CN106139166A - Chitosan derivatives is MRI contrast agent and the preparation method of carrier - Google Patents
Chitosan derivatives is MRI contrast agent and the preparation method of carrier Download PDFInfo
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- CN106139166A CN106139166A CN201510167063.0A CN201510167063A CN106139166A CN 106139166 A CN106139166 A CN 106139166A CN 201510167063 A CN201510167063 A CN 201510167063A CN 106139166 A CN106139166 A CN 106139166A
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Abstract
The invention discloses MRI contrast agent that a kind of chitosan derivatives is carrier and preparation method thereof.This contrast agent includes: as the polyethyleneglycol modified chitosan of contrast agent main body；And, the secondary dentritic polyamidoamine with gadolinium chelate compound being mainly connected on chitosan main chain；Its preparation method includes: first provides polyethyleneglycol modified chitosan, is then coupled on alkynyl-modified secondary dentritic polyamidoamine by the cheland of gadolinium, then is connected on chitosan, it is thus achieved that described contrast agent.This chitosan derivatives is the good biocompatibility of the MRI contrast agent of carrier, easily biological-degradable, and possesses high relaxation rate, and its preparation method is simple, and desired reaction temperature is moderate, it is easy to control.
Description
Technical field
The present invention relates to the contrast agent of a kind of nuclear magnetic resonance, be specifically related to the base of a kind of nuclear magnetic resonance radiography
In MRI contrast agent and the preparation method of chitosan, belong to clinical medicine mr imaging technique field.
Background technology
Along with the development of science and technology, nuclear magnetic resonance has become a kind of effective means of Clinical detection solid tumor.Become compared to its other
As technology, nuclear magnetic resonance has many good qualities, as without ionization radiation injury, the tissue resolution of superelevation and threedimensional locating ability.
But in order to improve sensitivity and the accuracy rate of imaging further, it usually needs contrast agent carrys out Enhanced Imaging contrast.At present, clinical
Contrast agent be generally the gadolinium chelate compound of little molecule.This kind of little molecular contrast agents is applied to organism and still there are disadvantages that, as
Blood circulation time is short, relaxation rate is low, without targeting, there is certain toxicity, even can cause the fiber of organism nephrocyte
Change.Therefore high relaxation rate, low toxicity and there is tissue or tumor-targeting becomes the focus of MRI contrast agent development.
In recent years, little molecule Gd contrast agent covalency or the non-covalent research being combined with macromolecule are got more and more.By little point
Sub-contrast agent is combined with macromolecule, can with reinforcement internal stability, change hydrophobic property, drop the low molecular speed of rotation, raising
Relaxivity, prolongation blood circulation time and residence time in the tissue, additionally can carry out specificity chemical modification to macromolecule,
Strengthen tissue or the targeting of organ, be electric neutrality by complex decorating, osmotic pressure can be made close with blood plasma, thus reduce
Toxic and side effects.But drain in vivo due to macromole and limit its application in clinic more slowly.Therefore, find degradable
Macromole is particularly important as the carrier of little molecular contrast agents.
Summary of the invention
Offer one is provided there is good biocompatibility, easily biological-degradable and high relaxation
The chitosan derivatives of the features such as rate is MRI contrast agent of carrier and preparation method thereof, to overcome deficiency of the prior art.
For realizing aforementioned invention purpose, the technical solution adopted in the present invention is as follows:
Among a case study on implementation of the present invention, it is provided that a kind of chitosan derivatives is the preparation method of the MRI contrast agent of carrier,
Including: by diethylene triamine pentacetic acid (DTPA) and Gd3+It is coupled on alkynyl-modified secondary dentritic polyamidoamine, is formed with gadolinium
The secondary dentritic polyamidoamine of chelate,
And, by click chemistry reaction, the secondary dentritic polyamidoamine with gadolinium chelate compound is connected to polyethyleneglycol modified
Chitosan main chain on, it is thus achieved that described contrast agent.
