elemental analysis and obtains being averaged for the substance
Molecular formula is Gd@C82(OH)13(NHCH2CH2COOH)6, hereinafter referred to as GF.
Fig. 2 is infrared spectroscopy in 3300cm-1The strong absorption peak of left and right is attributed to the stretching vibration of O-H, in 1740 Hes
1630cm-1Locate the bending vibration that medium absorption peak is attributed to the stretching vibration of C=O, N-H, in 1568,1400 and 1300cm-1
The strong peak at place is respectively the stretching vibration peak of the stretching vibration of C=C, the bending vibration of O-H and C-O, C-N.As shown in Figure 2,
Contain above-mentioned hydrophilic radical in the embedded metal fullerene structure of Beta-alanine modification of the present invention, i.e. the present invention is water-soluble.
Embodiment 3, the detection of water-soluble metal fullerene GF Scavenging ability
The present invention detects the energy that water-soluble metal fullerene GF removes free radical by Electron Spin Resonance Spectra (ESR)
Power.
Detection method: the method that hydroxyl radical free radical is generated using uv induction, by 40 μ LDMPO aqueous solutions, 20 μ
The aqueous hydrogen peroxide solution of L100mmol/L and the mixing of 20 μ L deionized waters are closed purple with the ultraviolet irradiation 4min of 280nm wavelength
Outer holding is one minute dark, Free Radical Signal is detected, as blank control group；Experimental group replaces the deionized water in above-mentioned experiment
It is changed to isometric water-soluble metal fullerene of the various concentration of the preparation of embodiment 1.As shown in figure 3, water-soluble metal is rich
It strangles alkene and significantly reduces the hydroxyl radical free radical signal in solution, and elimination effect increases as concentration increases.
The treatment of embodiment 4, water-soluble metal fullerene GF to obesity
(1) Experiment on therapy
This experiment mouse model used is ob/ob mouse, which is a kind of leptin secretion gene defection type obesity
Mouse cannot normally generate leptin (a kind of protein hormone can participate in the metabolism of internal carbohydrate and fat) in vivo, because
This lacks the ob/ob mouse meeting excess ingestion food of leptin secretion, and relative to the normal mouse of wild type, weight is obviously increased,
Figure becomes larger, and suffers from obesity.The mouse is purchased from Nanjing University-Nanjing biological medicine research institute, tests quoted from U.S. Jackson
Room.
Mouse is divided into 6 groups, it may be assumed that blank+physiological saline group, blank+GF group, model group, treatment group -0.375mM, treatment
Group -0.75mM, treatment group -1.5mM, every group of 6 mouse.Blank+physiological saline group, blank+GF group are not with obesity
Healthy mice, its average weight is 23g when administration；Model group, treatment group -0.375mM, treatment group -0.75mM, treatment group -
1.5mM is ob/ob mouse, its average weight is 33g when administration.
Blank+physiological saline group: mouse peritoneal injects 150 μ l physiological saline.Start to be administered within the 6th week after mouse birth, often
It is administered once, and continues 16 days.
Blank+GF group: mouse injects 150 μ of 1.5mM solution that water-soluble metal fullerene GF prepared by embodiment 1 is prepared
l.Start to be administered within the 6th week after mouse birth, is administered once a day, continues 16 days.
Model group: mouse peritoneal injects 150 μ l physiological saline.Start to be administered within the 6th week after mouse birth, daily administration one
It is secondary, continue 16 days.
Treatment group -0.375mM: it is molten that mouse injects the 0.375mM that water-soluble metal fullerene GF prepared by embodiment 1 is prepared
150 μ l of liquid.Start to be administered within the 6th week after mouse birth, is administered once a day, continues 16 days.
Treatment group -0.75mM: mouse injects the 0.75mM solution that water-soluble metal fullerene GF prepared by embodiment 1 is prepared
150μl.Start to be administered within the 6th week after mouse birth, is administered once a day, continues 16 days.
Treatment group -1.5mM: mouse injects the 1.5mM solution that water-soluble metal fullerene GF prepared by embodiment 1 is prepared
150μl.Start to be administered within the 6th week after mouse birth, is administered once a day, continues 16 days.
(2) therapeutic effect
The weight of the 1st, 4,7,10, the 13 and 16 day measurement each group mouse during drug treatment, draws each group Mice Body
Weight change curve；And calculate the increase of each group mouse weight during entire treatment.
