CN109223827A - Application of the water-soluble fullerene structure in the drug of preparation treatment pulmonary fibrosis - Google Patents
Application of the water-soluble fullerene structure in the drug of preparation treatment pulmonary fibrosis Download PDFInfo
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Abstract
The invention discloses application of the water-soluble fullerene structure in the drug of preparation treatment pulmonary fibrosis, which 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.The case where water-soluble fullerene structure can treat pulmonary fibrosis in the present invention, hyperemia, oedema or hypertrophy including treating lung, treatment lung's collagen fiber hyperplasia, accumulation.And the effective component can be metabolized by organism and be excreted, and be had no toxic side effect, and have good biocompatibility.
Description
Technical field
The present invention relates to field of medicaments, in particular to a kind of water-soluble fullerene structure is in preparation treatment pulmonary fibrosis
Application in drug.
Background technique
Pulmonary fibrosis is with fibroblast proliferation and the aggregation of a large amount of extracellular matrixs and broken with inflammation damnification, institutional framework
The terminal phase of the bad major class lung disease being characterized changes, that is, normal alveolar tissue is by chemically or physical damage
Afterwards, fibroblast secretion collagen carries out textural anomaly caused by interstitial tissue of lung repairs (scar is formed).At present to it
The cause of disease and pathogenesis not yet illustrate, and clinically the main pathogenic of pulmonary fibrosis has: sucking inorganic or organic dust, radiation
Type damage, familial pulmonary fibrosis etc..It is now recognized that pulmonary fibrosis initial stage is chronic inflammation processes, such as sarcoidosis, Wei Genashi
Granulomatosis, environment agent (asbestos, silica are exposed to certain gases), is exposed to ionising radiation (such as treatment chest at infection
The radiation-therapy of tumour), chronic pathology (lupus) and some drugs treat (amiodarone, bleomycin, bleomycin A5, ring phosphorus
Amide, cytarabine, Karl Fischer reagents, mitomycin, busulfan, methopterin and furantoin) it can cause pulmonary fibrosis.
Clinically pulmonary fibrosis shows as progressive expiratory dyspnea and abnormal pulmonary function, its 5 years case fatality rate are reachable after making a definite diagnosis
50%-70%.Preferred treatment method of the glucocorticoid as idiopathic pulmonary fibrosis for a long time, is particularly suitable for acute stage
The treatment of pulmonary fibrosis, but it is weaker to the curative effect of chronic phase pulmonary fibrosis.In addition, glucocorticoid anti-inflammatory effect hold time it is short
Temporarily, late result is not good enough, clinically always searches for the new way for the treatment of idiopathic pulmonary fibrosis.Therefore find it is a kind of novel and
The drug of effective treatment pulmonary fibrosis is extremely urgent.
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.
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 pharmaceutical ester of the above three or the above three can medicine
Application of the salt in the drug of preparation treatment pulmonary fibrosis.Lung fiber is treated another object of the present invention is to provide a kind of
The pharmaceutical composition and method of change.
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
It is prepared by the pharmaceutical salt of the composition of the embedded metal fullerene of dissolubility, the pharmaceutical ester of the above three or the above three
Treat the application in the drug of pulmonary fibrosis.
The present invention also provides a kind of methods for treating pulmonary fibrosis, including having to subject's application with pulmonary fibrosis
At least one effective component selected from the group below of effect amount: water-soluble fullerene, water-soluble embedded metal fullerene, the water
The composition of the fullerene of dissolubility and the water-soluble embedded metal fullerene, the above three pharmaceutical ester and more than three
The pharmaceutical salt of person.
The present invention also provides a kind of pharmaceutical composition for treating pulmonary fibrosis, including at least one are selected from the group below effectively
Ingredient: water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and it is described it is water-soluble in
The composition of engaged column fullerene, the pharmaceutical ester of the above three, the above three officinal salt, described pharmaceutical composition is also
Including at least one of pharmaceutical carrier, pharmaceutical diluent and pharmaceutical excipient.