In a more excellent embodiment, described preparation method farther includes: by the Polyethylene Glycol of chitosan and end carboxyl in room temperature
Reaction obtains polyethyleneglycol modified chitosan, and the molecular weight of described chitosan is Mw 40000～50000Da, described
The 10～20% of the molal quantity that throwing amount is chitosan structure unit of Polyethylene Glycol.
Preferably, chitosan is 8～12h with the Polyethylene Glycol of end carboxyl in the time of room temperature reaction.
In a more excellent embodiment, described preparation method farther includes: using acid solution that concentration is 3～6wt% as
Reaction dissolvent, modifies on polyethyleneglycol modified chitosan by azido compound by substitution reaction, and the response time is
20～26h, it is thus achieved that be modified with the chitosan of azido group and Polyethylene Glycol.
Preferably, wherein acid solution is the mixed liquor of isopyknic hydrochloric acid and acetic acid.
Preferably, azido compound is the epoxychloropropane of hydrazoic acid or Azide.
In one more excellent embodiment, described preparation method farther includes: by the Acibenzolar of diethylene triamine pentacetic acid (DTPA) by condensation
Reaction forming is on secondary dentritic polyamidoamine, it is thus achieved that coupling has the dendrimer of diethylene triamine pentacetic acid (DTPA).
In one more excellent embodiment, described preparation method farther includes: when pH value is 5～7, by Gd3+It is chelated to
On the secondary dentritic polyamidoamine of diethylene triamine pentacetic acid (DTPA) (DTPA) coupling, it is thus achieved that coupling has diethylenetriamine five
Acetic acid and Gd3+Secondary dentritic polyamidoamine.
In a more excellent embodiment, described preparation method farther includes: under conditions of there is catalyst, makes to be modified with folded
The chitosan of nitrogen groups and Polyethylene Glycol and coupling have diethylene triamine pentacetic acid (DTPA) and Gd3+Secondary dentritic polyamidoamine pass through
Click chemistry reaction forming, the response time is 20～26h, it is thus achieved that described contrast agent, and described catalyst is at least selected from five water
Copper sulfate and sodium ascorbate.
Present invention also offers and a kind of adopt the MRI contrast agent that chitosan derivatives is carrier that aforementioned preparation process obtains.
Among an embodiment, described chitosan derivatives is that the MRI contrast agent of carrier includes:
As the polyethyleneglycol modified chitosan of contrast agent main body,
The secondary dentritic polyamidoamine with gadolinium chelate compound being mainly connected on chitosan main chain.
Among a preferred embodiment, described contrast agent has a structure shown in following formula:
Wherein, n is the integer between 100～300.
This chitosan derivatives is that the MRI contrast agent of carrier uses chitosan to have bio-compatible as contrast agent main body, chitosan
Property is good, and the low and biodegradable advantage of bio-toxicity, the molecular size range of chitosan can not limit.Gadolinium chelate compound is connected to
On secondary dentritic polyamidoamine, then modify on chitosan by click chemistry, by increasing capacitance it is possible to increase the size of contrast agent molecule,
Increase spin correlation time, thus improve relaxivity, and extend its blood circulation time.Gadolinium chelate compound is predominantly located at secondary poly-
On the side chain of the chitosan of amide amine dendrimer grafting, thus improve the gadolinium charging ratio of unit formula amount.Find through test, should
Contrast agent relaxation rate (9.53mM-1·s-1) apparently higher than the relaxation rate (4.25mM of little molecular contrast agents-1·s-1)。
Compared with prior art, the beneficial effect comprise that the biology of the MRI contrast agent that this chitosan derivatives is carrier
The compatibility is good, easily biological-degradable, and possesses high relaxation rate, and its preparation method is simple, and reaction condition is gentle, it is easy to control.
Accompanying drawing explanation
The invention will be further elaborated with detailed description of the invention below in conjunction with the accompanying drawings.
Fig. 1 a is the preparation technology flow chart of a kind of contrast agent in the embodiment of the present invention 1；
Fig. 1 b is the structural formula of a kind of contrast agent in the embodiment of the present invention 1；
Fig. 2 is chitosan, CS-PEG, CS-PEG-N3And the infrared spectrogram of contrast agent of the present invention；
Fig. 3 is contrast agent of the present invention and Gd-DTPA relaxation rate comparison diagram；
Fig. 4 is the T1 weighted imaging comparison diagram of polymeric contrast agent of the present invention and Gd-DTPA；
Fig. 5 is the polymeric contrast agent of the present invention cytotoxicity side view in A549 cell.