Mouse subcutaneous fat, perirenal fat and gonadal fat are taken after drug treatment, count fat content to verify
Therapeutic effect of the water-soluble metal fullerene GF to obesity.
1) each group mouse weight changes
As shown in figure 4, the weight gain of ob/ob mouse is suppressed during being treated, and suppressed degree
It is positively correlated with administration concentration, wherein treatment group -1.5mM weight and model group body weight from the 7th day has significant difference, and protects
Hold treatment end, and treatment group -0.375mM is then without positive effect, treatment group -0.75mM is then between two groups of height.
Weight is more only infused after blank mouse peritoneal injection 1.5mM water-soluble metal fullerene GF normal saline solution not with obesity
That penetrates physiological saline has slight decline, but does not occur significant difference.
2) each group mouse weight increases
(# and ## indicate have significantly with blank group to the weight gain quality of mouse after treating from start to end as shown in Figure 5
Sex differernce, * and * * indicate there is significant difference with model group, i.e. model group and blank group has significant difference, treatment group and mould
Type group has significant difference), the weight gain of healthy mice of the model group ob/ob mouse weight relative to blank group without obesity
Significantly, but after being treated, body weight evolution is significantly reduced, and negatively correlated with administration concentration.
3) various fat content statistics after mouse materials
As shown in Figure 6 materials after to main adipose tissue (perirenal fat, subcutaneous fat and gonadal fat) quality into
Row counts (# and ## indicate there is significant difference with blank group, * and * * indicates there is significant difference with model group), in model group
Ob/ob obesity Mice Body in these three fat contents increase 7-10 times, after treatment relative to normal mouse, internal rouge
Fat content has decline, and wherein perirenal fat improves unobvious, and accounting declines more in vivo for subcutaneous fat and gonadal fat
Obviously.
After the above results can illustrate the normal saline solution of intraperitoneal injection water-soluble metal fullerene GF, ob/ob mouse
Obesity symptom improved, intracorporal fat content reduces.
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, water-soluble embedded metal fullerene, the water-soluble fullerene and described water-soluble
The composition of embedded metal fullerene, the pharmaceutical ester of the above three or the pharmaceutical salt of the above three of property are controlled in preparation
Treat the application in the drug of obesity.
2. application according to claim 1, it is characterised in that:
The water-soluble fullerene includes one or more fullerenes selected from the group below: (1) surface modification has hydrophilic radical
Fullerene；(2) fullerene wrapped up by hydrophily biological micromolecule；(3) it is loaded by the carrier material with biocompatibility
Fullerene；(4) the water-soluble supramolecular system fullerene being self-assembly of；
The water-soluble embedded metal fullerene includes one or more embedded metal fullerenes selected from the group below: (1) surface
It is modified with the embedded metal fullerene of hydrophilic radical；(2) the embedded metal fullerene wrapped up by hydrophily biological micromolecule；(3)
The embedded metal fullerene loaded by the carrier material with biocompatibility；(4) the water-soluble supermolecule being self-assembly of
It is embedded metal fullerene.
3. application according to claim 1, it is characterised in that:
The fullerene includes that one or more general formulas are C2mThe cage structure being made of carbon atom, 30≤m≤60, optionally
There is C60, C70, C84；
The embedded metal fullerene 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, 30≤n≤60；0≤x≤3；Optionally there is Gd@C82。
4. application according to claim 2, it is characterised in that: the hydrophilic radical include hydroxyl, carboxyl, sulfydryl, amino,
One of water-soluble amino acids residue is a variety of；The hydrophily biological micromolecule includes at least one in amino acid and peptide chain
Kind；The carrier material with biocompatibility includes at least one of liposome and cell membrane carrier.
5. application according to claim 4, it is characterised in that: the water-soluble amino acids residue is alanine residue, sweet
At least one of histidine residue, serine residue, arginine residues, lysine residue and tianmenine residue.
6. application according to claim 1, it is characterised in that: the general formula of the water-soluble fullerene is C2a(OH)b
(Amino Acid)c, Amino Acid represents water-soluble amino acids residue；30≤a≤60, optional a are 30 or 35；0<b<
50, optional 0 <b < 30, also optional b=13,20,24 etc.；0≤c < 20, optional c=2-15, also optional c=6.
