CN108478598A - A kind of water-soluble fullerene nano material and the preparation method and application thereof - Google Patents
A kind of water-soluble fullerene nano material and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of water-soluble fullerene nano materials and the preparation method and application thereof.Water-soluble fullerene nano material, its general structure are C2n(OH)x(Amino Acid)y；Wherein, 20≤n≤60；0≤x<50；0≤y<20；Amino Acid are water-soluble amino acids.The present invention applies in the drug for preparing treatment tumour, and the tumour is at least one of liver cancer, lung cancer, colorectal cancer, kidney, cancer of pancreas, osteocarcinoma, breast cancer, oophoroma, prostate cancer, the cancer of the esophagus, gastric cancer, carcinoma of mouth, rhinocarcinoma, laryngocarcinoma, cholangiocarcinoma, cervical carcinoma, uterine cancer, carcinoma of testis, meningioma, cutaneum carcinoma, melanoma and sarcoma.Good water solubility of the present invention has good compatibility with organism, can obviously block tumor vessel, quickly cuts off tumor tissues nutrition supply；Its manufacturing cost is low.
Description
The present invention claims Beijing Fu Nakang Bioisystech Co., Ltd to submit on October 8th, 2016 to Patent Office of the People's Republic of China
, application No. is CN201610878746.1, it is entitled " a kind of water-soluble fullerene nano material and preparation method thereof with
Using " Chinese patent application priority, all the contents of the application are hereby incorporated by reference in the present invention.
Technical field
The present invention relates to a kind of water-soluble fullerene nano materials and the preparation method and application thereof, belong to biological medicine neck
Domain.
Background technology
Cancer, also known as malignant tumour are bodies under the stimulation of various carcinogenic factors, and the cell of local organization loses
Cellular abnormalities proliferation and transfer caused by normal gene regulation.According to the international cancer of the World Health Organization (WHO) subordinate
Disease research institution delivers《World's cancer report in 2014》, cancer has become whole world morbidity at present and dead main original
Cause；2012, the quantity of global new cancer patient increased about 14,000,000, and the The dead quantity of same period cancer patient also reaches
8200000；It will be also indicated that in report within 20 years futures, the quantity of annual new cancer patient is possible to 14,000,000 from 2012
Rise to 22,000,000.It is current for the efficient diagnosis of cancer and treatment have become urgent need to resolve in contemporary medical science significant problem it
One.
Conventional treatment of cancer at present is faced with many challenges, such as chemotherapy is by injecting, takes orally mode general
Chemotherapeutics imports in cancer patient's body, also in normal structure to have in addition to tumor locus due to the poor selectivity of chemotherapeutics more
Distribution, this also results in prodigious toxic side effect, such as alopecia, bone marrow suppression, cardiac toxic, neurotoxicity and hepatotoxicity
Deng；In addition, the drug resistance generated in chemotherapy process, often leads to proving an abortion for chemotherapy.Seek new treatment of cancer side
Method is extremely urgent to reach thoroughly healing and elimination cancer to overcome shortcoming and defect existing for conventional cancer therapy.In recent years
Come, what nanotechnology was advanced by leaps and bounds, which develop into, opens up treatment of cancer new way and bring new hope and may.Existing nanotechnology
Include mainly in the research of biomedical sector：Nanosecond medical science imaging and diagnosis, photo-thermal therapy, gene therapy, drug delivery etc..
Kroto in 1985 et al. has found C60, and the model of ball-type hollow molecules is proposed, it is named as fullerene.Closely
Nian Lai, the industrial rapid development of fullerene and the nanotechnology based on fullerene-based material emerge in multitude, and people are for richness
It strangles alkene and its derivative effect gives great concern.Fullerene and embedded metal fullerene are due to its unique structure and change
Physical property is learned, there is very extensive application in biomedical sector.