Detailed description of the invention
Below in conjunction with specific embodiment, such scheme is described further.Should be understood that these embodiments are to use
It is not limited in the explanation present invention limit the scope of the present invention.The implementation condition used in embodiment can basis
Being actually needed and do adjustment further, not marked implementation condition is usually the condition in normal experiment.
Embodiment 1 chitosan derivatives is the preparation method of the MRI contrast agent of carrier, and refering to Fig. 1 a, it is concrete
Step is as follows: in a case study on implementation, and the preparation method of this contrast agent can comprise the steps:
(1) PEG-COOH dissolving is made into the solution of 5% (w/w), then the PH of solution is adjusted to 6, then adds
Entering NHS, after stirring 5min, addition EDC makes the mol ratio of EDC:NHS:COO be 1:1:0.8.In above solution stirring
By being slowly dropped to after activated carboxylic, to be dissolved in volume fraction be 1%CH to 30min3In chitosan in COOH, reactant liquor is in room
10h is stirred under temperature.Lyophilizing after being dialysed by reactant liquor, obtains polyethyleneglycol modified chitosan (CS-PEG).
(2) CS-PEG is dissolved in the glacial acetic acid of 5wt% and the equal-volume mixed liquor of hydrochloric acid, adds the epoxy chlorine of Azide
Propane.Reactant liquor aluminium foil lucifuge, 25 DEG C of reaction 24h.The product methanol solution containing 40% ammonia precipitates, and filters, and will
End-product with methanol, water, washing with acetone, is dried in vacuum drying oven, must be modified with azido group and poly-second by precipitation successively
Chitosan (the N of glycol3-CS-PEG)。
(3) take secondary dentritic polyamidoamine, add DMF and dissolve, after dissolving completely, drip under condition of ice bath
In the DMF solution of DTPA-NHS extremely, dropping process leads to N2Protection.After being added dropwise to complete, remove ice bath, room temperature reaction 3 days.
After reaction terminates, decompression is distilled off solvent DMF, and last gained dope is dissolved in water and dialyses, lyophilizing, and obtaining coupling has two
The dendrimer (G2-DTPA) of ethylene pentaacetic acid.
(4) G2-DTPA is dissolved in water, drips GdCl wherein3·6H2The aqueous solution of O, dropping limit, limit NaOH regulates
PH=6, after 42 DEG C of reaction 10h, dialysis lyophilizing, obtaining coupling has diethylene triamine pentacetic acid (DTPA) and Gd3+Secondary daiamid tree
Shape molecule (G2-DTPA-Gd).
(5) N is taken3-CS-PEG is dissolved in the aqueous acetic acid of 1%, take drop to respectively after G2-DTPA-Gd is dissolved in water aforementioned molten
In liquid.After twice deoxygenation of multigelation, continue logical N2, add sodium ascorbate and copper sulphate pentahydrate, 40 DEG C of reaction 24h.Reaction
After mixed liquor dialysis, lyophilizing, (following also known as contrast agent of the present invention, such as figure to obtain described contrast agent PEG-CS-G2-DTPA-Gd
Shown in 1b).
Embodiment 2 measures the infrared light of CS, CS-PEG, CS-PEG-N3 and CS-PEG-G2-DTPA-Gd
Spectrogram, including: use pressed disc method sample preparation, respectively detection chitosan raw material, CS-PEG, CS-PEG-N3 and
The INFRARED ABSORPTION of CS-PEG-G2-DTPA-Gd, as shown in Figure 2.