7. application according to claim 1, it is characterised in that: the general formula of the water solubility embedded metal fullerene is M@C2d
(OH)e(Amino Acid)f, Amino Acid represents water-soluble amino acids residue；M is selected from rare earth metal, optional rare earth metal
For Gd, La etc.；30≤d≤60, optional d are 41 or 30 or 35；0 < e < 50, optional 0 < e < 30, also optional e=13,20,
24 etc.；0≤f < 20, optional f=2-15, also optional f=6.
8. application according to claim 4, it is characterised in that: surface modification has the water-soluble fullerene of hydroxyl/embedded
The preparation method of metal fullerene includes: (a) by aqueous hydrogen peroxide solution (optional, hydrogen peroxide in aqueous hydrogen peroxide solution
Mass percentage be 1-30%) and sodium hydroxide solution/potassium hydroxide solution (optionally, sodium hydroxide solution/hydroxide
Sodium hydroxide/potassium hydroxide mass percentage is 10-80% in potassium solution) and mixing (it is optional, it is water-soluble according to hydrogen peroxide
Liquid and sodium hydroxide solution/potassium hydroxide solution volume ratio are 1-10:1 mixing), be added in mixed liquor fullerene ontology/
Embedded metal fullerene ontology (it is optional, 20-500mg fullerene ontology/embedded metal is added in every 10-200ml mixed liquor
Fullerene ontology), (optional, the reaction is to be stirred to react 4-24h for reaction at 50-80 DEG C of temperature；Optionally, stirring turns
Speed is 1000r/min), filtering retains filtrate；(b) excessive ethyl alcohol (optional, the concentration of alcohol is added in the filtrate
For 85%-100%), it is heavy to collect afterwards by centrifugation (optional, centrifugal rotational speed 10000r/min, centrifugation time 1-10min)
It forms sediment, the precipitating is dissolved in water, obtains solution；(c) solution for obtaining (b) step carries out dialysis treatment, and optionally, dialysis is extremely
The solution room temperature conductivity less than 1 μ s/cm；Optionally, the solution after the dialysis is freeze-dried, with
Just hydroxylating fullerene solid/hydroxylating embedded metal fullerene solid is obtained.
9. application according to claim 4, it is characterised in that: surface modification has the water-soluble of hydroxyl and amino acid residue
Fullerene/embedded metal fullerene preparation method includes: that (a) uses water-soluble amino acids and the water-soluble ammonia of NaOH/KOH preparation
(optional, the mass ratio of water-soluble amino acids and NaOH/KOH are 1:1-10 to base acid-base solution, are also optionally 1:2 or 1:1-
8；Optionally, the mass fraction of NaOH/KOH can be 10~50% in water soluble amino acid-base solution, it is also optional for 14% or
10~30%)；It (b) is 1-1000:1 according to amino acid and fullerene ontology/embedded metal fullerene ontology molar ratio, optionally
For 50-1000:1,100-1000:1,200-1000:1, by amino acid-base solution and fullerene ontology/embedded metal fullerene sheet
Body is mixed；(c) by 40-80 DEG C of said mixture reaction (optional, the reaction is to be stirred to react 1-7 hours), filtering
Remove unreacted a small amount of solid powder；(d) filtrate dialysis removes small molecular weight impurity, and after filtering, obtained dark brown solution is i.e.
For water-soluble fullerene/embedded metal fullerene of amino acid modification of the invention.Optionally, bag filter used in dialysing
Molecular cut off Mw=3500, the aperture 200-220nm of miillpore filter used in the filtering after dialysis.
10. application according to claim 1, it is characterised in that: the treatment obesity includes: 1) to tend to weight just
Often；2) body fat content is reduced, the optional body fat includes subcutaneous fat, perirenal fat, in gonadal fat
It is at least one.
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| CN111317746A (en) * | 2018-12-13 | 2020-06-23 | 中国科学院化学研究所 | Application of fullerene structure in preparation of drug for treating Alzheimer disease |
| CN111514306A (en) * | 2020-04-23 | 2020-08-11 | 中国科学院化学研究所 | Fullerene nano-particles for enhancing anti-tumor immunotherapy |
| WO2021180225A1 (en) * | 2020-03-12 | 2021-09-16 | 青岛农业大学 | New application of c60 and method for measuring activity of products thereof |
| 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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