CN101569751A - Tumor-targeted nonionic dendritic macromolecule magnetic resonance imaging contrast agent - Google Patents
Tumor-targeted nonionic dendritic macromolecule magnetic resonance imaging contrast agent Download PDFInfo
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- CN101569751A CN101569751A CNA2009100527894A CN200910052789A CN101569751A CN 101569751 A CN101569751 A CN 101569751A CN A2009100527894 A CNA2009100527894 A CN A2009100527894A CN 200910052789 A CN200910052789 A CN 200910052789A CN 101569751 A CN101569751 A CN 101569751A
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Abstract
The invention discloses a tumor-targeted nonionic dendritic macromolecule magnetic resonance imaging contrast agent and a preparation method thereof. The contrast agent is a spherical nano composite particle prepared by taking a PAMAM dendritic macromolecule as a nuclear, folic acid as a targeting group, polyethyleneglycols (PEG) with different molecular weights as linking arms between the targeting group and a macromolecular carrier, and diethylenetriamine pentaacetic acid (DTPA) as a Gd<3+> ligand; and the preparation method comprises the following steps: reacting H2N-PEG-FA with folic acid residue and diethylenetriamine pentaacetic acid double active ester (SuO-DTPA-SuO) to obtain SuO-DTPA-PEG-FA; and then bonding the SuO-DTPA-PEG-FA on the surface of the PAMAM to obtain PAMAM-DTPA-PEG-FA; and finally chelating the PAMAM-DTPA-PEG-FA and Gd<3+>. The imaging contrast agent prolongs the circulation time in blood, improves the relaxation rate, can be effectively distributed in tumor tissues, reduces the toxicity on normal tissues, and has the advantages of long-acting circulation in vivo, improvement of the relaxation rate, reduction of the medicament consumption and the like.
Description
Technical field
The present invention relates to magnetic resonance imaging contrast, especially a kind of cancer target, energy long-acting circulation nonionic polyamide-amide (PAMAM) dendritic macromolecule magnetic resonance imaging contrast agent and preparation method thereof in blood.
Technical background
Nuclear magnetic resonance (MRI) technology is one of new technique in the medical imageology, it utilizes in the organism different tissues, and the different magnetic resonance signal of generation comes imaging under the influence of magnetic field adding, and the diagnosis in clinical practice more than 30% will be used magnetic resonance imaging contrast (MRI contrast agent).Contrast agent can shorten the relaxation time of proton, strengthens the magnetic resonance signal contrast of normal structure and pathological tissues, thereby improves the definition of image.Contrast agent commonly used clinically at present all is the micromolecule contrast agent, as: Magnevist, (NMG)
2[Gd (DTPA) (H
2O)]; Omniscan, Gd (DTPA2DMA); Prohance, Gd (HP
2DOCA) and Dotarem, (NMR) [Gd (DOTA) (H
2O), (wherein NMR is a N-methyl glucoside amine root).Though these contrast agent can satisfy some diagnosis requirements, the part that comes with some shortcomings, as: because molecule is less, osmotic pressure is bigger in vivo, from the outside seepage of blood vessel wall, enters intercellular substance easily, and therefore metabolic rate in vivo is very fast, is unfavorable for angiography; The micromolecule contrast agent distributes does not in vivo in addition have specificity biology, and inorganizable selectivity is bigger to normal tissue toxicity.Therefore synthetic a kind of stable, good water solubility, that tumor is had a targeting, nonionic, high relaxation rate, toxic and side effects is low, can long-acting circulation macromolecular contrast agent just particularly necessary.
The PAMAM dendrimer is a kind of Performances of Novel Nano-Porous meter level macromolecule of synthetic in recent years, and its a large amount of cavity of height cladodification, monodispersity, spherical surface and intramolecule makes it have unique character and characteristics.This class novel tree-like macromole can strictness be controlled its bulk of molecule on molecular level in building-up process, features such as shape, structure and end group kind, make it have very regular meticulous structure, the tree-shaped polymer non-immunogenicity of what is more important, hereditary-less toxicity and cytotoxicity, can not cause the immunoreation of body, can not cause transformation and cell death, thereby in a lot of fields,, demonstrate superior application prospect particularly in the medicine and pharmacology field.Ground such as Z.Jaszberenyi have synthesized Gd (III) chelate of PAMAM dendrimer, experiment shows that PAMAM dendrimer gadolinium chelate compound has higher relaxation rate, better imaging to when longer blood circulation time, as magnetic resonance imaging contrast have very optimistic potential using value (J Biol.Inorg.Chem.2007,12:406-420).
