CN101584870A - A kind of tree shaped polymer targeted contrast agent and preparation method thereof - Google Patents
A kind of tree shaped polymer targeted contrast agent and preparation method thereof Download PDFInfo
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- CN101584870A CN101584870A CNA2009100533698A CN200910053369A CN101584870A CN 101584870 A CN101584870 A CN 101584870A CN A2009100533698 A CNA2009100533698 A CN A2009100533698A CN 200910053369 A CN200910053369 A CN 200910053369A CN 101584870 A CN101584870 A CN 101584870A
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Abstract
The invention discloses a kind of tree shaped polymer targeted contrast agent and preparation method thereof, its contrast agent is a nanoparticle, and its structure is: the targeting group T that is in outermost end; Hydrophilic polyglycol chain as linking arm; Be positioned at the tree shaped polymer PAMAM of centronucleus; The paramagnetic metal X of in-vivo imaging; Its general formula is: PAMAM-PEG
(n)-T/X.Its preparation method: it is the targeting group that the PEG of different molecular weight and targeting radical reaction get an end, and an end is amino: NH
2-PEG
(n)-T; Again with NH
2-PEG
(n)-T and PAMAM-COOH promptly get macromolecular ligand: T-PEG with 32: 1 molar ratio reaction
(n)-PAMAM; With this part and paramagnetic metal ion solution chela and PAMAM-PEG
(n)-T/X.Preparation method of the present invention is simple to operate, and mild condition safety is suitable for applying.And the gained contrast agent, cytotoxicity is little, relaxation rate height, white mouse body endosome imaging effect is fine; Tumor bearing nude mice, during in-vivo imaging, targeting is obvious.
Description
Technical field
The invention belongs to biological medicine and nanosecond medical science technical field, relate to a kind of tree shaped polymer targeted contrast agent and preparation method thereof, be used in particular for the contrast agent of pulmonary carcinoma hypersensitivity MRI imaging.
Background technology
Cancer is becoming serious day by day global problems, almost there are 7,000,000 people to die from cancer every year at present, main cancer kind is: and pulmonary carcinoma (about 130 die ten thousand deaths dies/year), gastric cancer (about 100 die ten thousand deaths dies/year), hepatocarcinoma (about 66 die ten thousand deaths dies/year), colon cancer (about 66 death/years) and mastocarcinoma (about 50 die ten thousand deaths dies/year) and, pulmonary carcinoma causes the more people's of manying death than any other cancer.Pulmonary carcinoma is a kind of malignant tumor that comes from bronchial mucosa or body of gland, and M ﹠ M ranks first and is ascendant trend year by year at the malignant tumor meta.
The early diagnosis of pulmonary carcinoma and clinical analysis accurately are directly connected to the selection and the prognosis evaluation of therapeutic scheme.(Magnetic Resonance Imaging MRI) was applied to since the human diagnosis, and this technology has been developed rapidly and extensive use in fields such as biology, medical science with NMR (Nuclear Magnetic Resonance)-imaging first from Lauterbur in 1973.The MRI contrast agent can overcome the restriction of common imaging sequence, changes the signal intensity that proton produced, thereby improves the contrast of normal and pathological tissues.As the MRI contrast agent that is applied to human body, the medicine basic demands such as biocompatibility is strong except satisfying, good water solubility and stability, also should have retention time in relaxation rate preferably, targeting and the suitable body.Paramagnetic metal ion Fe
2+, Fe
3+, Mn
2+, Dy
3+And Gd
3+Can with the part complexation after form the water solublity paramagnetic contrast agent.
Tree shaped polymer (Dendrimers) is a kind of nano molecular of synthetic, and generation is respectively about 1～13nm its diameter range from G0 generation to G10, the earliest by Americanized scholar doctor D.A.Tomalia invention and successfully synthetic.With the linear macromolecule pharmaceutical carrier comparatively speaking, tree shaped polymer is spherical in shape, and coils agglomerating unlike linear macromolecule at random.The big I finely regulating of molecular weight (monodispersity is good), the pharmacokinetics behavior has repeatability.In its building-up process, the artificial kind of the volume of controlling polymers, form and end group.Tree shaped polymer has that dissolubility height, adhesiveness are low, high response and can with characteristics such as other materials are miscible, can be used as unimolecule nanoparticle delivery medicine or gene.Over more than 10 year, tree shaped polymer numerous areas such as from material science to the biomedicine has all received increasingly extensive concern.The more important thing is the tree shaped polymer non-immunogenicity, can not cause the immunoreation of body, hereditary-less toxicity and cytotoxicity can not cause transformation and cell death.Introduce carboxyl as the tree shaped polymer surface, then can make up ideal Gd
3+Part.
