CN108201540A - Application of the fullerene structure in the drug for preparing treatment leukaemia - Google Patents
Application of the fullerene structure in the drug for preparing treatment leukaemia Download PDFInfo
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Abstract
The invention discloses a kind of application of fullerene structure in the drug for preparing treatment leukaemia, the fullerene structure includes at least one selected from the group below as active ingredient：The pharmaceutical salt of oil-soluble fullerene, oil-soluble embedded metal fullerene, the composition of the oil-soluble fullerene and the oil-soluble embedded metal fullerene, water-soluble fullerene, water-soluble embedded metal fullerene, the composition of the water-soluble fullerene and the water-soluble embedded metal fullerene, above six pharmaceutical ester or more six.The application active ingredient can be efficiently enriched among marrow, rapid-action, have good biocompatibility；It and can be in the ripe preceding use of Leukemia Model for pre- preventing leukemia；It is used after falling ill in leukaemia, it, can fast preventing and hemopoietic function of bone marrow and other organ damages impaired in reparation leukaemia due to characteristic of the active ingredient with the targeting enrichment of marrow position.
Description
Technical field
The present invention relates to field of medicaments, more particularly to a kind of fullerene structure answering in the drug for preparing treatment leukaemia
With.
Background technology
Recently as the change of environment, the incidence of leukaemia is higher and higher, seriously endangers people's health.White blood
Disease is a kind of candidate stem cell malignant clone disease.After leukaemia, because Leukemia Cell Proliferation is out of control, differentiation barrier
Hinder, mechanism largely proliferation accumulation, and infiltrate other non-hematopoietic tissues in hematopoietic tissue such as apoptosis is obstructed, normal hematopoiesis can be inhibited
The symptoms such as different degrees of anaemia, bleeding, hepatosplenomegaly, skeleton pain can clinically occur for function.According to different standards,
Leukaemia can have different classification.It can be divided into acute leukemia and chronic leukemia by the emergency of onset；By sick cell system
Row classification, is clinically often divided into lymphocytic leukemia, myelocytic leukemia, cell mixing leukaemia etc. by leukaemia, wherein：
The T and B cell system of grain of the sick cell including medullary system, single, red, macronucleus system and Lymphatic System.It is reported that the white blood of China each department
Sick incidence accounts for the 6th in various tumours.Although the methods and drug of emerging in recent years a variety for the treatment of leukaemia, such as：It will
Emerging targeted drug and immunotherapy method introduce the country, but because its effect is general, easily generate drug resistance, spend high etc.
Defect cannot still be widely used, therefore radiation and chemotherapy is still the clinically used therapy of leukaemia at present.Many institute's weeks
Know, most of radiation and chemotherapies also damage the normal cell of human body, have larger side effect, especially while cancer cell is killed
It is may to generate secondary injury to patient for the lethal effect of bone marrow cell even to aggravate leukaemia, seriously affects disease
The quality of life of people and its application clinically.And generally acknowledge the bone marrow transplantation therapy method that can thoroughly treat leukaemia, it is first
The marrow until matching with patient is first needed, while a large amount of fund is needed to carry out guarantee, and is still had after bone-marrow transplantation multiple
Risk is sent out, many patients are because the pain and high expense that transplanting is brought are unwilling to receive second transplant.
To sum up, it can find and a kind of treat common leukaemia (mainly acute lymphoblastic leukemia, acute myelogenous is white
Blood disease, acute monocytic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia), mitigate conditions of patients,
The smaller drug of side effect has important clinical researching value.
Fullerene is another allotrope of the carbon in addition to graphite, diamond and agraphitic carbon.This kind of substance
Refer to the cage structure being made of carbon atom, the most molecule of content is C60, followed by C70, C84, secondly content phase
To less C76, C78, C82 etc..Carbon cage inside additionally, due to fullerene is cavity structure, therefore its internal cavities can embed
Not homoatomic, ion or cluster, referred to as embedded fullerene such as La C60, represent that La is embedded in the cage structure of C60,
Represent at, vivid expresses embedded meaning.
The information for being disclosed in the background technology part is merely intended to increase the understanding of the general background to the present invention, without answering
When being considered as recognizing or imply that information composition has been the prior art well known to persons skilled in the art in any form.
Invention content
The purpose of the present invention is to provide a kind of application of fullerene structure in the drug for preparing treatment leukaemia, this hairs
Bright another object is to provide a kind of pharmaceutical composition and method for treating leukaemia.Active ingredient fowler of the present invention
Alkene structure can be efficiently enriched in marrow, rapid-action, can quickly be killed leukaemia cell, be damaged in prevention and reparation leukaemia
Hemopoietic function of bone marrow and other organ damages.
