CN106619715A - Application of amino-acid-modified metallofullerene water-soluble nanoparticles in preparation of tumor vascular disrupting agents - Google Patents
Application of amino-acid-modified metallofullerene water-soluble nanoparticles in preparation of tumor vascular disrupting agents Download PDFInfo
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Abstract
The invention discloses application of amino-acid-modified metallofullerene water-soluble nanoparticles in the preparation of tumor vascular disrupting agents; the amino-acid-modified metallofullerene water-soluble nanoparticles have a structural general formula: metallofullerene-(OH)x(amino acid)y, wherein metallofullerene is metallic fullerene, with 0</=x</=50 and 0</=y</=50, and amino acid is a water-soluble amino acid. The tumor vascular disrupting agents prepared by applying the amino-acid-modified metallofullerene water-soluble nanoparticles to their preparation have higher biosafety, have zero toxic and side effects for normal biological tissues, are low in dosage and are good in treatment effect.
Description
Technical field
The present invention relates to amino acid modified metal fullerene water-soluble nanoparticles are in tumor vessel blocker is prepared
Application, belong to nano biological field of medicaments.
Background technology
At present cancer is had become after cardiovascular disease, threatens the second largest killer of human survival health.Tumor
Growth and transfer are dependent on the presence of vasoganglion, and tumor vessel is the nutrition channel and route of metastasis of cancerous cell.By selectivity
Established tumor vessel net fast shut-off tumor blood supply is destroyed, induced tumor cell occurs ischemic necrosis, be that one kind has conscientiously
The suppression tumour growth of effect, prevent transfer method, this concept by Juliana Denekamp in nineteen eighty-two propose, accordingly
Medicine is referred to as vascular disrupting agents (Vascular disrupting agents, VDAs).Other any direct aggression tumor cells
Method, to a great extent can only the respite state of an illness, recurrence is difficult to avoid, and this is also at present operation, the limitation of chemicotherapy
It is located.
Modern medicine proves that normal blood vessels need one-year age to grow up to, and is made up of inner membrance, middle film and adventitia
Three layers of compact structure, and tumor vessel only can be formed with 4 days, be the single thin film being made up of endotheliocyte in structure.And by
In constituting, tumor vascular endotheliocyte gap is larger, structure is imperfect, causes tumor vessel to generally comprise a large amount of nanometer chis
The aperture of degree, enables small molecule and some nano-particle open-works and goes out.Tumor vessel blocker exactly make use of tumor vessel
With the difference of normal blood vessels, there are antibody and the class of small molecule two at present.For example, 3G4 antibody Tarvacin is by combining tumor vessel
The Phosphatidylserine of endotheliocyte kills pancreatic cancer cell.Small molecule vascular disrupting agents are divided into microtubule depolymerization thing and flavone two again
Class medicine, the Colchicine binding site that microtubule depolymerization thing passes through combining with vascular endothelial cell tubulin β subunits, causes micro-pipe
Depolymerization, actin and tubulin are separated, and then destroy the cytoskeleton of vascular endothelium.Colchicine and podophyllotoxin are exactly Jing
The microtubule depolymerization medicine of allusion quotation.
Because tumor vessel is very different compared with Normal tissue vascular, tumor vascular endotheliocyte gap is larger, structure
It is imperfect, cause tumor vessel to generally comprise the aperture of a large amount of nanoscales, due to the high-permeability and retention effect of tumor
(EPR effects), nano-particle can be embedded in these aperture destruction tumor vessels, bleed profusely so as to import inside tumor, cut off
The nutrition supply of tumor tissues, and then inhibit the growth of tumor.Vascular disrupting agents have become current tumor vascular targeting and control
One of the study hotspot in treatment field, with the continuous development of scientific research, it will enter clinical practice, become oncotherapy
Disruptive technology.
The content of the invention
It is an object of the invention to provide amino acid modified metal fullerene water-soluble nanoparticles are preparing tumor vessel
Application in blocker, the amino acid modified metal fullerene water-soluble nanoparticles of the present invention are applied to prepare tumor vessel resistance
In disconnected agent, the tumor vessel blocker biological safety that it is prepared is higher, normal biological tissue is had no toxic side effect, for treating
Effect it is good.