In antitumor properties, the experimental results find that there is the metal fullerene of different modifying certain tumor suppression to imitate
Fruit, and itself does not have toxic side effect, can be generated under very low dosage stronger tumor killing effect (Yang D et al.,
ACS Nano,2010.4(2):1178-1186.Liang XJ et al.,P.Natl.Acad.Sci.,2010.107(16):
7449-7454.Kang S et al.,P.Natl.Acad.Sci.,2012.109(38):15431-15436.Zhen,M et
al.Sci.China Mater.,2015(58):799-810).But the widely applied difficult point of embedded metal fullerene is
How largely to synthesize and detach.And relative to embedded metal fullerene, the yield and cost of empty fullerene are all greatly lowered,
Its water-soluble nano material has huge application value.
Invention content
The object of the present invention is to provide a kind of water-soluble fullerene nano materials and the preparation method and application thereof.Water of the present invention
Dissolubility is good, has good compatibility with organism, can obviously block tumor vessel, quickly cuts off tumor tissues nutrition supply；Its
Manufacturing cost is low.
Water-soluble fullerene nano material provided by the invention, its general structure are C2n(OH)x(Amino Acid)y；
Wherein, 20≤n≤60；0≤x<50；0≤y<20；
Amino Acid are water-soluble amino acids.
Above structure general formula indicates that hydroxyl and water-soluble amino acids are all connected on fullerene.
In the general structure of water-soluble fullerene nano material of the present invention, n concretely 30 or 35.
In the present invention, as y=0, i.e., there is no amino acid in the general structure of the described water-soluble fullerene nano material, institute
It is Fullerol to state water-soluble fullerene nano material；
When a variety of amino acid participate in react when, due to different aminoacids in the reaction to the compatibility of Fullerene Carbon cage not
Together, the amino acid of carbon cage surface modification and hydroxy number are also different.
In above-mentioned nano material, the water-soluble amino acids are alanine, glycine, serine, arginine, lysine
At least one of with tianmenine.
In above-mentioned nano material, the hydration grain size of the nano material is 1~1000nm.
In the present invention, the general structure of the water-soluble fullerene nano material is C2n(OH)x(Amino Acid)y, can
Change the quantity of x, y by adjusting reaction condition, adjusts intermolecular interaction, received to change the water-soluble fullerene
The hydration grain size that rice material is reunited in a solvent.
Water-soluble fullerene nano material of the present invention can be prepared by existing method, e.g., as y=0, can pass through phase transfer
Reactive liquid solution (XingG the et al, J.Phys.Chem.B., 2004 (108) that catalyst participates in:11473-11479) or fowler
Alkene powder directly reacts (Zheng J et al., Carbon, 2013,65,175) with aqueous slkali and is prepared；As y ≠ 0, i.e.,
When containing amino acid group, document (Carbon, 2006 (44) are can refer to:496-500) method recorded is prepared.
The present invention also provides application of the nano material in the drug for preparing treatment tumour.
In above-mentioned application, the tumour be liver cancer, lung cancer, colorectal cancer, kidney, cancer of pancreas, osteocarcinoma, breast cancer,
Oophoroma, prostate cancer, the cancer of the esophagus, gastric cancer, carcinoma of mouth, rhinocarcinoma, laryngocarcinoma, cholangiocarcinoma, cervical carcinoma, uterine cancer, carcinoma of testis, meninx
At least one of tumor, cutaneum carcinoma, melanoma and sarcoma；
The dosage form of the drug of the treatment tumour is pharmaceutically acceptable dosage form.
The present invention also provides a kind of drug, the active constituent of the drug is the water-soluble fullerene nano material.
In above-mentioned drug, the dosage form of the drug is pharmaceutically acceptable dosage form.
In above-mentioned drug, when the dosage form of the drug is injection, the solvent of the drug can be water, physiology salt
At least one of water, PBS buffer solution and Tris-HCl solution；The concentration of the physiological saline can be 0.85~0.90%；PBS
The concentration of buffer solution can be 0.01~0.1mol/L, the component of composition concretely Na2HPO4、KH2PO4, NaCl and KCl；
The concentration of Tris-HCl solution can be 0.05mol/L；
The concentration of the water-soluble fullerene nano material can be 1~100mg/mL.