In order to realize purpose, the present invention provides following technical schemes：
Application of a kind of fullerene structure in the drug for preparing treatment leukaemia, wherein the fullerene structure is included extremely
A kind of few active ingredient selected from the group below：Oil-soluble fullerene, oil-soluble embedded metal fullerene, the oil-soluble richness
Strangle the composition, water-soluble fullerene, water-soluble embedded metal fowler of alkene and the oil-soluble embedded metal fullerene
Alkene, the composition of the water-soluble fullerene and the water-soluble embedded metal fullerene, above six it is pharmaceutical
The pharmaceutical salt of ester or more six.
The present invention also provides a kind of method for treating leukaemia, including applying effective quantity to the subject with leukaemia
Fullerene structure, the fullerene structure includes at least one active ingredient selected from the group below：Oil-soluble fullerene, oil are molten
Composition, the water of the embedded metal fullerene of property, the oil-soluble fullerene and the oil-soluble embedded metal fullerene
The fullerene of dissolubility, water-soluble embedded metal fullerene, the water-soluble fullerene and the water-soluble embedded metal
The pharmaceutical salt of the composition of fullerene, above six pharmaceutical ester or more six.
The present invention also provides a kind of pharmaceutical composition for treating leukaemia, including at least one fullerene selected from the group below
Structure：Oil-soluble fullerene, oil-soluble embedded metal fullerene, the oil-soluble fullerene and it is described it is oil-soluble in
The composition of engaged column fullerene, water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene
Composition, above six pharmaceutical ester with the water-soluble embedded metal fullerene, above six it is pharmaceutical
Salt；Described pharmaceutical composition further includes at least one in pharmaceutical carrier, pharmaceutical diluent and pharmaceutical excipient
Kind.
In another embodiment, the oil-soluble fullerene is carbon cage for above application, method or pharmaceutical composition
Outer surface is coated with the fullerene of oil solution, and the oil-soluble embedded metal fullerene is coated with oil solution for carbon cage outer surface
Embedded metal fullerene, such as：Carbon cage outer surface is coated with the fullerene of olive oil, and carbon cage outer surface is coated with sunflower oil
Embedded metal fullerene.
In another embodiment, the oil solution can be one-component for above application, method or pharmaceutical composition
Oil, or the miscella of different oil solutions.Usually vegetable oil, such as olive oil, linseed oil, sunflower oil, corn
Embryo oil etc., also including animal fat, such as saualane.
Above application, method or pharmaceutical composition in another embodiment, the oil-soluble fullerene be pass through by
Fullerene raw material carries out oil-soluble and is modified what is obtained, and the oil-soluble embedded metal fullerene is by by embedded metal fullerene
Raw material carries out oil-soluble and is modified what is obtained.
In another embodiment, the oil-soluble is modified as fullerene for above application, method or pharmaceutical composition
At least one of raw material and embedded metal fullerene raw material are scattered in the oil solution, obtain mixed liquor；By the mixing
Liquid after ball milling or ultrasound, successively through centrifugation removal precipitation, then gained upper liquid filtering to get.What is obtained is oil-soluble
Modification liquid.
Above application, method or pharmaceutical composition in another embodiment, during the oil-soluble is modified, often
Disperse 0.05-500mg fullerenes raw material and/or embedded metal fullerene raw material in 1ml oil solutions, the disclosure of the range should be by
The disclosure of all numerical value in the range of being considered as, optionally there is 0.05-1mg, 0.05-10mg, 0.05-100mg etc..
Above application, method or pharmaceutical composition in another embodiment, by the mixed liquor through ball milling or ultrasound
30min-15h。
In another embodiment, the water-soluble fullerene includes choosing for above application, method or pharmaceutical composition
From at least one fullerene of the following group：(1) carbon cage outer surface is modified with the fullerene of hydrophilic radical；(2) it is born by water-solubility carrier
The fullerene of load.
Above application, method or pharmaceutical composition in another embodiment, the water-soluble embedded metal fowler
Alkene includes at least one embedded metal fullerene selected from the group below：(1) carbon cage outer surface is modified with the embedded metal of hydrophilic radical
Fullerene；(2) the embedded metal fullerene loaded by water-solubility carrier.
In another embodiment, the hydrophilic radical includes hydroxyl, carboxylic for above application, method or pharmaceutical composition
It is one or more in base, sulfydryl and amino.It is optionally：Water-soluble embedded metal fullerene is water soluble hydroxy Gd@
C82, water-soluble fullerene are water soluble hydroxy C60 or water soluble hydroxy C70.
In another embodiment, the water-solubility carrier is normal in medicine for above application, method or pharmaceutical composition
Pharmaceutical carrier, including at least one of liposome, polymer micelle, protein.Optionally, the polymer micelle is
Poly (glycolide-lactide) polyethylene glycol (PEG-PLGA), polylysine or chitosan；The protein is albumin or transferrins.
In another embodiment, the water-soluble fullerene is to pass through for above application, method or pharmaceutical composition
Water-soluble modified acquisition is carried out to fullerene raw material；The water-soluble embedded metal fullerene is by embedded metal richness
It strangles alkene raw material and carries out water-soluble modified acquisition.