In another embodiment, the water-soluble fullerene is selected from down for above-mentioned application, method or pharmaceutical composition
That organizes is one or more: (1) carbon cage outer surface is modified with the fullerene of hydrophilic radical；(2) carbon cage outer surface is by hydrophily biology
The fullerene of small molecule package；(3) fullerene loaded by the carrier material with biocompatibility；(4) it is self-assembly of
Water-soluble supramolecular system fullerene.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the water-soluble embedded metal fowler
Alkene is selected from the group below one or more: (1) carbon cage outer surface is modified with the embedded metal fullerene of hydrophilic radical；(2) outside carbon cage
The embedded metal fullerene that surface is wrapped up by hydrophily biological micromolecule；(3) it is loaded by the carrier material with biocompatibility
Embedded metal fullerene；(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 lanthanide element, Sc and Y, 30≤n≤60,0≤x≤3, example
Such as: Gd@C82、Gd3N@C80.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 and water-soluble amino acids residue are a variety of.
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.It is also optional, the water soluble amino
Sour residue is at least one of alanine residue, serine residue and lysine residue
In another embodiment, the hydrophily biological micromolecule includes for above-mentioned application, method or pharmaceutical composition
At least one of amino acid and protein；Optionally, the protein is albumin or transferrins.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the carrier with biocompatibility
Material includes at least one of liposome, polymer micelle and cell membrane carrier；Optionally, the polymer micelle is poly- second third
Lactide polyethylene glycol (PEG-PLGA), polylysine or chitosan.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the general formula of the water-soluble fullerene
For C2n(OH)x(Amino Acid)y, Amino Acid represents water-soluble amino acids residue；30≤n≤60, optional n be 30 or
35；0 < x < 50, optional 20 < x < 30, also optional x=24；0≤y<20；The water-soluble embedded metal fullerene nanometer
The general formula of particle is M@C2a(OH)b(Amino Acid)c, Amino Acid represents water-soluble amino acids residue；M is selected from rare earth gold
Belong to, optional rare earth metal is Gd, La etc.；30≤a≤60, optional a are 41 or 30 or 35；0≤b<50；0<c<20.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the water-soluble fullerene and water-soluble
Property embedded metal fullerene hydration radius be 1-1000nm, be optionally 80-180nm.
In another embodiment, the water-soluble fullerene is to pass through for above-mentioned application, method or pharmaceutical composition
Water-soluble modified acquisition is carried out to raw material fullerene；The water-soluble embedded metal fullerene is by the embedded gold of raw material
Belong to fullerene and carries out water-soluble modified acquisition.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the water-soluble modified method be with
Any one of lower method: (1) method of surface modification hydrophilic radical is generally anti-by solid-liquid or liquid liquid in the presence of alkali
It should realize, specially mix at least one of raw material fullerene and raw material embedded metal fullerene with hydrogen peroxide and aqueous slkali
And reacted, then wash, it then dialyses, water soluble hydroxy derivative corresponding with raw material can be obtained.If necessary to obtain
Sodium hydroxide in above-mentioned steps is substituted for ammonium hydroxide by water-soluble amino derivative.(2) method of physics cladding can be with
By at least one of fullerene and embedded metal fullerene in polyethylene glycol, polyvinylpyrrolidone and cyclodextrin at least
A kind of mixing simultaneously carries out ball milling or ultrasound etc. and can be obtained by the water-soluble fullerene structure being wrapped by corresponding with raw material, such as poly-
The fullerene of ethylene glycol cladding and/or the embedded metal fullerene of coated with polyethylene glycol, the fowler of polyvinylpyrrolidone cladding
The embedded metal fullerene of alkene and/or polyvinylpyrrolidone cladding.(3) residual when containing amino acid in water-soluble fullerene structure
When the number of base is not 0, (a) prepares water soluble amino acid-base solution (optional, water using water-soluble amino acids and NaOH/KOH
The molar ratio of dissolubility amino acid and NaOH/KOH are 1:1-10, are also optionally 1:2 or 1:1-8；Optionally, water-soluble amino acids
The mass fraction of NaOH/KOH can be 10~50% in aqueous slkali, it is also optional for 14% or 10~30%)；(b) according to amino
Acid is 1-1000:1 with fullerene ontology/embedded metal fullerene ontology molar ratio, is optionally 50-1000:1,100-1000:
1,200-1000:1, amino acid-base solution is mixed with fullerene ontology/embedded metal fullerene ontology；It (c) will be above-mentioned
40-80 DEG C of mixture reaction (optional, the reaction is to be stirred to react 1-7 hours), is filtered to remove unreacted a small amount of solid
Powder；(d) filtrate dialysis removes small molecular weight impurity, and after filtering, obtained dark brown solution is amino acid modification of the invention
Water-soluble fullerene/embedded metal fullerene.Optionally, the molecular cut off Mw=of bag filter used in dialysing
3500, the aperture 200-220nm of miillpore filter used in the filtering after dialysis.