The targeting contrast agent can improve it in target organ or in-house concentration and reduce the absorbtivity of background tissues to contrast agent, thereby improves the sensitivity of imaging.Studies show that general more than on the normal cell of folacin receptor quantity on the tumor cell surface, activity is stronger, and the folic acid key is linked on the contrast agent, can improve the active targeting of contrast agent to tumor cell.From passive targeting, the endotheliocyte on the blood vessel of normal structure is arranged closely, and the gap is less, is generally less than 8nm, and the gap of cancerous issue medium vessels wall is much bigger, between 100～800nm.Therefore can utilize specific nanometer size effect to be implemented in the passive targeting of the Nano medication in the blood circulation process.Studies show that the microgranule of intravenous injection particle diameter 700～3000nm can be by pulmonary's capillary bed mechanical filter detention, and stop considerable time, finally entered lung tissue or alveolar by the picked-up of monokaryon macrophage.For avoiding the contrast agent nanoparticle to hold back the image-forming diagnose result who causes thromboembolism even lead to errors because of pulmonary's capillary bed mechanical filter, contrast agent particle can not be excessive.Folacin receptor also extensively is present on the normal renal proximal tubules, but can not enter kidney by glomerular filtration during greater than 10nm when grain diameter usually.
Although in the past twenties years, medical imaging technology has had many progress, how in early days our ability of the stage discovery tumor to still limited.The folic acid residue synthesizes the particle with specific nanoscale size by bio-compatibility macromole binding to the tree shaped polymer surface, utilize passive target and initiatively targeting combine, realize the high targeting of pulmonary carcinoma and the system of responsive radiography is not appeared in the newspapers both at home and abroad as yet.Based on the design of the nano-complex particle of the high bio-compatibility of having of nanoscale effect with synthetic, it is untimely and miss the situation of best occasion for the treatment to be expected to overcome present pulmonary carcinoma clinical diagnosis, alleviate and cause the highest disease of mortality rate among this cancer of pulmonary carcinoma killer and bring human harm, have important research value and application prospect.
Summary of the invention
The object of the present invention is to provide a kind of good biocompatibility, targeting is good, the MRI macromolecular contrast agent that the pulmonary carcinoma earlier detection is worked.
Another purpose of the present invention is to provide a kind of preparation method and purposes that lung carcinoma cell is had the of new generation tree-like nanometer polymer contrast agent of targeting.
The object of the present invention is achieved like this:
A kind of tree shaped polymer targeted contrast agent, characteristics are that this contrast agent is a nanoparticle, have following structure:
Be in the targeting group of outermost end; Hydrophilic polyglycol chain as linking arm; Be positioned at the tree shaped polymer PAMAM of centronucleus; The paramagnetic metal X of in-vivo imaging;
Its general formula is: PAMAM-PEG
(n)-T/X; Wherein X is paramagnetic metal ion: Fe
2+, Fe
3+, Mn
2+, Dy
3+Or Gd
3+PEG is that molecular weight is the Polyethylene Glycol of 1000～10000Da; T is the targeting group; PAMAM is a tree shaped polymer; The targeting group is folic acid, galactose or polypeptide.