Above 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 at least one of fullerene raw material and embedded metal fullerene raw material with hydrogen peroxide and alkali are mixed and gone forward side by side
Row reaction, then washed with ethyl alcohol, it then dialyses, you can obtain water soluble hydroxy derivative corresponding with raw material.It obtains if necessary
Water-soluble amino derivative is obtained, the sodium hydroxide in above-mentioned steps is substituted for ammonium hydroxide.(2) noncovalent interaction is by dredging
Water-hydrophobic effect makes water-solubility carrier form corresponding water-soluble material with fullerene raw material or embedded metal fullerene raw material.
Above application, method or pharmaceutical composition in another embodiment, the alkali concretely sodium hydroxide or
Person's potassium hydroxide.
Above application, method or pharmaceutical composition in another embodiment, weigh 50~300mg C60 or C70 or
Gd@C82Solid, the hydrogen peroxide of 5~30ml 20~40%, the aqueous slkali of 2~20ml 1M-3M, under conditions of 50~100 DEG C
Mixing, until corresponding C60 or C70 or Gd@C82Solid all dissolves.In the description herein, performance is that ratio between each substance is closed
System is not limited by 50~300mg, 5~30ml and the specific reaction scales of 2~20ml in practical application, can proportionally into
Row expands.
Above application, method or pharmaceutical composition in another embodiment, the fullerene raw material 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 application, method or pharmaceutical composition in another embodiment, the embedded metal fullerene raw material packet
Include M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nIn it is one or more,
In：M, A represents metallic element and M, A are selected from any one in lanthanide element, Sc and Y, 30≤n≤60；0≤x
≤3.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.
Above application, method or pharmaceutical composition in another embodiment, oil-soluble fullerene, it is oil-soluble in
The composition, water-soluble of engaged column fullerene, the oil-soluble fullerene and the oil-soluble embedded metal fullerene
Fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and the water-soluble embedded metal fullerene
Composition, six pharmaceutical salt of above six pharmaceutical ester or more average particle diameter ranging from 1-
1000nm is optionally 10-250nm or 10-150nm etc..
In another embodiment, it is thin that the leukaemia includes acute lymphoblastic for above application, method or pharmaceutical composition
Born of the same parents' leukaemia, acute myeloblastic leukemia, acute monocytic leukemia, chronic lymphocytic leukemia, chronic granulocytic
Leukaemia.The cause of disease of the leukaemia can be by virus, chemistry, radiation, and the factors such as heredity cause.
In another embodiment, the treatment leukaemia includes for above application, method or pharmaceutical composition：1) make white
At least one of leukocyte disorder, blood platelet disorders, haemoglobin anomaly and erythrocyte abnormality tend to be normal caused by blood disease,
Such as：Make the quantity of leucocyte declined caused by leukaemia, the platelet counts declined, the amount of hemoglobin declined and decline
Erythrocyte number at least improves more than 20%；2) make the content of leukaemia cell reduce at least 20%；3) palliating leukemia is brought
The complication such as hepatosplenomegaly；4) skeleton pain that palliating leukemia is brought, breathes hard.
Drug or aforementioned pharmaceutical compositions in above application in another embodiment, the drug or pharmaceutical composition
Can be that tablet, pill, powder, pastille, sachet, cachet, elixir, suspending agent, emulsion, solution, syrup, gas are molten
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 active ingredient after subject is applied to, such as：Active ingredient can be mixed with carrier, with load
Body is diluted or is encapsulated in the carrier.
Drug or aforementioned pharmaceutical compositions in above application in another embodiment, suitable for as carrier, figuration
Some of agent and diluent examples 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, methyl hydroxybenzoate and propyl ester, talcum powder, magnesium stearate and liquid paraffin.
Drug or aforementioned pharmaceutical compositions in above 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 application in another embodiment, the water-soluble fullerene
And/or a concentration of 0.1mM-10mM of water-soluble metal fullerene in the formulation；The oil-soluble fullerene and/or oil-soluble gold
Belong to a concentration of 500ppm-5000ppm (mg/kg) of fullerene in the formulation.
The above method in another embodiment, leukaemia compared with the lighter can with single dose or the next day apply active ingredient,
Leukaemia severe patient can also apply with multi-dose or day after day, the next day or continuous use after leukaemia symptom can obtain notable prevention.
In another embodiment, the subject is leukemia patient or animal to the above method, and animal can be to feed
Newborn animal, such as mouse, rabbit, monkey.
In another embodiment, the mode of the application for injection or takes orally the above method；Optionally, the injection
For intravenous injection, active ingredient enters directly to play a role in vivo through blood circulation, and without infiltration, pharmaceutical quantities used are small, treat
Effect is high；Or be orally ingested, it is filtered absorption of through digestive system, it is less side effects, it is significant in efficacy.