Summary of the invention
One of purpose of the present invention is to provide a kind of tumor cell is had targeting, water solublity, good biocompatibility, the long-acting circulation nonionic dendritic macromolecule magnetic resonance imaging contrast agent of energy in blood;
Two of purpose of the present invention is to provide the preparation method of this contrast agent.
The concrete technical scheme that realizes the object of the invention is as follows:
A kind of dendritic macromolecule magnetic resonance imaging contrast agent of tumor-targeted nonionic, be to be that amino integer is nuclear for polyamide-amide (PAMAM) dendrimer with the end group, (DTPA or DOTA) is coupled to the PAMAM surface by amido link with chelating agen, with different molecular weight Polyethylene Glycol (PEG) is that linking arm is bonded to chelating agen one end with targeting group (folic acid), last chelating agen and Metal Gd
3+Complexation and the ball shaped nano compound particle made; The particle diameter of this ball shaped nano compound particle is 60～100nm; Its particle diameter adopts different molecular weight polyethylene glycol to regulate and control.
The preparation method of above-mentioned contrast agent may further comprise the steps:
A, with polyethylene glycol diamines (H
2N-PEG-NH
2) end and folic acid (FA) coupling, make it have the folic acid residue;
B, with the reaction of chelating agen diethylenetriamine pentaacetic acid (DTPA) and step a products therefrom;
C, step b products therefrom is reacted with PAMAM;
D, with c products therefrom and GdCl
3Reactant aqueous solution is got the filtrate dialysis, lyophilization.
Synthesizing of 1 tumor-targeted nonionic PAMAM dendritic macromolecule magnetic resonance radiography
1.1 macromolecule ligand is synthetic
1.1.1H
2N-PEG-FA's is synthetic
With FA and N, N-dicyclohexylcarbodiimide (DCC) (mol ratio 1: 1.1～1: 1.3) is dissolved in the exsiccant dimethyl sulfoxide (DMSO), adds a small amount of pyridine, behind lucifuge stirring at room reaction 1～2h, presses folic acid and H under the nitrogen protection
2N-PEG-NH
2Mol ratio is 1: 1～1.2: 1 adding H
2N-PEG-NH
2, continuing stirring reaction 40～50h, a small amount of distilled water diluting of reactant liquor filters, and removes by-product N, N-1,3-Dicyclohexylurea (DCU), after the concentrated dialysis of filtrate, lyophilization is further purified with silicagel column at last, gets yellow solid H
2N-PEG-FA.
1.1.2SuO-DTPA-PEG-FA synthetic
With diethylenetriamine pentaacetic acid bisgallic acid acid anhydride (DTPAA, DTPA bisgallic acid acid anhydride)) be suspended among the exsiccant DMF, under 70～100 ℃, by DTPAA and N-hydroxy-succinamide (NHS) mol ratio is to add NHS and catalytic amount 4-dimethylamino naphthyridine (DMAP) in 1: 2～1: 2.5, behind stirring reaction 4～6h under this temperature, be cooled to room temperature, product is precipitated out with the alcohol-ether mixed liquor, precipitation is used isopropyl alcohol, methanol wash successively, use the ether soaked overnight, leach solid, vacuum drying gets the two active ester (SuO-DTPA-SuO) of white solid DTPA;
With H
2N-PEG-FA is dissolved among the dry DMF, is added drop-wise in the DMF solution that contains SuO-DTPA-SuO SuO-DTPA-SuO and H under the condition of ice bath
2The N-PEG-FA mol ratio is controlled to be 1: 1～and 1.5: 1, reaction 40～60h, reactant liquor molecular cut off are 2000 bag filter, the 60～72h that dialyses in DMF, at the ice ether sedimentation, must yellow solid powder SuO-DTPA-PEG-FA.