Invention further provides one kind efficiently blocking tumor vascular tumor therapeuticing method, includes the following steps：1)
The drug of effective dose is given to lotus knurl organism；
2) it is swollen to the lotus knurl organism with the radiant energy source to match with the water-soluble fullerene nano material
Tumor position is irradiated.
In above-mentioned tumor therapeuticing method, the tumour be liver cancer, lung cancer, colorectal cancer, kidney, cancer of pancreas, osteocarcinoma,
Breast cancer, oophoroma, prostate cancer, the cancer of the esophagus, gastric cancer, carcinoma of mouth, rhinocarcinoma, laryngocarcinoma, cholangiocarcinoma, cervical carcinoma, uterine cancer, testis
At least one of cancer, meningioma, cutaneum carcinoma, melanoma and sarcoma；
The dosage of the drug can be 1mg/kg~100mg/kg；The specific total dosage of lotus knurl organism according to
The weight of the lotus knurl organism converts；
The administering mode of the drug is using at least one of intravenous injection, intraperitoneal injection, oral and topical administration；
The frequency of used radio frequency source irradiation can be 1~1000MHz, concretely 200MHz, 1~200MHz, 200~
1000MHz or 150~500MHz, transmission power can be 1mW~10kW, organism absorb irradiation power can be 1~
The time of 1000mW, concretely 5mW, the irradiation can be 10min~2h, concretely 1h, 10min~1h, 1h~2h or
10min~1.5h；
The lotus knurl organism is mammal, concretely at least one of people, mouse, rabbit, pig, monkey and dog.
In the present invention, the effective dose refers to when method through the invention gives the drug, it is sufficient to effectively be passed
Pass the amount of the active constituent for treating tumour.
In the present invention, injects the drug and carry out the irradiation after 0~1h；Concretely 10min or 10min~50h.
The present invention is in antineoplaston, and after drug injection is entered organism, tumour portion is reached by blood circulation
Position stimulates with after-applied radio frequency, the nano particle of tumor locus is made to play a role in the blood vessel, treats tumour；Due to tumour blood
Pipe is very different compared with Normal tissue vascular, and tumor vascular endothelial cell gap is larger, structure is imperfect, leads to tumor vessel
The aperture for generally comprising a large amount of nanoscales, due to the high-permeability and retention effect (EPR effects) of tumour, fullerene nanometer
Particle can be embedded in these apertures and destroy tumor vessel, bleed profusely to import inside tumor, cut off the nutrition of tumor tissues
Supply, and then inhibit the growth of tumour.
The present invention also provides a kind of suit efficiently blocking tumor vascular tumour, which includes the drug and production
The equipment of raw radiant energy source.
In above-mentioned suit, the frequency of the equipment transmitting for generating radiant energy source is the irradiation of used radio frequency source
Frequency can be 1~1000MHz, concretely 200MHz, and transmission power can be 1mW~10kW, and concretely 20W, organism inhale
The power of the irradiation of receipts can be 1~1000mW, concretely 5mW, radio frequency irradiation bomb be pulse mode.
The present invention has the following advantages：
Compared with cyclophosphamide, taxol that current clinic generally uses etc., good water solubility of the present invention has very with organism
Good compatibility, toxicity is low, efficient to the inhibition of tumour；When in use, dosage is small, and single therapy can reach high suppression
Ratio of outflow；Compared to embedded metal fullerene drug, drug cost of the present invention is more cheap, is more advantageous to popularity application.
Description of the drawings
Fig. 1 is C of the present invention70(OH)29Thermogravimetric analysis and difference quotient thermal gravimetric analysis curve.
Fig. 2 is C of the present invention70(OH)13(CH2OHCHNHCOOH)4Thermogravimetric analysis and difference quotient thermal gravimetric analysis curve.
Fig. 3 is C of the present invention70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4Hydration grain size curve in pure water.
Fig. 4 is present invention C in pure water70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4High-resolution atomic force it is aobvious
Micro mirror picture.
Fig. 5 is C of the present invention70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4To the therapeutic effect of rat liver cancer tumour
Figure.