Active ingredient in the present invention has following all properties：(1) surface is hydrophily or lipophilicity, can be through
It is entered in organism by intravenous injection or oral way and passes through blood circulation and be enriched in marrow；(2) it is water-soluble effectively into
Point with rigidity (being unlikely to deform) so that it can by the endothelial cell gap of marrow blood sinus, extra vascular pressure differential is utilized
Into in marrow；(3) the fat-soluble characteristic of fat-soluble active ingredient makes it easier to enter cell, can be via gavage
Or it is injected intraperitoneally into organism and passes through blood circulation and reach internal organs.
Term used herein " treatment " includes its generally accepted meaning, which includes preventing, prevention, press 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 " active ingredient ", " active ingredient fullerene structure " or " fullerene structure " refer to
Oil-soluble fullerene, oil-soluble embedded metal fullerene, the oil-soluble fullerene and the oil-soluble embedded gold
Belong to composition, water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and the institute of fullerene
It states in the composition of water-soluble embedded metal fullerene, above six pharmaceutical ester or more six pharmaceutical salt
At least one.
Term used herein " effective quantity " refer to active ingredient 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 people in the art
The observation result of member's gained by known technology and under similar situation is and determining.It is determining to apply the effective of active ingredient
When amount or dosage, the diagnostician participated in is considered as many factors, and the factor includes but not limited to：The kind of mammal
Belong to；Volume, age and general health；Involved 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 " fullerene raw material " refers to the fowler not being modified by water-soluble modified or oil-soluble
Alkene, i.e. fullerene ontology.
Term used herein " embedded metal fullerene raw material " refers to by water-soluble modified or oil-soluble not change
The embedded metal fullerene of property, i.e. embedded metal fullerene ontology.
In order to facilitate metering, all about water-soluble fullerene, water-soluble metal fullerene, oil-soluble fowler in the present invention
The quantitative restrictions such as the concrete content of alkene or oil soluble metal fullerene, concentration are with its corresponding fullerene ontology or embed
Concrete content, concentration of metal fullerene ontology etc. are weighed, such as：Oil-soluble fullerene in the formulation a concentration of
0.1mM-10mM refers to can detect a concentration of 0.1mM- of fullerene ontology carbon cage in the formulation by oil-soluble modification
10mM；In another example：The content that carbon cage outer surface is coated with the fullerene of oil solution is 100 μM of fullerene sheets referred in oil solution
The content of body carbon cage is 100 μM.
Compared with prior art, the active ingredient for the treatment of leukaemia has following effect in the present invention：
1) the special physicochemical properties of active ingredient and its specific particle size, make it can be quick through blood circulation
It is enriched among marrow, it is rapid-action, there is good biocompatibility；2) active ingredient maintains the height of fullerene molecule and is total to
Yoke and efficiently remove free radical the features such as, can leukaemia generation before use with pre- preventing leukemia；It is sent out when in leukaemia
It uses after being ill, since active ingredient has the characteristic of marrow position targeting enrichment, can quickly kill leukaemia cell, quick
The hemopoietic function of bone marrow and other organ damages being damaged in prevention and reparation leukaemia；3) active ingredient is to bone marrow cell and normal
Cell does not have apparent cytotoxicity, safe and non-toxic, can be metabolized outside bioagent；4) active ingredient prepare it is simple and quick,
Available for industrializing.
Description of the drawings
Fig. 1 is the effect that water soluble hydroxy empty fullerene kills leukaemia cell in cellular level in embodiment 1,
Middle Control represents blank control group, and PBS represents negative control group, and 30 μM, 50 μM, 100 μM and 200 μM represent experiment respectively
4 concentration groups of group.
Fig. 2 is the effect that water soluble hydroxy gadolinium metal fullerene kills leukaemia cell in cellular level in embodiment 2.
Wherein Control represents blank control group, and PBS represents negative control group, and 30 μM, 50 μM, 100 μM and 200 μM represent real respectively
Test 4 concentration groups of group.
Fig. 3 is for water soluble hydroxy empty fullerene in embodiment 3 in cellular level to the work of Human umbilical vein endothelial cells
With wherein Control represents blank control group, 30 μM, 50 μM, 100 μM, 200 μM and 500 μM represent experimental group respectively 5
Concentration group.
Fig. 4 is for water soluble hydroxy gadolinium metal fullerene in embodiment 4 in cellular level to Human umbilical vein endothelial cells
Effect, wherein Control represent blank control group, and 30 μM, 50 μM, 100 μM, 200 μM and 500 μM represent the 5 of experimental group respectively
A concentration group.
Specific embodiment
Below in conjunction with the accompanying drawings, the specific embodiment of the present invention is described in detail, it is to be understood that the guarantor of the present invention
Shield range is not restricted by specific implementation.