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.
Above-mentioned application, method or pharmaceutical composition in another embodiment, described in water-soluble modified method (1)
Aqueous slkali is sodium hydroxide solution or potassium hydroxide solution.
Above-mentioned application, method or pharmaceutical composition in another embodiment, weigh 50~200mg C60Solid or C70
Solid or Gd@C82The hydrogen peroxide of solid and 3~15ml 20~40%, the aqueous slkali of 2~10ml5~60%, 50~100
Hybrid reaction is all dissolved to solid under conditions of DEG C, then uses ethanol washing, and dialysis obtains corresponding hydroxylation derivative,
That is water-soluble fullerene structure.In the description herein, performance is proportionate relationship between each substance, not by 50 in practical application
The limitation of~200mg, 5~15ml and the specific reaction scale of 2~10ml, can proportionally be expanded.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the raw material fullerene include it is a kind of or
A variety of general formulas are C2mThe cage structure being made of carbon atom, 30≤m≤60, such as；C60, C70, C84Deng.
Above-mentioned application, method or pharmaceutical composition in another embodiment, the raw material embedded metal fullerene packet
Include M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nOne of or it is a variety of,
In: M, A represent metallic element and M, A are selected from any one in lanthanide element, Sc and Y, 30≤n≤60,0≤x
≤3；Such as: Gd@C82、Gd3N@C80.N represents nitrogen, and C represents carbon, and S represents element sulphur, and lanthanide element includes
La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.
In another embodiment, the treatment pulmonary fibrosis includes following for above-mentioned application, method or pharmaceutical composition
At least one: 1) so that the organ coefficient of lung is tended to be normal；(2) hyperemia, oedema, hyperplasia or the hypertrophy of lung are treated；3) make in lung
Threadiness reduce；4) lactic dehydrogenase, catalase, superoxide dismutase, gluathione caused by pulmonary fibrosis are treated
The rising of fabk polypeptide, glutathione peroxidase, malonaldehyde；5) lung's collagen fiber hyperplasia or accumulation are treated；6) inhibit
The overexpression of transforming growth factor TGF-β；7) hydroxyproline content is reduced.
In another embodiment, the pulmonary fibrosis can be by common chronic for above-mentioned application, method or pharmaceutical composition
The inductions such as inflammation, infection, environment agent, radiation, chronic pathology, drug, chemical toxicant generate；Wherein: the chronic inflammation includes
But it is not limited to sarcoidosis, Wei Genashi granulomatosis etc. at present clinically；The environment agent includes but is not limited to asbestos, dioxy
SiClx is exposed to certain gases etc.；The radiation includes but is not limited to X-ray, gamma-rays etc.；Chronic pathology includes but is not limited to
Lupus, pharyngitis, bronchitis etc.；The drug include but is not limited to amiodarone, bleomycin, bleomycin A5, cyclophosphamide, Ah
Sugared cytidine, Karl Fischer reagents, mitomycin, busulfan, methopterin and furantoin etc.；The chemical toxicant includes but is not limited to four
Chlorination carbon, alcohol etc..