Fig. 6 is saline control group rat liver cancer tumour photo before and after treatment.
Fig. 7 is function and effect figure of the different reagents to H22 tumours；Wherein Fig. 7 a) it is C of the present invention70(OH)29It is swollen to treat H22
After tumor for 24 hours at when dissected tumour a large amount of extravasated blood photo；Fig. 7 b) be saline control group H22 tumours HE dye picture；Figure
7c) it is C of the present invention70(OH)29The HE of tumour dyes picture for 24 hours after treatment H22 tumours；Fig. 7 d) it is C70(OH)13
(CH2OHCHNHCOOH)4The HE of tumour dyes picture for 24 hours after treatment H22 tumours.
Fig. 8 is physiological saline group, C70(OH)29、C70(OH)13(CH2OHCHNHCOOH)4Mouse each organ for 24 hours after treatment
HE dyes picture；In Fig. 8, a1-a5 is respectively the HE dyeing pictures of the physiological saline group treatment heart, liver, spleen, lung, kidney, and b1-b5 divides
It Wei not C70(OH)29The HE dyeing pictures of the heart, liver, spleen, lung, kidney are treated, c1-c5 is respectively C70(OH)13(CH2OHCHNHCOOH)4
Treat the HE dyeing pictures of the heart, liver, spleen, lung, kidney
Fig. 9 is physiological saline group, C70(OH)29、C70(OH)13(CH2OHCHNHCOOH)4Treatment to S180 sarcoma
Front and back effect contrast figure, wherein Fig. 9 a1、a2、a3Respectively physiological saline group, C70(OH)29、C70(OH)13
(CH2OHCHNHCOOH)4To the picture before the treatment of S180 sarcoma；Fig. 9 b1、b2、b3Respectively physiological saline group, C70
(OH)29、C70(OH)13(CH2OHCHNHCOOH)4To the picture after the treatment of S180 sarcoma.
Specific implementation mode
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
In following embodiments, general formula C2n(OH)x(Amino Acid)yWater-soluble fullerene nano material, hydroxy number
And amino acid number is weighted average, is as obtained by elemental analysis and thermogravimetric analysis COMPREHENSIVE CALCULATING.
Embodiment 1, C70(OH)x(Amino Acid)ySynthesis
(1) Fullerol C70(OH)29Synthesis
By C in toluene solution70It is mixed with a concentration of 50% NaOH solution, a small amount of phase transfer catalyst tetramethyl is added
Ammonium hydroxide (TBAH), stirring for 24 hours, dialyse except excess NaOH after ethanol precipitation product is added, obtain product C70(OH)29, freezing
Kept dry.
(2)C70(OH)13(CH2OHCHNHCOOH)4Synthesis
By the aqueous slkali of NaOH and serine, (wherein NaOH mass fractions are 33%, and the molar ratio of serine and NaOH are
1:4) it is mixed with ethyl alcohol, is added dropwise to C70(serine and C70Molar ratio be 100:1) it in toluene solution, is stirred overnight
(12h) removes upper toluene layer, and lower layer's product dialysis removes excess NaOH, and freeze-drying preserves.
Embodiment 2, C70(OH)x(Amino Acid)yThe hydroxyl and amino acid number of modification
(1) C is measured70(OH)29Hydroxyl value
According to elemental analysis (Flash EA 1112) result：C 53.55%, H 3.19%, N<0.3%, in conjunction with thermogravimetric point
Analysis, difference quotient thermal gravimetric analysis curve calculating C (as shown in Figure 1)70(OH)xHydroxy number.From thermogravimetric analysis it is found that C70(OH)xGu
Contain 11.8% water in body powder, about 10 hydrones calculate the H content belonged in hydroxyl in conjunction with H content in elemental analysis
It is 1.87%, thus can calculates C70(OH)xMiddle hydroxy number is 29.