The preparation method of above-mentioned contrast agent is: with the paramagnetic metal ion wiring solution-forming and with concentration be the hydrochloric acid of 0.1M to be adjusted to pH value be 5.8～6.2, then with amine dendrimer part PAMAM-PEG
(n)Be added drop-wise to behind-T the dilute with water in the paramagnetic metal ion solution through regulating, lucifuge, dropping time are controlled at 30min～45min, react under the room temperature and cross gel column after 60～72 hours, collect the concentrated back lyophilizing of liquid and obtain contrast agent PAMAM-PEG (n)-T/X, keep in Dark Place; Its paramagnetic metal ion and amine dendrimer part PAMAM-PEG
(n)The mole ratio of-T is 10: 1～5: 1; The concentration of paramagnetic metal ion solution is 1～2M; Amine dendrimer part PAMAM-PEG
(n)The concentration of-T solution is 0.5～1mg/ml;
Described amine dendrimer part PAMAM-PEG
(n)The preparation of-T may further comprise the steps:
A) the Michael addition polyreaction by MA prepares the integer PAMAM macromole in generation;
B) PAMAM and succinic anhydride reaction formation end group is the PAMAM-COOH of carboxyl;
C) polyethylene glycol diamines (NH
2-PEG
(n)-NH
2) with molar ratio reaction such as T, be that condensing agent and catalyst react in dimethyl sulfoxide solvent with 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl), 4-dimethylamino naphthyridine (DMAP), obtain NH
2-PEG
(n)-T;
D) NH
2-PEG
(n)-T and PAMAM-COOH reaction, its mol ratio is 32: 1, the reactant liquor molecular cut off is the bag filter of 3500-15000, at H
260～the 72h that dialyses in 0, Rotary Evaporators concentrates, the fridge drying, amine dendrimer part PAMAM-PEG
(n)-T.
Above-mentioned contrast agent application is in the early stage diagnostic imaging of pulmonary carcinoma.
Contrast agent of the present invention has following characteristics:
1., have high bio-compatibility, non-immunogenicity and cytotoxicity;
2., the core texture size is meticulous adjustable, surperficial carboxyl controllable number;
3., tree shaped polymer surface carboxyl is intensive, but a plurality of paramagnetic metal ions of complexation, thereby strengthen the sensitivity of radiography by the relaxation rate that improves contrast agent;
4., initiatively targeting and passive target combine and lung carcinoma cell are had the susceptiveness that high Targeting Performance further improves imaging, realize the earlier detection to pulmonary carcinoma, find the morning that helps pulmonary carcinoma, early treatment;
5., the hydrophilic high mol finishing can prolong the blood circulation time of nano-complex particle, strengthen to contain the water solublity of gadolinium tree shaped polymer and strengthen it in stability in blood;
6., form nanoparticle comparatively speaking, cause body harmful thereby the nanoparticle that the tree shaped polymer part forms can not discharge metal ion because of dissociating in the blood circulation process with linear polymeric polymeric disk coiled group.
Description of drawings
Fig. 1 is a contrast agent structural representation of the present invention, among the figure:
The targeting group;
Linking arm;
Tree-like high polymer PAMAM; Paramagnetic metal ion.
Fig. 2 is contrast agent PAMAM-PEG of the present invention
(n)-FA/Gd infrared spectrum
Fig. 3 is contrast agent PAMAM-PEG of the present invention
(1000)The particle diameter that-FA/Gd forms is at the SEM of 80nm nanometer figure
Fig. 4 is contrast agent PAMAM-PEG of the present invention
(4000)The particle diameter that-FA/Gd forms is at the SEM of 100nm nanometer figure
Fig. 5 is the TEM figure that contrast agent PAMAM-PEG of the present invention (n)-FA/Gd forms different-grain diameter
The specific embodiment
The invention will be further described below in conjunction with specific embodiment:
1.PAMAM synthetic
A) 0.5G PAMAM-Me's is synthetic
Get 9g ethylenediamine and 30g methanol, in there-necked flask, drip the 103.2g acrylic acid methyl ester. while stirring, rate of addition is one of a per second, at 25 ℃, stirring 24h.With product distilling under reduced pressure 3 hours under-5 ℃, the condition of 133.3Pa, obtain weak yellow liquid then.
B) 1.0G PAMAM-NH
2Synthetic
Get 20.2g 0.5 generation AMAM in there-necked flask, add 60g methanol, stir, drip the 72g ethylenediamine, rate of addition is 1d/s, at 25 ℃, stirring 24h.Product distilling under reduced pressure 3 hours under-5 ℃, the condition of 266.6Pa then obtains faint yellow viscous liquid, i.e. 1.0G PAMAM-NH
2
C) repeat a), b) step is up to obtaining purified 4.0G PAMAM
2.PAMAM-COOH synthetic
The PAMAM (4.0 generation) that gets 0.2mmol is dissolved among the anhydrous DMSO N
2Protection adds the succinic anhydride of 0.02mmol catalyst DMAP and 12.8mmol, 40 ℃, stirred 48 hours, solvent DMSO dialysis is removed, filtering insoluble matter, lyophilization obtain PAMAM-COOH.