The amino acid modified metal fullerene water-soluble nanoparticles that the present invention is provided are preparing tumor vessel blocker
In application；
The general structure of the amino acid modified metal fullerene water-soluble nanoparticles is metallofullerene-
(OH)x(Amino Acid)y；
Wherein, metallofullerene is metal fullerene；
0≤x<50；0≤y<20；
Amino Acid are water-soluble amino acid.
In above-mentioned application, the metal fullerene includes；M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@
C2n、M2O@C2nAnd MmA3-mN@C2nIn at least one；Wherein, M, A are metallic element, and described M, A are selected from Sc, Y and group of the lanthanides
At least one in metallic element, 30≤n≤60,0≤m≤3, and n, m are integer；
The water-soluble amino acid be alanine, glycine, serine, arginine, lysine and ASP in extremely
Few one kind.
In the present invention, lanthanide element is lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium
(Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutecium (Lu)；
The rare earth metal concretely Gd, the metal fullerene concretely Gd@C82、Gd3N@C80。
In above-mentioned application, the hydrated diameter of the nano-particle can be 1～1000nm, concretely 100-150nm.
In above-mentioned application, preparing the amino acid modified metal fullerene water-soluble nanoparticles includes following step
Suddenly：The aqueous slkali of the water-soluble amino acid is mixed with metal fullerene, nucleophilic addition is carried out, that is, obtains the amino
The metal fullerene water-soluble nanoparticles of acid modification；
The mass fraction of alkali can be 10～50% in the aqueous slkali of the water-soluble amino acid, concretely 14%, 10～
14%th, 14～50% or 11～25%；The alkali concretely sodium hydroxide；
The water-soluble amino acid can be 1～100 with the mol ratio of the metal fullerene：1.
In above-mentioned application, the temperature of the nucleophilic addition can be 50～100 DEG C, concretely 50 DEG C；The parent
The time of core additive reaction can be 1～30h, concretely 1.5h, 1～1.5h, 1.5～7h or 1～5h；
In the preparation method, the step of after the nucleophilic addition also including impurity is filtered to remove.
Present invention also offers a kind of tumor vessel blocker, the active component of the tumor vessel blocker is the amino
The metal fullerene water-soluble nanoparticles of acid modification.
In above-mentioned tumor vessel blocker, the dosage form of the tumor vessel blocker is pharmaceutically acceptable dosage form.
In above-mentioned tumor vessel blocker, when the dosage form of the tumor vessel blocker is injection, its solvent is
At least one in water, normal saline, PBS and Tris-HCl solution；The concentration of the normal saline is concretely
0.85～0.90%；The concentration of PBS concretely 0.01～0.1mol/L, the component of PBS composition specifically may be used
For Na2HPO4、KH2PO4, NaCl and KCl；The concentration of Tris-HCl solution concretely 0.05mol/L；
The concentration of the metal fullerene nano material of the water-soluble amino acid modification can be 0.5～10mmol/L, specifically
Can be 1mmol/L, 0.5～1mmol/L, 1～10mmol/L or 0.5～5mmol/L.
Invention further provides one kind efficiently blocks tumor vascular tumor therapeuticing method, comprise the steps：1)
To the tumor vessel blocker for suffering from knubble biological body and giving effective dose；
2) tumor life is suffered to described with the radiant energy source matched with the water-soluble amino acid fullerene nanomaterial
The tumor locus of object carry out radio frequency irradiation.
In above-mentioned tumor therapeuticing method, the tumor be hepatocarcinoma, pulmonary carcinoma, colorectal carcinoma, renal carcinoma, cancer of pancreas, osteocarcinoma,
Breast carcinoma, ovarian cancer, carcinoma of prostate, the esophageal carcinoma, gastric cancer, oral cancer, rhinocarcinoma, laryngeal carcinoma, cancer of biliary duct, cervical cancer, uterus carcinoma, testis
At least one in cancer, meningioma, skin carcinoma, melanoma and sarcoma；
The dosage of the tumor vessel blocker can be 1mg/kg～100mg/kg, concretely 2mg/kg；Specifically
The total dosage of knubble biological body of suffering from is converted according to the body weight of the lotus knurl organism；
The administering mode of the medicine is using at least one in intravenous injection, lumbar injection, oral and topical administration；
The frequency of the radio frequency irradiation can be 1～1000MHz, concretely 200MHz, 1～200MHz, 200～
1000MHz or 50～500MHz, transmission power be 1mW～10kW, concretely 5mW, 1mW～5mW, 5mW～10kW or 1mW～
100mW, the time of the irradiation can be 10min～2h, concretely 30min, 10min～30min, 30min～2h or 20min
～1h；
It is described to suffer from knubble biological body for mammal；The concretely at least one in people, Mus, rabbit, pig, monkey and Canis familiaris L..