Experimental method described in following embodiments is conventional method unless otherwise specified；The reagent and material, such as
Without specified otherwise, commercially obtain.The culture medium of leukaemia cell used in following embodiment is added with 20%
The IMDM culture mediums (Iscove ' s Modified Dulbecco Medium) of FBS (fetal calf serum), IMDM culture mediums and FBS
It buys in Beijing Baeyer enlightening Bioisystech Co., Ltd).The raw materials used Gd@C of following embodiment82Solid powder is bought in Xiamen
Good fortune is taken in the fresh material Science and Technology Ltd., molecular weight 1141, purity 99.1%.The raw materials used C60 solid powders of following embodiment
It buys and takes in the fresh material Science and Technology Ltd. in Xiamen good fortune, molecular weight 720, purity 99%.CCK-8 experiments can used in following embodiment
Reflect living cells quantity, can be detected with commercial kit.
Prepare embodiment
Preparation example 1
Water soluble hydroxy gadolinium metal fullerene is prepared by following preparation method：
1) by 300mg Gd@C82Solid powder is added in the single port bottle of 300ml, and it is 30% to be separately added into 20ml volume fractions
Aqueous hydrogen peroxide solution and 10ml 2M sodium hydrate aqueous solution, oil bath heating to 70 DEG C, react 6h；
2) small molecule is removed using M.W.=3500 bag filters after reacting, is monitored using conductivity meter and is completed until dialysing,
The product that ultrafiltration centrifuges is water soluble hydroxy metal fullerene (Gd@C82)m(OH)n, measured through DLS, water-soluble
Average grain diameter in liquid is 140-150nm, and particle diameter distribution is uniform.
Preparation example 2
Water soluble hydroxy gadolinium metal fullerene is prepared by following preparation method：
1) by 50mg Gd@C82Solid powder is added in the single port bottle of 100ml, and it is 30% to be separately added into 7ml volume fractions
The sodium hydrate aqueous solution of aqueous hydrogen peroxide solution and 3ml 2M, oil bath heating react 2h to 50 DEG C.
2) small molecule is removed using M.W.=3500 bag filters after reacting, is monitored using conductivity meter and is completed until dialysing,
The product that ultrafiltration centrifuges is water soluble hydroxy metal fullerene (Gd@C82)m(OH)n, measured through DLS, water-soluble
Average grain diameter in liquid is 140-150nm, and particle diameter distribution is uniform.
Preparation example 3
Water soluble hydroxy empty fullerene is prepared by following preparation method：
1) 200mg C60 solid powders are added in the single port bottle of 200ml, it is 30% to be separately added into 15ml volume fractions
The sodium hydrate aqueous solution of aqueous hydrogen peroxide solution and 6ml 2M, oil bath heating react 5h to 70 DEG C；
2) small molecule is removed using M.W.=3500 bag filters after reacting, is monitored using conductivity meter and is completed until dialysing,
The product that ultrafiltration centrifuges is water soluble hydroxy fullerene (C60)m(OH)n, measured through DLS, in aqueous solution flat
Equal grain size is 150nm, and particle diameter distribution is uniform.
Preparation example 4
1) by 50mg C60Solid powder is added in the single port bottle of 100ml, is separately added into the mistake that 10ml volume fractions are 30%
Aqueous solution of hydrogen and the sodium hydrate aqueous solution of 5ml 2M are aoxidized, oil bath heating reacts 6h to 70 DEG C.
2) small molecule is removed using M.W.=3500 bag filters after reacting, is monitored using conductivity meter and is completed until dialysing,
The product that ultrafiltration centrifuges is water soluble hydroxy fullerene (C60)m(OH)n, measured through DLS, in aqueous solution flat
Equal grain size is 150nm, and particle diameter distribution is uniform.
More than, contain in the water soluble hydroxy empty fullerene of gained or water soluble hydroxy metal fullerene after dialysis
More liquid can also be carried out ultrafiltration centrifugal concentrating, but regardless of whether being concentrated, raw metal fullerene or raw material embed
The water-soluble modified of metal fullerene has been completed, if being concentrated does not influence its use, as long as will be water-soluble rich during use
It strangles alkene or water-soluble metal fullerene is adjusted to suitable concentration.
Preparation example 5
Oil cladding empty fullerene and/or metal fullerene are prepared by following preparation method：1) by fullerene raw material
And/or the solid powder (buy in Xiamen good fortune take in the fresh material Science and Technology Ltd.) and olive oil of metal fullerene raw material, flax
The edible oils such as seed oil in varing proportions (such as：200mg empty fullerene C60 solid powders and 200ml olive oil mixing and ball milling)
It mixes, in the ball mill ball milling 6-12h；2) it using centrifuge after reacting, is centrifuged repeatedly away with rotating speed 12000r uncoated
Fullerene solid, until no solid powder is centrifuged.3) the hollow richness entered using ultraviolet-visible spectrometer test cladding
Strangle the specific concentration of alkene/metal fullerene.