Embodiment 3 is tested polymeric contrast agent of the present invention on the MRI tester of 0.5T and is relaxed with Gd-DTPA
Henan time T1And T1Weighted imaging, including:
Compound concentration is the above two sample of 0.1～1.0mM respectively, after test, with concentration as abscissa,
The inverse in relaxation time is that vertical coordinate carries out linear fit and obtains the contrast agent of the present invention and the relaxation of Gd-DTPA
Rate is respectively 9.53mM-1·s-1And 4.25mM-1·s-1(Fig. 3).The contrast agent relaxation rate of the present invention apparently higher than
Gd-DPTA.By both T under variable concentrations1Weighted imaging (Fig. 4) is it can be seen that with concentration
Increasing, both of which has the trend brightened, but the contrasting effects of contrast agent of the present invention is the brightest in Gd-DTPA.
The cytotoxicity detection of embodiment 4 contrast agent
The contrast agent of the present invention cytotoxicity (Fig. 5) in A549 cell is measured by WST method.96
Orifice plate enters A549 cell suspension 100 μ L with the density kind of every hole 5000～8000 cell, 96 orifice plates are put
In CO2In incubator, 37 DEG C are cultivated 24h.Contrast agent of the present invention is dissolved in complete medium, mistake
Filter bacterium, with complete medium, polymer solution is diluted to 0.01～2mM different concentration.The most again will not
Joining in 96 orifice plates with the polymer solution of concentration, every hole adds 100 μ L, and it is complete that matched group adds 100 μ L
Full culture medium, continues to cultivate 24h.Finally removing culture medium, every hole adds 100 μ L fresh cultures, so
Rear every hole adds 10 μ L WST, is placed in incubator cultivation 2h, measures the suction at 450nm by microplate reader
Receipts value OD450nm.Each polymer concentration and matched group do 4 Duplicate Samples.Cell is calculated according to light absorption value
Relative survival rate.Blank group is i.e. not added with cell and polymer solution, and matched group is i.e. not added with polymer solution.
Comparative survival rate of cells (%)=100 × (experimental group OD-blank group OD)/(matched group OD-blank group OD)
As it is shown in figure 5, A549 cell hatch with PEG-CS-G2-DTPA-Gd after survival rate and concentration phase
Close, at Gd3+When concentration is less than 0.1mM, survival rate is all close to 100%, to survival rate during 0.5mM 80%
Above.Showing contrast agent molecule concentration inanimate object toxicity when below 0.1mM of the present invention, about 0.5mM has
Relatively low bio-toxicity.
Examples detailed above only for technology design and the feature of the present invention are described, its object is to allow and is familiar with technique
People be to will appreciate that present disclosure and implement according to this, can not limit the scope of the invention with this.
All equivalent transformations done according to spirit of the invention or modification, all should contain in protection scope of the present invention
Within.
Claims (9)
1. a chitosan derivatives is the MRI contrast agent of carrier, it is characterised in that including:
Polyethyleneglycol modified chitosan as contrast agent main body；
And, the secondary dentritic polyamidoamine being mainly connected on chitosan main chain, and described secondary daiamid is tree-like
Gadolinium chelate compound it is also associated with on molecule.
Chitosan derivatives the most according to claim 1 is the MRI contrast agent of carrier, it is characterised in that it has following formula institute
Show structure:
Wherein, n is the integer between 100～300.
Chitosan derivatives the most according to claim 1 and 2 is the MRI contrast agent of carrier, it is characterised in that described radiography
The relaxation rate of agent is at 9.53mM-1·s-1Above.
4. chitosan derivatives according to any one of claim 1-3 is the preparation method of MRI contrast agent of carrier, and its feature exists
In including:
By diethylene triamine pentacetic acid (DTPA) and Gd3+It is coupled on alkynyl-modified secondary dentritic polyamidoamine, is formed with gadolinium chela
The secondary dentritic polyamidoamine of compound,
And, by click chemistry reaction, the secondary dentritic polyamidoamine with gadolinium chelate compound is connected to polyethyleneglycol modified
Chitosan main chain on, it is thus achieved that described contrast agent.
Chitosan derivatives the most according to claim 4 is the preparation method of the MRI contrast agent of carrier, it is characterised in that bag
Include: the Polyethylene Glycol of chitosan Yu end carboxyl is obtained polyethyleneglycol modified chitosan at room temperature reaction, described chitosan
Molecular weight is Mw 40000～50000Da, and the throwing amount of described Polyethylene Glycol is chitosan structure unit molal quantity
10～20%, the response time is 8～12h.