Drug or aforementioned pharmaceutical compositions in above-mentioned application in another embodiment, the drug or pharmaceutical composition
It is molten to can be tablet, pill, powder, pastille, sachet, cachet, elixir, suspending agent, emulsion, solution, syrup, gas
Glue, ointment, soft hard gelatin capsule, suppository, aseptic injectable solution or aseptic packaging powder-injection preparation.It will be effective in the present invention
Ingredient is prepared into drug or method known to a person of ordinary skill in the art can be used to prepare in the method for pharmaceutical composition, makes it
Quick-release, sustained release or sustained release effective component after being applied to subject, such as: effective component can be mixed with carrier, with load
Body dilution or encapsulating are in the carrier.
Drug or aforementioned pharmaceutical compositions in above-mentioned application are suitable for as carrier, figuration in another embodiment
Some examples of agent and diluent include lactose, dextrose, sucrose, sorbierite, mannitol, starch, resin, Arabic gum, phosphorus
Sour calcium, alginate, tragacanth, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, aqueous syrup
(water syrup), methylcellulose, methylparaben and propyl ester, talcum powder, magnesium stearate and liquid paraffin.
Drug or aforementioned pharmaceutical compositions in above-mentioned application in another embodiment, the drug or pharmaceutical composition
The auxiliary agents such as lubricant, wetting agent, emulsification and suspending agent, preservative, sweetener or corrigent can also be also comprised.
Drug or aforementioned pharmaceutical compositions in above-mentioned application in another embodiment, when the drug or the medicine
Compositions in liquid form in the presence of, concentration of the effective component in the drug or described pharmaceutical composition be 0.01-
50mg/mL is optionally 0.01-10mg/mL, 0.01-20mg/mL, 0.01-30mg/mL, 0.01-40mg/mL；When the medicine
Object or described pharmaceutical composition in solid form in the presence of, concentration of the effective component in the drug or described pharmaceutical composition
It is optionally 0.01-10mg/g for 0.01-50mg/g, 0.01-20mg/g, 0.01-30mg/g, 0.01-40mg/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, pig, ox, sheep, horse etc..
In another embodiment, the administration dosage of the effective component is 1mg/kg/d-500mg/kg/ to the above method
D is optionally 1-100mg/kg/d, 1-20mg/kg/d, 1-10mg/kg/d, and the application course for the treatment of can be -30 days 5 days, according to disease
Feelings can be taken or take for a long time in short term；The method of application of effective component can be Neulized inhalation, tracheal instillation, intravenous injection, abdomen
Chamber injection, oral and topical 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 " that any qualifier is not added are each meant not by water
Soluble modified fullerene, i.e. fullerene ontology.
Term used herein " raw material embedded metal fullerene ", " the embedded metal fullerene " that any qualifier is not added
It each means not by water-soluble modified embedded metal fullerene, i.e. embedded metal fullerene ontology.
Term used herein " water-soluble fullerene " refers to what fullerene ontology obtained after water-soluble modified
Water-soluble modified fullerene.
Term used herein " water-soluble embedded metal fullerene " refers to embedded metal fullerene ontology by water
The water-soluble modified embedded metal fullerene obtained after soluble modified.
In order to facilitate metering, all about water-soluble fullerene in the present invention, water-soluble embedded metal fullerene
The quantitative restriction such as concrete content, concentration is contained with its corresponding fullerene ontology or the specific of embedded metal fullerene ontology
Amount, concentration etc. are measured, such as: the administration dosage of effective component is that 1mg/kg/d-500mg/kg/d refers to every 1 day every 1kg
The effective component to be applied of mouse in corresponding fullerene ontology carbon cage amount be 1mg-500mg.
The invention has the benefit that
Water-soluble fullerene structure can treat pulmonary fibrosis in the present invention, hyperemia, oedema or hyperplasia including treating lung
The case where hypertrophy, treatment lung's collagen fiber hyperplasia, accumulation.And the effective component can be metabolized by organism and be excreted,
It has no toxic side effect, there is good biocompatibility.
Detailed description of the invention
Fig. 1 is gained C in the embodiment of the present invention 170The thermogravimetric analysis of-OH and difference quotient thermal gravimetric analysis curve.