Embodiment 1, water soluble hydroxy empty fullerene kill the effect of leukaemia cell in cellular level
1) experimental subjects：Select Kg-1a cells (human acute myeloid leukemia cell) and HL-60 cells (the acute early children of people
Grain leukaemia cell) for the leukaemia cell that is studied.
2) experimental method：By Kg-1a cells and Kg-1a cells respectively with every hole ca.1x104A concentration is planted respectively 96
In orifice plate, each leukaemia cell plants 6 × 6 holes, wherein：
Blank control group：Each leukaemia cell needs 6 holes altogether, leukaemia cell is inoculated in hole, added with white in hole
The culture medium of blood disease cell is not added with water soluble hydroxy empty fullerene in hole；
Experimental group：Each leukaemia cell needs 6 × 4 holes altogether, and leukaemia cell is inoculated in hole, added with white blood in hole
The 3 gained water soluble hydroxy empty fullerene of culture medium and preparation example of sick cell, experimental group are provided with water soluble hydroxyization sky
4 various concentrations (its ultimate density is made to be respectively 30 μM, 50 μM, 100 μM and 200 μM) of heart fullerene, each concentration is all provided with
6 holes are put, experiment is in triplicate；
Negative control group：Each leukaemia cell needs 6 holes altogether, leukaemia cell is inoculated in hole, added with white in hole
The culture medium of blood disease cell and the PBS solution with water soluble hydroxy empty fullerene same volume in experimental group；
After the completion of sample-adding, by each group in 37 DEG C, 5%CO2Under conditions of be incubated for 24 hours after, suck culture medium, delayed with PBS
Fliud flushing is washed three times；Cell culture medium is added, in 37 DEG C, 5%CO2Cell incubator in continue culture for 24 hours, then use CCK-
8 kits (buying in green skies Bioisystech Co., Ltd) detect cell viability, and microplate reader measures OD values at 450mM wavelength.
3) experimental result：As shown in figure 1 and table 1：
Table 1
Wherein：Control expression blank control groups, PBS expression negative control groups, 30 μM, 50 μM, 100 μM and 200 μM points
Not Biao Shi experimental group 4 concentration groups.
From Fig. 1 and table 1 it can be seen that：As the addition of water soluble hydroxy empty fullerene gradually increases, two kinds of types
Leukaemia cell vigor also with being declined, and leukaemia cell's vigor of negative control group is all risen.More than
The result shows that：On a cellular level, water soluble hydroxy empty fullerene has certain effect for the killing of leukaemia cell's vigor
Fruit.
Embodiment 2, water soluble hydroxy metal fullerene kill the effect of leukaemia cell in cellular level
1) experimental subjects：Select Kg-1a cells (human acute myeloid leukemia cell) and HL-60 cells (the acute early children of people
Grain leukaemia cell) for the leukaemia cell that is studied.
2) experimental method：By Kg-1a cells and Kg-1a cells respectively with every hole ca.1x104A concentration is planted respectively 96
In orifice plate, each leukaemia cell plants 6 × 6 holes, wherein：
Blank control group：Each leukaemia cell needs 6 holes altogether, leukaemia cell is inoculated in hole, added with white in hole
The culture medium of blood disease cell is not added with water soluble hydroxy metal fullerene in hole；
Experimental group：Each leukaemia cell needs 6 × 4 holes altogether, and leukaemia cell is inoculated in hole, added with white blood in hole
The 1 gained water soluble hydroxy gadolinium metal fullerene of culture medium and preparation example of sick cell, experimental group are provided with water soluble hydroxy
4 various concentrations (its ultimate density is made to be respectively 30 μM, 50 μM, 100 μM and 200 μM) of gadolinium metal fullerene, each concentration
6 holes are respectively provided with, experiment is in triplicate；
Negative control group：Each leukaemia cell needs 6 holes altogether, leukaemia cell is inoculated in hole, added with white in hole
The culture medium of blood disease cell and the PBS solution with water soluble hydroxy gadolinium metal fullerene same volume in experimental group；
After the completion of sample-adding, by each group in 37 DEG C, 5%CO2Under conditions of be incubated for 24 hours after, suck culture medium, delayed with PBS
Fliud flushing is washed three times；Cell culture medium is added, in 37 DEG C, 5%CO2Cell incubator in continue culture for 24 hours, then use CCK-
8 kits (buying in green skies Bioisystech Co., Ltd) detect cell viability, and microplate reader measures OD at 450mM wavelength
Value.
3) experimental result：As shown in Fig. 2 and table 2：
Table 2
Wherein：Control expression blank control groups, PBS expression negative control groups, 30 μM, 50 μM, 100 μM and 200 μM points
Not Biao Shi experimental group 4 concentration groups.