3.NH
2-PEG
(1000)-FA's is synthetic
With the FA of 0.2mol be dissolved among the DMSO, stirring, N
2Protection adds EDC/NHS activation 2h, then polyethylene glycol diamines (the NH of mol ratio such as input
2-PEG
(1000)-NH
2), room temperature, lucifuge, stirring 24 hours, it is in 1000 the bag filter that product is transferred to molecular cut off, dialysis 72h, concentrates, crosses silicagel column and separate and purify, lyophilization obtains NH
2-PEG
(1000)-FA, the lucifuge cryopreservation.
4.FA-PEG
(1000)-PAMAM's is synthetic
The PAMAM-COOH that gets 0.05mmol is dissolved among the DMSO, adds the EDC/NHS activated carboxyl of catalytic amount, reacts the mono-substituted NH that drops into 0.32mmol after two hours
2-PEG
(1000)-FA, N
2Protection, room temperature, stirring 72h get FA-PEG
(1000)-PAMAM (PP
(1000)F).Molecular cut off is to dialyse in 5000 the bag filter, the dialysis purification, and product concentrates, lyophilization, obtains macromolecular ligand FA-PEG
(1000)-PAMAM.With particle diameter and the Zeta potential that dynamic light scattering is surveyed, use its dispersibility of gel permeation chromatography.
5.FA-PEG
(1000)The preparation of-PAMAM/Gd
Take by weighing 3.75g (10mmol) GdCl
3.6H
2O is dissolved in the 10mL water, regulates about pH value to 6 with the dilute hydrochloric acid of 0.01mol/L, slowly drips the PP of 10ml again
(1000)The aqueous solution 10mg/ (1mmol) of F, stirring at room 72 hours is crossed the Sephadex-G25 gel column, and concentrated, lyophilization get end product: contrast agent FA-PEG
(1000)-PAMAM/Gd.
Embodiment 2
1.PAMAM synthetic
A) 0.5G PAMAM-Me's is synthetic
Get 9g ethylenediamine and 30g methanol, in there-necked flask, drip the 103.2g acrylic acid methyl ester. while stirring, rate of addition is one of a per second, at 25 ℃, stirring 24h.With product distilling under reduced pressure 3 hours under-5 ℃, the condition of 133.3Pa, obtain weak yellow liquid then, be 0.5G PAMAM-Me.
B) 1.0G PAMAM-NH
2Synthetic
Get 20.2g 0.5 generation AMAM in there-necked flask, add 60g methanol, stir, drip the 72g ethylenediamine, rate of addition is 1d/s, at 25 ℃, stirring 24h.Product distilling under reduced pressure 3 hours under-5 ℃, the condition of 266.6Pa then obtains faint yellow viscous liquid, i.e. 1.0G PAMAM-NH
2
C) repeat a), b) step is up to obtaining purified 4.0G PAMAM
2.NH
2-PEG
(2000)-FA's is synthetic
The FA of 0.2mol is dissolved in DMSO, stirring, N
2Protection adds EDC/NHS activation 2h, the polyethylene glycol diamines (NH of mol ratios such as back input
2-PEG
(2000)-NH
2), room temperature, lucifuge, stirring 24 hours, molecular cut off is dialysis 72 hours in 2000 the bag filter, concentrate, lyophilization, crosses silicagel column and separates and purify, and obtains the product list and replaces NH
2-PEG
(2000)-FA, the lucifuge cryopreservation.
3.COOH-PEG
(2000)-FA's is synthetic
Get the NH of 20mmol
2-PEG
(2000)-FA is dissolved among the anhydrous DMSO, N
2Protection adds the succinic anhydride of 0.02mmolDMAP catalyst and 40mmol, and 40 ℃, stir 48h, molecular cut off is to dialyse in 2000 the bag filter, the dialysis purification, and lyophilization obtains COOH-PEG
(2000)-FA
4.FA-PEG
(2000)-PAMAM's is synthetic
Get the PAMAM-NH of 0.05mmol
2Be dissolved among the DMSO, treat all COOH-PEG of dissolving back input 0.32mmol
(2000)-FA, N
2Protection, stirring at room 72h, molecular cut off dialyse in 10000 the bag filter, the dialysis purification, and product concentrates, lyophilization.Survey PP with dynamic light scattering
(2000)The particle diameter of F and Zeta potential are with its dispersibility of gel permeation chromatography.