Fig. 2 is the grading curve of GF-OH in embodiment 3.
Fig. 3 is C in embodiment 370The grading curve of-OH.
Fig. 4 is different group mouse weight change curves in embodiment 5.
Fig. 5 is the organ coefficient of different group mouse lungs in embodiment 5.
Fig. 6 is HE the and VG stained slice of different group mouse lungs in embodiment 5.
Fig. 7 is the hydroxyproline content of different group mouse lungs in embodiment 5.
Fig. 8 is transforming growth factor (TGF-β) relative expression quantity of different group mouse lungs in embodiment 5.
Fig. 9 is the TGF-β western blot figure of different group mouse lungs in embodiment 5.
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 unless otherwise specified, is
Conventional method.The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.Gd@C82
Solid and C70Solid is purchased from Xiamen good fortune and takes in the fresh material Science and Technology Ltd., purity 99%.
The metal fullerene Gd@C of embodiment 1, hydroxyl modified82With the empty fullerene C of hydroxyl modified70Preparation
(a) by 7mL mass percentage be 30% aqueous hydrogen peroxide solution and 3mL mass percentage be 40% hydrogen
100mL round-bottomed flask is added in sodium hydroxide solution, adds 200mg Gd@C82Or C70, later be added magnetic stir bar (model:
B200 it) and using magnetic stirring apparatus is stirred for 24 hours under conditions of temperature 70 C, revolving speed 1000r/min, uses filter sizes
Brown yellow solution is obtained by filtration in the solvent filter of 200nm.
(b) brown yellow solution for obtaining (a) step is added in the centrifuge tube of 50ml, and adding excessive concentration is 95%
Ethyl alcohol, under conditions of revolving speed 10000r/min be centrifuged 4min after remove upper layer colourless solution, the precipitating of collection is dissolved in super
In pure water, yellow clear solution is obtained.
(c) yellow clear solution that (b) step obtains is packed into the bag filter that cutoff is 3500 and is put into ultrapure water
Middle dialysis, the conductivity dialysed to ultrapure water obtain yellow solution in bag filter less than 1 μ s/cm.
(d) solution in bag filter is fitted into 50mL plastic centrifuge tube, using being put into freeze drier after liquid nitrogen frozen
In be freeze-dried 48h under conditions of -50 DEG C, vacuum degree 10Pa, obtain the metal fullerene Gd@C of yellow solid hydroxyl modified82
The empty fullerene C of (hereinafter referred to as GF-OH) or hydroxyl modified70(hereinafter referred to as C70- OH) and be fitted into standby in brown sample bottle
With.
Embodiment 2, water solubility GF-OH and C70The measurement of each element content in-OH
The C that above-described embodiment 1 is prepared70- OH nano particle carries out elemental analysis (Flash EA1112), and combines
Thermogravimetric and difference quotient thermogravimetric interpretation of result its connect hydroxyl value.In the result of elemental analysis, the C70In-OH, C content is
37.85%, H content 1.51%, N content < 0.3%.From thermogravimetric analysis (Fig. 1) it is found that C70Contain 3.7% in-OH solid powder
Water, about 5 hydrones can calculate carbon cage surface modification 24 in conjunction with the ratio of H content in elemental analysis and C content
Hydroxyl.So C70The average formula of-OH is C70(OH)24·5H2O。
The Gd@C that above-described embodiment 1 is prepared82Corresponding hydroxylation derivative (hereinafter referred to as Gd@C82(OH)n) into
Row element analysis, C content 76.6%, H content 0.89%, N content is less than 0.6%.
Embodiment 3, water solubility GF-OH and C70The measurement of-OH hydration partial size
The GF-OH and C for taking a small amount of embodiment of the present invention 1 to prepare70The pure water that-OH powder is dissolved in pH=7.0 respectively is made into 100
μM/weak solution of L, and due to intermolecular interaction, GF-OH and C70- OH is agglomerated into nano particle in water, forms average hydration
Particle of the partial size in 1~200nm.