In the present invention, the effective dose is referred to when the medicine is given by the method for the present invention, it is sufficient to effectively passed
Pass the amount for treating the active component of tumor.
In the present invention, inject the medicine carries out the irradiation after 0～1h；Concretely 10min～2h.
The present invention, by the way that drug injection is entered after organism, by blood circulation tumor portion is reached in antineoplaston
Position, with after-applied radio frequency irradiation, the nano-particle for making tumor locus plays a role in the blood vessel, reaches the mesh of fast treating tumor
's；Because tumor vessel is very different compared with Normal tissue vascular, tumor vascular endotheliocyte gap is larger, structure is not complete
It is whole, cause tumor vessel to generally comprise the aperture of a large amount of nanoscales, due to the high-permeability and retention effect (EPR of tumor
Effect), metal fullerene nano-particle can be embedded in these aperture destruction tumor vessels, and blocking blood flow has cut off tumor tissues
Nutrition supply, and then inhibit the growth of tumor.
Present invention also offers a kind of suit for efficiently blocking tumor vascular tumor, the suit includes the tumor vessel
Blocker and the equipment for producing radiant energy source.
In above-mentioned suit, the frequency of the equipment transmitting for producing radiant energy source is used radio frequency source irradiation
Frequency can be 1～1000MHz, and transmission power can be 1mW-10kW, and the power of the irradiation that organism absorbs can be 1～1000mW,
Radio frequency irradiation bomb can be pulse mode.
The present invention has advantages below：
1st, the present invention is not limited, you can treatment by tumor by the very strong action of radio of penetrance in organism distribution
Tumor near organism surface, can also treat the tumor of organism deep organ or tissue.
2nd, for tumor vessel and the difference of normal blood vessels, specific inhibition tumor vessel treats tumor to the present invention, so as to
With broad spectrum activity.
3rd, metal fullerene carbon cage integrity amino acid modified in the present invention is higher, and biological safety is higher, to normal
Biological tissue has no toxic side effect.
4 cyclophosphamide, paclitaxels commonly used with current clinic etc. compare, tumor vessel blocker administration of the present invention
Dosage is little, and toxicity is low, and single therapy can just reach high tumour inhibiting rate；Compared to similar metal Fullerol medicine, tumor blood of the present invention
Pipe blocker more reduces on its basis dosage, and the radio frequency irradiation time is shorter after administration, treatment speed faster,
Curative effect is high.
Description of the drawings
The Gd@C prepared in Fig. 1, the embodiment of the present invention 182(OH)13(NHCH2CH2COOH)6(being abbreviated as GF-Ala)
Thermogravimetric analysiss and difference quotient thermal gravimetric analysis curve.
Fig. 2, the Gd@C of the water soluble hydroxy of the embodiment of the present invention 2 modification82The thermogravimetric analysiss of nano-particle (being abbreviated as GF-OH)
And difference quotient thermal gravimetric analysis curve.
The magnetization curve and the intensity of magnetization-temperature curve of two kinds of medicines of Fig. 3, GF-Ala and GF-OH.
The high-resolution atomic force microscope images of two kinds of medicines of Fig. 4, GF-Ala and GF-OH.
The fluorescent quenching matched curve of two kinds of medicines of Fig. 5, GF-Ala and GF-OH, thus can be calculated the egg of two kinds of medicines
White combination rate, wherein F0It is the fluorescence of albumen when being not added with fullerene, F is the fluorescence for adding albumen after fullerene, and Q is that fullerene is dense
Degree.