5.FA-PEG
(2000)The preparation of-PAMAM/Gd
Take by weighing 3.75g (10mmol) GdCl
3.6H
2O is dissolved in the 10mL water, regulates about pH value to 6 with the dilute hydrochloric acid of 0.01mol/L, slowly drips the PP of 10ml again
(1000)The aqueous solution 10mg/ (1mmol) of F, stirring at room reaction 60h crosses the Sephadex-G25 gel column, and gleanings concentrates, lyophilization gets end product: contrast agent FA-PEG
(2000)-PAMAM/Gd.
Embodiment 3
1.PAMAM synthetic
A) 0.5G PAMAM-Me's is synthetic:
Get 9g ethylenediamine and 30g methanol, in there-necked flask, drip the 103.2g acrylic acid methyl ester. while stirring, rate of addition is one of a per second, at 25 ℃, stirring 24h.With product distilling under reduced pressure 3 hours under-5 ℃, the condition of 133.3Pa, obtain weak yellow liquid then.
B) 1.0G PAMAM-NH
2Synthetic
Get 20.2g 0.5 generation AMAM in there-necked flask, add 60g methanol, stir, drip the 72g ethylenediamine, rate of addition is 1d/s, at 25 ℃, stirring 24h.Product distilling under reduced pressure 3 hours under-5 ℃, the condition of 266.6Pa then obtains faint yellow viscous liquid, i.e. 1.0G PAMAM-NH
2
C) repeat a), b) step is up to obtaining purified 4.0G PAMAM
2.NH
2-PEG
(4000)-FA's is synthetic
The FA of 0.2mol is dissolved in DMSO, stirring, N
2Protection adds EDC/NHS activation 2h, the polyethylene glycol diamines (NH of mol ratios such as back input
2-PEG
(4000)-NH
2), room temperature, lucifuge, stirring 24 hours, molecular cut off is dialysis 72 hours in 4000 the bag filter, concentrate, lyophilization, crosses silicagel column and separates and purify, and obtains the product list and replaces NH
2-PEG
(4000)-FA, the lucifuge cryopreservation.
3.COOH-PEG
(4000)-FA's is synthetic
Get the NH of 20mmol
2-PEG
(4000)-FA is dissolved among the anhydrous DMSO, N
2Protection adds the succinic anhydride of 0.02mmol catalyst DMAP and 40mmol, and 40 ℃, stir 48h, molecular cut off is to dialyse in 4000 the bag filter, and dialysis removes the DMSO that desolvates, the filtering insoluble matter, and lyophilization obtains COOH-PEG
(4000)-FA
4.FA-PEG
(4000)-PAMAM's is synthetic
Get the PAMAM-NH of 0.05mmol
2Be dissolved among the DMSO, treat all COOH-PEG of dissolving back input 0.32mmol
(4000)-FA, N
2Protection is stirring at room 72h down.Molecular cut off is to dialyse in 20000 the bag filter, removes and desolvates and unreacted reactant.Product concentrates, lyophilization.Survey PP with dynamic light scattering
(4000)The particle diameter of F and Zeta potential are with its dispersibility of gel permeation chromatography.
5.FA-PEG
(4000)The preparation of-PAMAM/Gd
Take by weighing 3.75g (10mmol) GdCl
3.6H
2O is dissolved in the 10mL water, regulates about pH value to 6 with the dilute hydrochloric acid of 0.01mol/L, slowly drips the PP of 10ml again
(4000)The aqueous solution 10mg/ (1mmol) of F, stirring at room 64h,, cross the Sephadex-G25 gel column, gleanings concentrates, lyophilization, gets end product, macromolecular contrast agent FA-PEG
(4000)-PAMAM/Gd.
Embodiment 4-6
Remove and use FeCl respectively
3, FeCl
2, MnCl
2Substitute GdCl
3Outward, other is with embodiment 1.
Embodiment 7-9
Remove and use FeCl respectively
3, FeCl
2, MnCl
2Substitute GdCl
3Outward, other is with embodiment 2.
Embodiment 10-12
Remove and use FeCl respectively
3, FeCl
2, MnCl
2Substitute GdCl
3Outward, other is with embodiment 3.
Embodiment 13-15
Except that substituting the folic acid (FA) with galactose, other is respectively with embodiment 1,2,3.
Embodiment 16-18
Except that substituting the folic acid (FA) with polypeptide, other is respectively with embodiment 1,2,3.