The nano particle in the pure water of pH=7.0 is determined using dynamic light scattering (DLS, Zetasizer Nano ZSP)
Hydration partial size, the average grain diameter of GF-OH is 146.1nm, and grading curve is referring to fig. 2；C70The average grain diameter of-OH is
135.9nm, grading curve is referring to Fig. 3.
Embodiment 4 prepares injection solution
The GF-OH or C of corrresponding quality in Example 170- OH solid is dissolved in the physiological saline of respective volume, room
Warm ultrasound 5 minutes, is encapsulated in vial, injection solution is made.
Embodiment 5GF-OH and C70- OH treats the pulmonary fibrosis of bleomycin induction
1, animal model: selecting 8 weeks male C57BL/6 mouse, and average weight 20g is randomly divided into 6 groups, every group 6,6 groups
Respectively blank control group (Control), bleomycin (BLM)+physiological saline (Saline) group, BLM+GF-OH high dose (H)
Group, BLM+GF-OH low dosage (L) group, BLM+C70- OH (H) group, BLM+C70- OH (L) group.
2, experimental method:
(1) it models: passing through the Method Modeling of disposable tracheal instillation administration bleomycin (BLM).
Other 5 groups of mouse other than blank control group apply 10% chloraldurate according to the dosage of 3ml/kg and carry out fiber crops
It after liquor-saturated, is fixed on operating table, cuts off throat's skin, blunt separation after exposing tracheae, draws bleomycin with 1ml syringe
(PBS prepares 5mg/kg) solution, maximum injection volume are no more than 0.1ml and are disposed vertically mouse from tracheae fast injection, revolve
Turn 3 weeks, so that bleomycin is uniformly distributed in lung, sew up a wound, makes mouse naturally awake.
Blank control group injects the PBS of same volume in the same way.
(2) be administered: the modeling same day is calculated as Day 0, since Day 3, daily according to experimental group to each group mouse atomization
Corresponding drug is given in administration 15min sucking, in which:
BLM+GF-OH high dose group and BLM+C70The relative medicine of atomized medicine introducing is embodiment 4 respectively in-OH high dose group
The concentration of middle preparation is the GF-OH and C of 0.50mM70-OH；BLM+GF-OH low dose group and BLM+C70Mist in-OH low dose group
The relative medicine for changing administration is that the concentration prepared in embodiment 4 is the GF-OH and C of 0.25mM respectively70-OH.Above-mentioned 4 groups start
It is applied daily after administration 1 time, applies 150 μ L every time, be applied to and put to death mouse；
Blank control group (Control), bleomycin (BLM)+physiological saline (Saline) group are given and above-mentioned 4 groups of applications
The identical physiological saline of volume.
(3) experimental result:
(i) every 2d record mouse weight variation.
From the changes of weight curve (such as Fig. 4) of each group mouse as can be seen that BLM+Saline group and BLM+C70- OH (L) group
Quickly, and other groups of weight loss are relatively slow for decline after modeling for weight, and the changes of weight of BLM+GF-OH (H) group with
Control group is more consistent.
(ii) when 21 Day, each group mouse is put to death, serum and lung tissue are taken.Detect lactic dehydrogenase and third in serum
The concentration of dialdehyde；Lung tissue is weighed and calculates its organ coefficient (the organ coefficient i.e. weight of experimental animal internal organs and its body
The ratio of weight), the concentration of the lactic dehydrogenase and malonaldehyde in lung tissue is detected, and lung tissue is subjected to HE dyeing and VG dye
Color.
Organ coefficient result: Fig. 5 gives the organ coefficient of the lung of different group mouse, from figure 5 it can be seen that BLM+
The organ coefficient of the lung of Saline group is apparently higher than control group.Organ coefficient increases, and represents internal organs and congested, oedema or increasing has occurred
The physiopathologic variations such as raw hypertrophy, illustrate that chemotherapeutics bleomycin may cause hyperemia, oedema or the increasing of mice organs
Raw hypertrophy etc., and each treatment group reduces these lesions to a certain extent, compared to BLM+Saline group, each treatment group
Organ coefficient significantly reduces, and wherein BLM+GF-OH high dose group is better than BLM+C70- OH high dose group, BLM+GF-OH low dose group
Better than BLM+C70- OH low dose group.