Average hydration radius and Zeta electric potential of the two kinds of medicines of Fig. 6, GF-Ala and GF-OH in pH=7 compares.
In Fig. 7, the embodiment of the present invention 2 GF-Ala medicines before the treatment, treatment after and treatment after 24h nuclear magnetic resonance figure
Piece.
The tumour inhibiting rate of two kinds of medicines compares in Fig. 8, the embodiment of the present invention 2, and during long-term observation 12 days, mouse tumor exists
The neoplastic state change of different time points, and the gross tumor volume of mice and weight are contrasted after 12 days.
Two kinds of medicines tumor vascular environmental scanning photo (wherein a after 24h after the treatment in Fig. 9, the embodiment of the present invention 2
For GF-Ala plus radio frequency, b is the partial enlarged drawing of a, and c adds radio frequency, d to be not added with radio frequency for GF-Ala for GF-OH, and e is normal saline
Plus radio frequency, f is an injecting normal saline).
Specific embodiment
Experimental technique used in following embodiments if no special instructions, is conventional method.
Material used, reagent etc. in following embodiments, if no special instructions, commercially obtain.
In following embodiments, the Gd@C of water soluble hydroxy modification82Nano-particle, skeleton symbol is Gd@C82(OH)26(write a Chinese character in simplified form
For GF-OH), its preparation method reference literature Carbon, 2013,65,175.
Embodiment 1, metal fullerene alanine nano-particle Gd@C82(OH)13(NHCH2CH2COOH)6Preparation
About 10mg Gd@C82Solid is added in 10ml single port bottles, adds β-the third ammonia that 6ml NaOH mass fractions are 14%
(Beta-alanine is 1 with the mol ratio of NaOH to acid-base solution:2), 1.5h is stirred vigorously at 50 DEG C, black solid gradually dissolves generation
Dark brown solution.Unreacted a small amount of pressed powder is filtered to remove, filtrate removes small molecule using the dialysis of Mw=3500 bag filters
Impurity, using the dark brown solution obtained after 220nm filtering with microporous membranes the amino acid modified metal fowler of the present invention is
Alkene water-soluble nanoparticles Gd@C82(OH)13(NHCH2CH2COOH)6(it is also called the metal fullerene nanometer of Beta-alanine modification
Granule, skeleton symbol is Gd@C82(OH)13(NHCH2CH2COOH)6, it is abbreviated as GF-Ala).
The metal fullerene water-soluble nanoparticles elementary analysiss result of the Beta-alanine of table 1 modification
To Beta-alanine of the present invention modification metal fullerene water-soluble nanoparticles carry out elementary analysiss gained carbon, nitrogen,
Protium ratio, as shown in table 1.As shown in Table 1, can be drawn in former pressed powder containing 11.5% according to thermogravimetric curve analysis
Water, through calculating 13 H are about2O molecules, in conjunction with elementary analysiss, further speculate that the Average molecular formula for obtaining the material is
Gd@C82(OH)13(NHCH2CH2COOH)6。
It is illustrated in figure 1 Gd@C82(OH)13(NHCH2CH2COOH)6(being abbreviated as GF-Ala) thermogravimetric analysiss and difference quotient thermogravimetric
Analysis curve, is computed in solid, containing 11.5% moisture content, to speculate that Average molecular formula is with reference to C, H, N content in elementary analysiss
Gd@C82(OH)13(NHCH2CH2COOH)6。
From Fig. 6 and Biao 2, Gd C of the present invention82(OH)13(NHCH2CH2COOH)6Mean diameter is in the water of pH=7
127.7nm, Zeta electric potential is -44.7mV.
Mean diameter and Z potential of the nano-particle of table 2 in the water of pH=7
The metal fullerene nano-particle of embodiment 2, Beta-alanine modification oncotherapy and effect pair under action of radio
Than
1st, lotus knurl rat animal model is set up：
Choose female BAl BIc/c mice of 5 weeks week old body weight in 16.0～20.0g, the μ L concentration of subcutaneous vaccination 100 for 5 ×
107The H22 hepatoma carcinoma cell of/ml.After growth about 5-7 days, tumor size reaches 50-100mm3Tested.