1.1.3PAMAM-DTPA-PEG-FA synthetic
SuO-DTPA-PEG-FA is dissolved among the dry DMF, be added drop-wise under the condition of ice bath in the PBS solution that pH 7.8～8.0 contains PAMAM, control SuO-DTPA-PEG-FA is 1: 1～2: 1 with the ratio of PAMAM upper end amido mole, stirring reaction 48～60h under the room temperature, the reactant liquor molecular cut off is 14000 bag filter, the 60～72h that dialyses in deionized water, lyophilization gets product.
1.2 polymeric contrast agent is synthetic
With PAMAM-DTPA-PEG-FA and excessive GdCl
3.6H
2O is blended in the citric acid solution of pH 5.5～6.0, and the stirring at room reaction is spent the night, and reactant liquor is at room temperature dialysed in deionized water, and lyophilization gets PAMAM-DTPA-PEG-FA/Gd.Gadolinium concentrations is measured with the inductively coupled plasma Atomic Emission Spectrometer AES.
The invention provides a kind of novel tumor-targeted nonionic dendrimer contrast agent, the preparation method of this contrast agent is provided simultaneously.Main innovation is: the introducing of the PEG of different molecular weight, make prepared contrast agent nano-complex particle size have controllability, particle size range is between 60～100nm, realize passive target, the introducing of targeting group simultaneously can realize initiatively targeting effect, after entering human body, can accumulate in tumor tissues more effectively, improve image contrast, can reduce non-specific adsorption after modifying with PEG in addition to plasma protein, thereby can be in blood long-acting circulation function, the early discovery of tumor is had great importance.
The invention provides a kind of novel tumor-targeted nonionic dendrimer contrast agent, have novelty and creativeness; The present invention proposes the preparation method of this tumor-targeted nonionic dendrimer contrast agent, have substantive technology contents.
Contrast agent provided by the invention, on the one hand, because the PAMAM molecular volume is bigger, can not in capillary wall, shuttle back and forth freely, thereby prolonged the circulation time in blood, and raising relaxation rate, on the other hand, because " the guided missile effect " of folic acid and passive target interaction energy can distribute polymeric contrast agent effectively in tumor tissues, reduce the toxicity to normal structure, simultaneously because the introducing of PEG, the motility of enhanced targeted molecular, and improved the water solublity and the biocompatibility of contrast agent, the present invention is to provide a kind of non-ionic contrast agent in addition, non-ionic contrast agent can reduce its osmotic pressure in vivo, retention time is shorter in vivo to have overcome ionic contrast agent, the shortcoming of getting rid of rapidly behind The book of Changes renal metabolism has long-acting in vivo circulation, improves advantages such as relaxation rate and minimizing dosage.
Description of drawings
Fig. 1 is a contrast agent structural representation of the present invention
Fig. 2 is 4.0 generation polyamide-amide (PAMAM
4.0) infared spectrum, abscissa is a wave number, vertical coordinate is an intensity in transmission
Fig. 3 is PAMAM
4.0-DTPA-PEG2000-FA infared spectrum, abscissa are wave number, and vertical coordinate is an intensity in transmission
Fig. 4 is 4.0 generation polyamide-amide (PAMAM
4.0)
1H NMR collection of illustrative plates
Fig. 5 is PAMAM
4.0-DTPA-PEG2000-FA
1H NMR collection of illustrative plates
Fig. 6 is PAMAM
4.0-DTPA-PEG4000-FA transmission electron microscope (TEM) figure
The specific embodiment
The invention will be further described below in conjunction with specific embodiment:
A) H
2N-PEG2000-FA's is synthetic
Get NH
2-PEG2000-NH
2(1.0g, 0.5mmol), FA (0.22g, 0.5mmol), DCC (0.12g 0.6mmol) is dissolved among the 10mL DMSO, adds 20 μ L pyridines, under the room temperature, and N
2Protection stirring reaction 48h.Reactant liquor filters with the dilution of 10mL deionized water, removes by-product DCU, is the 1000 bag filters 72h postlyophilizations of dialysing in deionized water with filtrate with molecular cut off, is further purified with silicagel column at last, must H
2N-PEG2000-FA, productive rate 65%.