Oxidation level result: lactic dehydrogenase oxidative stress relevant with pulmonary fibrosis to malonaldehyde in serum and lung tissue
Closely related, as shown in the table, pulmonary fibrosis caused by bleomycin can cause lactic acid dehydrogenase activity in serum and lung tissue
And the rising of mda content, illustrate that mouse body lipid levels of peroxide is higher, and fullerene, especially metal fullerene exist
This levels of peroxide can largely be mitigated, this is related to the excellent free radical scavenging ability of metal fullerene.
Lung tissue HE dyeing and VG coloration result: in VG dyeing, yellow is presented in muscle in the normal lung tissue of control group, and
Make VG dyeing that large area be presented along with the chronic inflammation of collagen fiber hyperplasia red.From the lung tissue HE of Fig. 6 dyeing and VG dye
Color slice sees that the drug of two kinds of fullerenes shows the therapeutic effect to pulmonary fibrosis, subtracts the threadiness in HE dyeing
It is few, make the red reduction in VG dyeing.The HE dyeing of BLM+GF-OH high dose group and VG coloring pathological section and control group are very
It is close, significantly improve the accumulation of lung's collagenous fibres.
The result of hydroxyproline content: hydroxyproline is the index of collagen deposition in lung tissue, as shown in fig. 7, compared to
The hydroxyproline content of Control group, BLM+Saline group dramatically increases, and illustrates in BLM+Saline group in mouse lung tissue
There is pulmonary fibrosis in collagen deposition, mouse lung tissue；And compared to BLM+Saline group, hydroxyl proline in each treatment group mouse
Content significantly reduces.
The result of transforming growth factor: transforming growth factor (TGF-β) is most important fibrogenic factor, be can induce thin
Extracellular matrix generates and fibroblast generates, and when overexpression will lead to Collagen fiber deposition and generate cicatricial tissue and fiber
Change.From in the lung tissue that Fig. 8 is shown in terms of the relative expression of TGF-β mRNA, GF-OH and C70The application of-OH significantly suppresses TGF-β
Expression in lung, this also matches with its protein immunoblot result in Fig. 9, i.e. GF-OH and C70The application of-OH significantly inhibits
TGF-β.
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 pulmonary fibrosis.
2. application according to claim 1, which is characterized in that
The water-soluble fullerene is selected from the group below one or more: (1) carbon cage outer surface is modified with the fowler of hydrophilic radical
Alkene；(2) fullerene that carbon cage outer surface is wrapped up by hydrophily biological micromolecule；(3) by the carrier material with biocompatibility
The fullerene of load；(4) the water-soluble supramolecular system fullerene being self-assembly of；
The water-soluble embedded metal fullerene is selected from the group below one or more: (1) carbon cage outer surface is modified with hydrophilic group
The embedded metal fullerene of group；(2) the embedded metal fullerene that carbon cage outer surface is wrapped up by hydrophily biological micromolecule；(3) quilt
The embedded metal fullerene of carrier material load with biocompatibility；(4) the water-soluble supramolecular system being self-assembly of
Embedded metal fullerene.
3. application according to claim 2, which is characterized in that
The fullerene includes that one or more general formulas are C2mThe cage structure being made of carbon atom, 30≤m≤60, optionally
For 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 lanthanide element, Sc and Y
Any one, 30≤n≤60,0≤x≤3；It is optionally Gd@C82、Gd3N@C80。
4. application according to claim 1, which is characterized in that the hydrophilic radical includes hydroxyl, carboxyl, sulfydryl, amino
With one of water-soluble amino acids residue or a variety of；Optionally, the water-soluble amino acids residue is alanine residue, sweet ammonia
One of sour residue, serine residue, arginine residues, lysine residue and tianmenine residue are a variety of.