2nd, oncotherapy and different pharmaceutical Contrast on effect are tested
Drugs compared：The Gd@C of water soluble hydroxy modification82Nano-particle, the substantial amounts of oh group of its surface modification, such as
Fig. 2 show its thermogravimetric analysis TGA and DTG curves, with reference to elementary analysiss C, H, N content (C 36.95%, H 2.36%, N<
0.3%) speculate that its Average molecular formula is Gd@C82(OH)26。
By tail vein injection Beta-alanine derivatization GF-Ala and hydroxylating GF-OH both medicines, (concentration is
1mmol/L, 2mg/kg) in mice with tumor body, with after-applied radio frequency (200MHz, 5mW) 30min is treated.Before respectively collection is treated,
After treatment and treatment after 24h T2 nuclear magnetic resonances, and for a long time observe two kinds of medicines tumor killing effect.Three matched groups are set,
A respectively injecting normal saline (Saline), injecting normal saline and applying radio frequency (Saline+RF), only injects Beta-alanine
The metal fullerene medicine (GF-Ala) of modification.
From the figure 3, it may be seen that the Effect magnetic moment of Jing measuring and calculations metal fullerene aminoacid nano-particle of the present invention is 8.9 μ, it is high
In the μ of similar metal Fullerol 8.5；As shown in Figure 4, while changing functional group or the molecule of carbon cage surface modification, nanometer is improved
The dispersibility and homogeneity of granule, is conducive to the stability of medicine；Secondly its with the affinity of vivo protein etc. also because surface is repaiied
Decorations different and there occurs change, according to Fluorescence quenching mechanism, according to F0/ (F0-F)=1/faKa [Q]+1/fa calculate medicine and
The binding constant of albumen, as shown in figure 5, obtain metal fullerene aminoacid nano-particle of the present invention being with the binding constant of albumen
0.98×105L·mol-1, similar metal Fullerol is only 0.13 × 105Lmol-1.By above-mentioned it is demonstrated experimentally that using this
Bright amino acid modified metal fullerene nano-particle GF-Ala is compared to similar metal Fullerol GF-OH in oncotherapy
In effect it is more excellent.It is hydroxyl modified to be embodied in the third amino acid modified metal fullerene nano-particle GF- (Ala)
Metal fullerene nano-particle GF- (OH) using dosage 1/5～1/10, be to change metal fullerene the reason for possible
Water-solubleization preparation method, reaction condition is more gentle, and the functional group of carbon cage surface modification or small molecule are less, the integrity of carbon cage
It is higher so that the magnetic of metal fullerene nano-particle is higher.
Fig. 7 show GF-Ala medicines of the present invention before the treatment, treatment after and treatment after 24h when tumor locus T2 magnetic be total to
Shake imaging situation.It can be seen from figure 7 that large area necrosis situation occurs in tumor center region after treatment, show in imaging
For blackening, 24h necrosis ratio is increased substantially after treatment.
Fig. 8 is the comparison of GF-Ala medicines of the present invention and GF-OH medicines long-term tumour inhibiting rate under Isodose.The present invention
Tumor tissues are presented significantly necrosis blackening phenomena after GF-Ala Drug therapys, and through the Continuous Observation of 12 days, tumor locus were several
Incrustation comes off；And GF-OH medicines show certain therapeutic effect compared to matched group, gross tumor volume when 12 days after its treatment
With the twice that weight is about GF-Ala medicines of the present invention.
Fig. 9 be GF-Ala medicines of the present invention, GF-OH medicines and matched group after the treatment 24h when tumor vascular environment sweep
Retouch photo.As can be observed from Figure GF-Ala medicines of the present invention tumor vascular endothelial cell after RF-assisted treatment occurs big
Coming off for scope, exposes vascular basement membrane, illustrate GF-Ala medicines of the present invention can quick targeting destroyed tumor blood vessel, cut off tumor
The nutrition supply at position.And GF-OH medicine endothelial denudations are less, tumor vascular attack is not so good as under Isodose
GF-Ala medicines of the present invention.
Claims (10)
1. application of the amino acid modified metal fullerene water-soluble nanoparticles in tumor vessel blocker is prepared；
The general structure of the amino acid modified metal fullerene water-soluble nanoparticles is metallofullerene- (OH)x
(Amino Acid)y；
Wherein, metallofullerene is metal fullerene；
0≤x<50；0≤y<20；
Amino Acid are water-soluble amino acid.