(2) C is measured70(OH)13(CH2OHCHNHCOOH)4Hydroxyl and serine number
According to elemental analysis (Flash EA 1112) result：C 47.99%, H 3.21%, N 2.68%, in conjunction with thermogravimetric
Analysis, difference quotient thermal gravimetric analysis curve calculating C (as shown in Figure 2)70(OH)x(CH2OHCHNHCOOH)yThe hydroxyl and serine of modification
Number.From thermogravimetric analysis it is found that C70(OH)x(CH2OHCHNHCOOH)yContain 12.8% water, about 15 moisture in solid powder
Son can calculate 4 Serine molecules of carbon cage surface modification in conjunction with the ratio of N content in elemental analysis and C content.Further according to
The surveyed powder H total amounts of elemental analysis and H2The difference of H content in O and serine, can calculate hydroxy number is 13, so the production
The Average molecular formula of object is C70(OH)13(CH2OHCHNHCOOH)4。
The measurement of embodiment 3, water-soluble fullerene nano material hydration grain size
The C for taking a small amount of embodiment of the present invention 1 to prepare70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4Powder is dissolved in water
It is made into weak solution, due to intermolecular interaction, C70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4It is agglomerated into and receives in water
Rice grain forms the particle for being hydrated grain 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 grain size, C70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4Average grain diameter be respectively 136.4 ± 0.5nm and
134.7 ± 0.4nm, referring to Fig. 3.
Using high-resolution atomic force microscope (4BioScience AFM) determine C70(OH)29And
C70(OH)13(CH2OHCHNHCOOH)4The size that nano particle is reunited in water is about 40nm and 60nm, referring to Fig. 4.Two kinds solely
The difference that cube method obtains particle size is mainly since the principle and meaning of measurement are different, and the grain size that DLS is obtained is by nanometer
Grain surrounding solvent molecules influence is more notable.
Embodiment 4, C70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4To the therapeutic effect of rat liver cancer tumour
Animal strains：Balb/c female mices, 5 weeks, weight was between 16-20g.
Tumor model：Rat liver cancer H22 tumor strains
Experiment packet：Drug A groups：C70(OH)29；Drug B groups：C70(OH)13(CH2OHCHNHCOOH)4(C70-Ser)；It is right
According to group：Physiological saline
Administering mode：Intravenous injection
Dosage：5mg/ml injects 0.15ml
Experimental method：Inoculate 100 μ L a concentration of 5 × 107The H22 liver cancer cells of/ml.After growth about 5-7 days, tumour
Size reaches 50-100mm3It is tested.Tail vein injection C is not passed through to drug A groups and B component70(OH)29And C70- Ser this
In in mice with tumor body, injection drug after ten minutes, applies radio frequency (200MHz, 5mW) and treats 1h two kinds of 150 μ L of drug.Control group
Inject the same dose of physiological saline.The variation of pretherapy and post-treatment tumor locus is observed, mice organs and tumour are taken after experiment,
It is fixed with 4% paraformaldehyde fixer.
Experimental result：Drugs compared group and control group (Fig. 5 and Fig. 6) can obviously find that tumor locus has occurred after treatment
Apparent blackening, with the extension of time, tumor locus blackening becomes apparent.It only observes in the present embodiment after treating for 24 hours,
Dissection mouse tumor finds that phenomenon of bleeding profusely occurs in inside tumor, and this is mainly due to tumor vessels to have compared with Normal tissue vascular
A great difference, tumor vascular endothelial cell gap is larger, structure is imperfect, and tumor vessel is caused to generally comprise a large amount of nanometers
The aperture of scale, fullerenic particles can be embedded in these apertures and destroy tumor vessel, bleed profusely to import inside tumor, cut off
The nutrition supply of tumor tissues, and then inhibit the growth of tumour.From HE stained slices (Fig. 7) it is found that C70(OH)29And C70-
After Ser treatments, a large amount of necrosis of tumour cell are withered, and the trend of vigorous growth is then presented in control group tumour cell.And from short
Phase observation sees, C70(OH)29And C70Both drugs of-Ser do not cause significantly to damage to each organ of mouse, with reference to Fig. 8.Explanation
Water-soluble fullerene nano material of the present invention has apparent inhibition to hepatic carcinoma.