In the above-described embodiments, made particle diameter, based on the pulmonary carcinoma or the hepatoma-targeting contrast agent of tree shaped polymer less than 100nm.Only in order to explanation the present invention but be not limited thereto, should be appreciated that in not departing from the scope of the present invention also can have multiple accommodation or alternative to the foregoing description.
Claims (3)
1, a kind of tree shaped polymer targeted contrast agent is characterized in that this contrast agent is a nanoparticle, has following structure:
Be in the targeting group of outermost end; Hydrophilic polyglycol chain as linking arm; Be positioned at the tree shaped polymer PAMAM of centronucleus; The paramagnetic metal X of in-vivo imaging;
Its general formula is: PAMAM-PEG
(n)-T/X; Wherein X is paramagnetic metal ion: Fe
2+, Fe
3+, Mn
2+, Dy
3+Or Gd
3+PEG is that molecular weight is the Polyethylene Glycol of 1000～10000Da; T is the targeting group; PAMAM is a tree shaped polymer; The targeting group is folic acid, galactose or polypeptide.
2, the preparation method of the described contrast agent of a kind of claim 1, it is characterized in that this method is: with the paramagnetic metal ion wiring solution-forming and with concentration is that to be adjusted to pH value be 5.8～6.2 for the hydrochloric acid of 0.1M, then with in the paramagnetic metal ion solution that is added drop-wise to behind amine dendrimer part PAMAM-PEG (n)-T dilute with water through regulating, lucifuge, dropping time are controlled at 30min～45min, react under the room temperature and cross gel column after 60～72 hours, collect the concentrated back lyophilizing of liquid and obtain contrast agent PAMAM-PEG (n)-T/X, keep in Dark Place; The mole ratio of its paramagnetic metal ion and amine dendrimer part PAMAM-PEG (n)-T is 10: 1～5: 1; The concentration of paramagnetic metal ion solution is 1～2M; The concentration of amine dendrimer part PAMAM-PEG (n)-T solution is 0.5～1mg/ml;
Described amine dendrimer part PAMAM-PEG
(n)The preparation of-T may further comprise the steps:
A) the Michael addition polyreaction by MA prepares the integer PAMAM macromole in generation;
B) PAMAM and succinic anhydride reaction formation end group is the PAMAM-COOH of carboxyl;
C) polyethylene glycol diamines (NH
2-PEG
(n)-NH
2) with molar ratio reaction such as T, be that condensing agent and catalyst react in dimethyl sulfoxide solvent with 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl), 4-dimethylamino naphthyridine (DMAP), obtain NH2-PEG (n)-T;
D) NH2-PEG (n)-T and PAMAM-COOH reaction, its mol ratio is 32: 1, the reactant liquor molecular cut off is the bag filter of 3500-15000, at H
260～the 72h that dialyses among the O, Rotary Evaporators concentrates, the fridge drying, amine dendrimer part PAMAM-PEG (n)-T.
3, the described contrast agent of a kind of claim 1 is characterized in that the application of this contrast agent in the early stage diagnostic imaging of pulmonary carcinoma.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105797174A (en) * | 2016-01-22 | 2016-07-27 | 复旦大学附属肿瘤医院 | Nanometer graphene oxide-based magnetic resonance imaging contrast agent and preparation method thereof |
| CN109513015A (en) * | 2018-12-11 | 2019-03-26 | 吉林化工学院 | A kind of tumor microenvironment responsiveness self assembly diagnosis and treatment integration reagent and preparation method thereof |
-
2009
- 2009-06-18 CN CNA2009100533698A patent/CN101584870A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105797174A (en) * | 2016-01-22 | 2016-07-27 | 复旦大学附属肿瘤医院 | Nanometer graphene oxide-based magnetic resonance imaging contrast agent and preparation method thereof |
| CN105797174B (en) * | 2016-01-22 | 2019-01-11 | 复旦大学附属肿瘤医院 | A kind of magnetic resonance imaging contrast and preparation method thereof based on nano graphene oxide |
| CN109513015A (en) * | 2018-12-11 | 2019-03-26 | 吉林化工学院 | A kind of tumor microenvironment responsiveness self assembly diagnosis and treatment integration reagent and preparation method thereof |
| CN109513015B (en) * | 2018-12-11 | 2021-06-04 | 吉林化工学院 | Tumor microenvironment responsive self-assembled diagnosis and treatment integrated reagent and preparation method thereof |
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