From Fig. 2 and table 2 it can be seen that：As the addition of water soluble hydroxy gadolinium metal fullerene gradually increases, two is various
The vigor of the leukaemia cell of class is also with being declined, and leukaemia cell's activity of negative control group is all risen.With
It is upper the result shows that：On a cellular level, water soluble hydroxy gadolinium metal fullerene has the killing of leukaemia cell's vigor certain
Effect.And the water soluble hydroxy gadolinium metal fullerene of same concentrations can kill more leukaemia cells, illustrate gold
The treatment leukaemia effect for belonging to fullerene is more more superior than empty fullerene.
The effect of embodiment 3, water soluble hydroxy empty fullerene to normal cell
1) experimental method：Kg-1a cells in embodiment 1 and HL-60 cells are replaced with into HUVEC cell (human umbilical veins
Endothelial cell) normal cell, negative control group is not provided with, experimental group sets the water soluble hydroxyization of 1 500 μM of concentration hollow more
Fullerene group makes its final concentration of 500 μM in hole, remaining step operation is identical with embodiment 1.
2) experimental result：As shown in Fig. 3 and table 3：
Table 3
Wherein：Control represents blank control group, and 20 μM, 50 μM, 100 μM, 200 μM and 500 μM represent experimental group respectively
5 concentration groups.
From Fig. 3 and table 3 it can be seen that：When being gradually increased with the addition of water soluble hydroxy empty fullerene, people's navel is quiet
The cell viability of arteries and veins endothelial cell has no decline, and under the incubation of high concentration fullerene, cell viability also has on a degree of
It rises.Show：On a cellular level, water soluble hydroxy empty fullerene acts on human normal cell line fanout free region.
The effect of embodiment 4, water soluble hydroxy gadolinium metal fullerene to normal cell
1) experimental method：Kg-1a cells in embodiment 2 and HL-60 cells are replaced with into HUVEC cell (human umbilical veins
Endothelial cell) normal cell, negative control group is not provided with, experimental group sets the water soluble hydroxy gadolinium gold of 1 500 μM of concentration more
Belong to fullerene group, make its final concentration of 500 μM in hole, remaining step operation is identical with embodiment 2.
2) experimental result：As shown in Fig. 4 and table 4,
Table 4
Wherein：Control represents blank control group, and 20 μM, 50 μM, 100 μM, 200 μM and 500 μM represent experimental group respectively
5 concentration groups.
From Fig. 4 and table 4 it can be seen that：As the addition of water soluble hydroxy gadolinium metal fullerene gradually increases, people's navel is quiet
The cell activity of arteries and veins endothelial cell has no decline, and under the incubation of high concentration fullerene, cell activity also has on a degree of
It rises.Show：On a cellular level, water soluble hydroxy metal fullerene acts on human normal cell line fanout free region.
The description of the aforementioned specific exemplary embodiment to the present 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 explain that the specific principle of the present invention and its reality should
With so that those skilled in the art can realize and utilize the present invention a variety of different exemplary implementations 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 application of fullerene structure in the drug for preparing treatment leukaemia, it is characterised in that：The fullerene structure
Including at least one selected from the group below：Oil-soluble fullerene, oil-soluble embedded metal fullerene, the oil-soluble fowler
The composition of alkene and the oil-soluble embedded metal fullerene, water-soluble fullerene, water-soluble embedded metal fullerene,
The composition of the water-soluble fullerene and the water-soluble embedded metal fullerene, above six pharmaceutical ester or
More than six pharmaceutical salt.
2. a kind of pharmaceutical composition for treating leukaemia, it is characterised in that：Including at least one active ingredient selected from the group below：Oil
The fullerene of dissolubility, oil-soluble embedded metal fullerene, the oil-soluble fullerene and the oil-soluble embedded metal
The composition of fullerene, water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and described
The pharmaceutical salt of the composition of water-soluble embedded metal fullerene, above six pharmaceutical ester or more six, also
Including pharmaceutical carrier, diluent or excipient.
3. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：The oil is molten
Property fullerene be coated with the fullerene of oil solution for carbon cage outer surface, the oil-soluble embedded metal fullerene is outside carbon cage
Surface is coated with the embedded metal fullerene of oil solution.
4. the pharmaceutical composition described in application according to claim 3 or claim 3, it is characterised in that：The oil is molten
Liquid includes at least one of olive oil, linseed oil, sunflower oil, maize germ, saualane.
5. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：It is described water-soluble
Property fullerene include at least one fullerene selected from the group below：(1) surface modification has the fullerene of hydrophilic radical；(2) by water
The fullerene of solubleness carrier load；The water-soluble embedded metal fullerene includes at least one embedded metal selected from the group below
Fullerene：(1) surface modification has the embedded metal fullerene of hydrophilic radical；(2) it is rich by the embedded metal of water-solubility carrier load
Strangle alkene.
6. the pharmaceutical composition described in application according to claim 5 or claim 5, it is characterised in that：It is described hydrophilic
Group includes one or more in hydroxyl, carboxyl, sulfydryl and amino；The water-solubility carrier includes liposome, polymer latex
At least one of beam, protein；Optionally, the polymer micelle is poly (glycolide-lactide) polyethylene glycol (PEG-PLGA), gathers
Lysine or chitosan；The protein is albumin or transferrins.
7. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：The oil is molten
Property fullerene be by by fullerene raw material carry out oil-soluble be modified obtain；The oil-soluble embedded metal fullerene is to pass through
Embedded metal fullerene raw material is subjected to oil-soluble and is modified what is obtained；The water-soluble fullerene be by by fullerene raw material into
The water-soluble modified acquisition of row；The water solubility embedded metal fullerene is water-soluble by the way that embedded metal fullerene raw material is carried out
Property be modified obtain.
8. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：The fowler
It is C that alkene raw material, which includes one or more general formulas,2mThe cage structure being made of carbon atom, 30≤m≤60；The embedded metal is rich
It strangles alkene raw material and includes M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MxA3-xN@C2nIn one kind
Or it is a variety of, wherein：M, A represents metallic element and M, A are selected from any one in Sc, Y and lanthanide element, 30≤n
≤60；0≤x≤3；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.
9. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：It is oil-soluble
Fullerene, oil-soluble embedded metal fullerene, the oil-soluble fullerene and the oil-soluble embedded metal fullerene
Composition, water-soluble fullerene, water-soluble embedded metal fullerene, the water-soluble fullerene and the water solubility
The composition of embedded metal fullerene, six pharmaceutical salt of above six pharmaceutical ester or more particle be averaged
Diameter range is 1-1000nm, is optionally 10-250nm.
10. the pharmaceutical composition described in application according to claim 1 or claim 2, it is characterised in that：The white blood
Disease includes acute lymphoblastic leukemia, acute myeloblastic leukemia, acute monocytic leukemia, the white blood of chronic lymphocytic
Disease, chronic granulocytic leukemia.
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| CN201611179099.1A CN108201540A (en) | 2016-12-19 | 2016-12-19 | Application of the fullerene structure in the drug for preparing treatment leukaemia |
| PCT/CN2017/117283 WO2018113684A1 (en) | 2016-12-19 | 2017-12-19 | Use of fullerene structure in preparation of drug for treating leukemia |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111939175A (en) * | 2020-07-06 | 2020-11-17 | 浙江大学 | Grapyne derivative capable of treating leukemia |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735099B (en) * | 2021-08-27 | 2023-11-07 | 山东大学 | Preparation method of electron transfer compound and fullerene/water stock solution with synergistic stability of surface hydroxyl groups |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5994410A (en) * | 1995-10-26 | 1999-11-30 | National Science Council | Therapeutic use of water-soluble fullerene derivatives |
| CN105267238A (en) * | 2015-10-15 | 2016-01-27 | 北京福纳康生物技术有限公司 | Micro-nano material for preventing and/or treating bone marrow suppression and application thereof |
| CN105903020A (en) * | 2016-01-21 | 2016-08-31 | 北京福纳康生物技术有限公司 | Fullerene micro-nano material with effects of prevention and/or treatment on myelosuppression and use thereof |
| CN106109494A (en) * | 2016-08-11 | 2016-11-16 | 中国科学院化学研究所 | Prevent and/or treat micro-nano material and the application thereof of bone marrow depression |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103347849B (en) * | 2012-02-06 | 2016-05-11 | 列夫·达维多维奇·拉斯涅特索夫 | Fullerene С60Homogeneous polyamino acid and assorted amino acids derivative, its preparation method and the pharmaceutical composition based on this derivative |
-
2016
- 2016-12-19 CN CN201611179099.1A patent/CN108201540A/en active Pending
-
2017
- 2017-12-19 WO PCT/CN2017/117283 patent/WO2018113684A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5994410A (en) * | 1995-10-26 | 1999-11-30 | National Science Council | Therapeutic use of water-soluble fullerene derivatives |
| CN105267238A (en) * | 2015-10-15 | 2016-01-27 | 北京福纳康生物技术有限公司 | Micro-nano material for preventing and/or treating bone marrow suppression and application thereof |
| CN105903020A (en) * | 2016-01-21 | 2016-08-31 | 北京福纳康生物技术有限公司 | Fullerene micro-nano material with effects of prevention and/or treatment on myelosuppression and use thereof |
| CN106109494A (en) * | 2016-08-11 | 2016-11-16 | 中国科学院化学研究所 | Prevent and/or treat micro-nano material and the application thereof of bone marrow depression |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111514306B (en) * | 2020-04-23 | 2022-05-13 | 中国科学院化学研究所 | Fullerene nano-particles for enhancing anti-tumor immunotherapy |
| CN111939175A (en) * | 2020-07-06 | 2020-11-17 | 浙江大学 | Grapyne derivative capable of treating leukemia |
| CN111939175B (en) * | 2020-07-06 | 2021-07-30 | 浙江大学 | Grapyne derivative capable of treating leukemia |
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Application publication date: 20180626 |