Embodiment 4, C70(OH)29And C70(OH)13(CH2OHCHNHCOOH)4To the therapeutic effect of murine sarcoma
Animal strains：Balb/c female mices, 5 weeks, weight was between 16-20g.
Tumor model：S180 sarcoma tumor strain
Experiment packet：Drug A groups：C70(OH)29；Drug B groups：C70(OH)13(CH2OHCHNHCOOH)4(C70-Ser)；It is right
According to group：Physiological saline
Administering mode：Intravenous injection
Dosage：5mg/ml injects 0.15ml
Experimental method：Inoculate 100 μ L a concentration of 5 × 107The S180 sarcoma cells of/ml.After growth about 5-7 days, swell
Tumor size reaches 50-100mm3It is tested.Tail vein injection C is not passed through to drug A groups and B component70(OH)29And C70-Ser
For 150 μ L of both drugs in mice with tumor body, injection drug treats 1h after ten minutes, with after-applied radio frequency (200MHz, 5mW).
Control group injects the same dose of physiological saline.Observe the variation of pretherapy and post-treatment tumor locus.Mice organs are taken at the end of experiment
And tumour, it is fixed with 4% paraformaldehyde fixer.
Experimental result：Drugs compared group and control group (Fig. 9) can obviously find that pretherapy and post-treatment tumor locus has occurred obviously
Blackening, illustrate C of the present invention70(OH)29And C70Both drugs of-Ser also have murine sarcoma preferable therapeutic effect.
Claims (8)
1. a kind of water-soluble fullerene nano material, its general structure is C2n(OH)x(Amino Acid)y；
Wherein, 20≤n≤60；0≤x<50；0≤y<20；
Amino Acid are water-soluble amino acids.
2. nano material according to claim 1, it is characterised in that：The water-soluble amino acids be alanine, glycine,
At least one of serine, arginine, lysine and tianmenine.
3. nano material according to claim 1 or 2, it is characterised in that：The hydration grain size of the nano material be 1~
1000nm。
4. application of the nano material in the drug for preparing treatment tumour described in any one of claim 1-3.
5. application according to claim 4, it is characterised in that：The tumour be liver cancer, lung cancer, colorectal cancer, kidney,
Cancer of pancreas, osteocarcinoma, breast cancer, oophoroma, prostate cancer, the cancer of the esophagus, gastric cancer, carcinoma of mouth, rhinocarcinoma, laryngocarcinoma, cholangiocarcinoma, uterine neck
At least one of cancer, uterine cancer, carcinoma of testis, meningioma, cutaneum carcinoma, melanoma and sarcoma；
The dosage form of the drug of the treatment tumour is pharmaceutically acceptable dosage form.
6. a kind of drug, it is characterised in that：The active constituent of the drug is any one of claim 1-3 water-soluble fowlers
Alkene nano material.
7. drug according to claim 6, it is characterised in that：The dosage form of the drug is pharmaceutically acceptable dosage form.
8. the drug described according to claim 6 or 7, it is characterised in that：When the dosage form of the drug is injection, the medicine
The solvent of object is at least one of water, physiological saline, PBS buffer solution and Tris-HCl solution；
A concentration of 0.1~50mg/mL of the water-soluble amino acids fullerene nanomaterial.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108853142A (en) * | 2017-05-09 | 2018-11-23 | 北京福纳康生物技术有限公司 | Water-soluble fullerene nano particle inhibits the application in tumour growth drug in preparation |
| CN112546069A (en) * | 2020-12-04 | 2021-03-26 | 河南精检生物科技有限公司 | Nano carbon material for blocking nutrition supply of diseased cells and preparation method and application thereof |
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| WO2018064963A1 (en) * | 2016-10-08 | 2018-04-12 | 北京福纳康生物技术有限公司 | Use of fullerene structure in preparation of medicament for treating tumor |
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| CN107137423A (en) | 2017-09-08 |
| CN108478598B (en) | 2021-05-07 |
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