6., according to the preparation method of the MRI contrast agent that the chitosan derivatives described in claim 4 or 5 is carrier, its feature exists
In also including: using acid solution that concentration is 3～6wt% as reaction dissolvent, the compound containing azido group is adornd poly-
On the chitosan that ethylene glycol is modified, the response time is 20～26h, it is thus achieved that be modified with the chitosan of azido group and Polyethylene Glycol.
Chitosan derivatives the most according to claim 4 is the preparation method of the MRI contrast agent of carrier, it is characterised in that bag
Include: the Acibenzolar of diethylene triamine pentacetic acid (DTPA) is connected to by condensation reaction tree-like point of the secondary daiamid of band alkynyl
On son, the response time is 12～20h, it is thus achieved that coupling has the secondary dentritic polyamidoamine of diethylene triamine pentacetic acid (DTPA).
8. according to the MRI contrast agent preparation method that the chitosan derivatives described in claim 4 or 8 is carrier, it is characterised in that
Including: when pH value is 5～7, by Gd3+It is chelated to coupling and has the secondary daiamid tree of diethylene triamine pentacetic acid (DTPA)
On shape molecule, the response time is 10～16h, it is thus achieved that coupling has diethylene triamine pentacetic acid (DTPA) and Gd3+Secondary daiamid
Dendrimer.
Chitosan derivatives the most according to claim 4 is the MRI contrast agent preparation method of carrier, it is characterised in that including:
Under conditions of there is catalyst, the chitosan being modified with azido group and Polyethylene Glycol is made to have diethylene triamine pentacetic acid (DTPA) with coupling
And Gd3+Secondary dentritic polyamidoamine by click chemistry reaction forming, the response time is 20～26h, it is thus achieved that described
Contrast agent, described catalyst is at least selected from copper sulphate pentahydrate and sodium ascorbate.
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| CN107328751A (en) * | 2017-06-27 | 2017-11-07 | 中国科学院合肥物质科学研究院 | A kind of SERS contrast agent of functionalization and its production and use |
| CN107661504A (en) * | 2017-10-25 | 2018-02-06 | 暨南大学 | A kind of golden nanometer particle of dendritic macromole modification and its preparation method and application |
| CN108310460A (en) * | 2018-02-02 | 2018-07-24 | 武汉大学 | Injectable high intensity Thermo-sensitive modified chitin based aquagel and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106832059A (en) * | 2017-03-08 | 2017-06-13 | 福州大学 | A kind of Tarceva Cy7 chitosan polymers with tumor-targeting |
| CN107328751A (en) * | 2017-06-27 | 2017-11-07 | 中国科学院合肥物质科学研究院 | A kind of SERS contrast agent of functionalization and its production and use |
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| CN107661504A (en) * | 2017-10-25 | 2018-02-06 | 暨南大学 | A kind of golden nanometer particle of dendritic macromole modification and its preparation method and application |
| CN107661504B (en) * | 2017-10-25 | 2020-07-03 | 暨南大学 | Dendritic macromolecule modified gold nanoparticle and preparation method and application thereof |
| CN108310460A (en) * | 2018-02-02 | 2018-07-24 | 武汉大学 | Injectable high intensity Thermo-sensitive modified chitin based aquagel and its preparation method and application |
| CN108310460B (en) * | 2018-02-02 | 2021-08-03 | 武汉大学 | Injectable high-strength temperature-sensitive modified chitin-based hydrogel and preparation method and application thereof |
| CN111281983A (en) * | 2018-12-06 | 2020-06-16 | 中国科学院苏州纳米技术与纳米仿生研究所 | Magnetic resonance imaging contrast agent, preparation method and application thereof |
| CN111281983B (en) * | 2018-12-06 | 2022-02-11 | 中国科学院苏州纳米技术与纳米仿生研究所 | Magnetic resonance imaging contrast agent, preparation method and application thereof |
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