5. application according to claim 1, which is characterized in that
The general formula of the water-soluble fullerene is C2n(OH)x(Amino Acid)y, Amino Acid represents water-soluble amino acids
Residue；30≤n≤60, optional n are 30 or 35；0 < x < 50, optional 20 < x < 30, also optional x=24；0≤y<20；
The general formula of the water-soluble embedded metal fullerene is M@C2a(OH)b(Amino Acid)c, Amino Acid represents water
Dissolubility amino acid residue；M is selected from rare earth metal, and optional rare earth metal is Gd, La etc.；30≤a≤60, optional a be 41 or
30 or 35；0<b<50；0≤c<20.
6. application according to claim 1, which is characterized in that the water-soluble fullerene is by raw material fullerene
Carry out water-soluble modified acquisition；The water-soluble embedded metal fullerene is by carrying out to raw material embedded metal fullerene
Water-soluble modified acquisition.
7. application according to claim 6, which is characterized in that the water-soluble modified method is appointing in following methods
It is a kind of:
(1) at least one of raw material fullerene and raw material embedded metal fullerene are mixed and is carried out with hydrogen peroxide and aqueous slkali
Reaction, then wash, it then dialyses, water soluble hydroxy derivative corresponding with raw material can be obtained；If necessary to obtain water solubility
Sodium hydroxide in above-mentioned steps is substituted for ammonium hydroxide by amination derivative；
(2) method of physics cladding can be by least one of fullerene and embedded metal fullerene and polyethylene glycol, poly- second
At least one of alkene pyrrolidone and cyclodextrin, which mix and carry out ball milling or ultrasound etc., can be obtained by quilt corresponding with raw material
The water-soluble fullerene structure of cladding；
(3) when containing amino acid residue in water-soluble fullerene structure, comprising the following steps: (a) uses water-soluble amino acids
Water soluble amino acid-base solution (optional, mole of water-soluble amino acids and NaOH and/or KOH is prepared with NaOH and/or KOH
Than for 1:1-10, being also optionally 1:2 or 1:1-8；Optionally, in water soluble amino acid-base solution NaOH/KOH mass fraction
Can be 10~50%, it is also optional for 14% or 10~30%)；(b) according to water-soluble amino acids and raw material fullerene and/or original
Material embedded metal fullerene molar ratio is 1-1000:1, is optionally 50-1000:1,100-1000:1,200-1000:1, by water
Dissolubility amino acid-base solution is mixed with raw material fullerene and/or raw material embedded metal fullerene；(c) by said mixture
40-80 DEG C of reaction (optional, the reaction is to be stirred to react 1-7 hours), is filtered to remove unreacted a small amount of solid powder；
(d) filtrate dialysis removes small molecular weight impurity, and after filtering, obtained dark brown solution is the water-soluble of amino acid modification of the invention
Fullerene/embedded metal fullerene of property.
8. application according to claim 7, which is characterized in that the water-soluble modified middle method for hydroxylation is to weigh 50
~200mg C60Solid or C70Solid or Gd@C82The hydrogen peroxide of solid and 3~15ml 20~40%, 2~10ml 5~
60% aqueous slkali, hybrid reaction is all dissolved to solid under conditions of 50~100 DEG C.
9. application according to claim 1, which is characterized in that the treatment pulmonary fibrosis includes at least one below:
1) organ coefficient of lung is made to tend to be normal；(2) hyperemia, oedema, hyperplasia or the hypertrophy of lung are treated；3) subtract the threadiness in lung
It is few；4) lactic dehydrogenase, catalase, superoxide dismutase, glutathione reductase, paddy caused by pulmonary fibrosis are treated
The rising of Guang sweet peptide peroxidase, malonaldehyde；5) lung's collagen fiber hyperplasia or accumulation are treated；6) inhibit transforming growth factor
The overexpression of TGF-β；7) hydroxyproline content is reduced.
10. application according to claim 1, which is characterized in that the drug is tablet, pill, powder, pastille, small medicine
It is capsule, cachet, elixir, suspending agent, emulsion, solution, syrup, aerosol, ointment, soft hard gelatin capsule, suppository, sterile
Inject one of solution and aseptic packaging powder-injection.
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