2. application according to claim 1, it is characterised in that：The metal fullerene includes；M@C2n、M2@C2n、MA@C2n、
M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2nAnd MmA3-mN@C2nIn at least one；Wherein, M, A are metallic element, described
M, A are selected from least one in Sc, Y and lanthanide element, 30≤n≤60,0≤m≤3, and n, m are integer；
The water-soluble amino acid is at least in alanine, glycine, serine, arginine, lysine and ASP
Kind.
3. application according to claim 1 and 2, it is characterised in that：The hydration particle diameter of the nano-particle be 1～
1000nm。
4. the application according to any one of claim 1-3, it is characterised in that：Prepare the amino acid modified metal rich
Strangle alkene water-soluble nanoparticles to comprise the steps：The aqueous slkali of the water-soluble amino acid is mixed with metal fullerene, is entered
Row nucleophilic addition, that is, obtain the amino acid modified metal fullerene water-soluble nanoparticles；
5. application according to claim 4, it is characterised in that：The quality of alkali point in the aqueous slkali of the water-soluble amino acid
Number is 10～50%；
The water-soluble amino acid is 1～100 with the mol ratio of the metal fullerene：1.
6. the application according to claim 4 or 5, it is characterised in that：The temperature of the nucleophilic addition is 50～100
℃；The time of the nucleophilic addition is 1～30h；
In the preparation method, the step of after the nucleophilic addition also including impurity is filtered to remove.
7. a kind of tumor vessel blocker, it is characterised in that：The active component of the tumor vessel blocker is in claim 1-6
Metal fullerene water-soluble nanoparticles amino acid modified described in any one.
8. tumor vessel blocker according to claim 7, it is characterised in that：The dosage form of the tumor vessel blocker is
Pharmaceutically acceptable dosage form.
9. one kind efficiently blocks tumor vascular tumor therapeuticing method, comprises the steps：1) given to suffering from knubble biological body
Tumor vessel blocker described in the claim 7 or 8 of effect dosage；
2) tumor life is suffered to described with the radio-frequency radiation energy source matched with the water-soluble amino acid fullerene nanomaterial
The tumor locus of object carry out irradiation.
10. tumor therapeuticing method according to claim 9, it is characterised in that：The tumor is that hepatocarcinoma, pulmonary carcinoma, colon are straight
Intestinal cancer, renal carcinoma, cancer of pancreas, osteocarcinoma, breast carcinoma, ovarian cancer, carcinoma of prostate, the esophageal carcinoma, gastric cancer, oral cancer, rhinocarcinoma, laryngeal carcinoma, gallbladder
At least one in pipe cancer, cervical cancer, uterus carcinoma, carcinoma of testis, meningioma, skin carcinoma, melanoma and sarcoma；
The dosage of the tumor vessel blocker is 1mg/kg～100mg/kg；
The administering mode of the medicine is using at least one in intravenous injection, lumbar injection, oral and topical administration；
The frequency of the irradiation is 1～1000MHz, and transmission power is 1mW～10kW, and the time of the irradiation is 10min～2h；
The lotus knurl organism is mammal.
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| PCT/CN2017/104665 WO2018064963A1 (en) | 2016-10-08 | 2017-09-29 | Use of fullerene structure in preparation of medicament for treating tumor |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107551272A (en) * | 2017-10-18 | 2018-01-09 | 北京福纳康生物技术有限公司 | N fullerene aminoacid derivates nano particle is preparing the application of illumination condition medicaments for treating tumors under and medicine |
| 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 |
| CN108201543A (en) * | 2016-12-19 | 2018-06-26 | 北京福纳康生物技术有限公司 | Application of the water-soluble fullerene structure in the drug for preparing treatment fatty liver |
| CN109925322A (en) * | 2017-12-19 | 2019-06-25 | 中国科学院化学研究所 | Application of the water-soluble fullerene structure in the drug of preparation treatment pancreatic 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 |
| CN112791225A (en) * | 2019-11-14 | 2021-05-14 | 美国发现集团有限公司 | Nano robot for tumor treatment and preparation method thereof |
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