B) SuO-DTPA-PEG2000-FA's is synthetic
With DTPAA (1.0g, 2.8mmoL) be suspended among the dry DMF of 10mL, stir down in 70 ℃ add NHS (0.65g, 5.6moL) and the DMAP of catalytic amount, stirring reaction 4h under this temperature, be cooled to room temperature, in the impouring 150mL isopropyl alcohol, leach solid, with dehydrated alcohol, ether washing, vacuum drying gets white powder solid SuO-DTPA-SuO, productive rate 80%;
Take by weighing H
2N-PEG2000-FA (0.5g, 0.2mmoL) be dissolved among the dry DMF of 15mL, be added drop-wise under the condition of ice bath and contain SuO-DTPA-SuO (0.14g, 0.2mmoL) in the DMF solution, behind reaction 4h under this condition, room temperature reaction 48h, the reactant liquor molecular cut off is 2000 the bag filter 72h that dialyses in DMF, at the ice ether sedimentation, get yellow solid powder SuO-DTPA-PEG-FA, productive rate 70%.
C) PAMAM
4.0-DTPA-PEG2000-FA's is synthetic
(1.0g 0.3mmoL) is dissolved among the dry DMF, is added drop-wise under the condition of ice bath to contain PAMAM with SuO-DTPA-PEG2000-FA
4.0(0.044g, 0.0063mmoL) in the PBS solution of pH8.0, stirring reaction 48h under the room temperature, reactant liquor molecular cut off are 14000 bag filter dialysis 72h, lyophilization gets the buff powder solid, productive rate 80%.
D) PAMAM
4.0-DTPA-PEG2000-FA/Gd's is synthetic
With PAMAM
4.0-DTPA-PEG2000-FA and GdCl
3.6H
2O is blended in the citric acid solution of pH6.0, and stirring at room reaction is spent the night, and with the reactant liquor 72h that at room temperature dialyses in deionized water, lyophilization gets PAMAM
4.0-DTPA-PEG2000-FA/Gd.
Gadolinium ion concentration is measured with the inductively coupled plasma Atomic Emission Spectrometer AES.
Embodiment 2
Preparation process is with embodiment 1, and fixedly the molecular weight of PEG is 2000, changes the algebraically of PAMAM, the PAMAM-DTPA-PEG-FA/Gd in synthetic respectively 3.0 generations, 4.0 generations, 5.0 generations.
Embodiment 3
Preparation process is with embodiment 1, and the fixing algebraically of PAMAM changes the molecular weight of PEG, and adopting molecular weight respectively is 1000,2000,4000 synthetic these dendrimer contrast agent, found that nano particle diameter obviously increases with the increase of PEG molecular weight.
The mensuration of relaxation rate
Macromolecular contrast agent and commercial contrast agent Magnevist Solution are made into the solution of 4 kinds of variable concentrations, and gadolinium ion concentration is respectively 0.24mmol/L, 0.12mmol/L, 0.06mmol/L, 0.03mmol/L.The solution that dilution is good is contained the T that surveys four kinds of contrast agent variable concentrations solution in the 1.5mL centrifuge tube on the 0.3T magnetic resonance device by the inversion recovery method
1Value is asked slope by following formula with graphing method, thereby gets relaxation rate r
1:
R wherein
1=1/T
1, T
1wBe the relaxation time of pure water, T
1mThe relaxation time that goes out for the actual measurement of variable concentrations contrast agent.
The foregoing description only is used to illustrate the present invention, but is not limited to this, should be appreciated that not break away from the spiritual scope of the present invention to also have multiple accommodation and alternative.
Claims (9)
1, a kind of dendritic macromolecule magnetic resonance imaging contrast agent of tumor-targeted nonionic, it is characterized in that this contrast agent be with polyamide-amide (PAMAM) dendrimer be nuclear, be the targeting group with folic acid, with different molecular weight Polyethylene Glycol (PEG) for being Gd as linking arm between targeting group and the macromolecular carrier and with diethylenetriamine pentaacetic acid (DTPA)
3+Part and the ball shaped nano compound particle made.
2, the dendritic macromolecule magnetic resonance imaging contrast agent of tumor-targeted nonionic as claimed in claim 1, the particle diameter that it is characterized in that described ball shaped nano compound particle is 60～100nm; Its particle diameter adopts different molecular weight polyethylene glycol to regulate and control.
3, the preparation method of the described contrast agent of a kind of claim 1 is characterized in that this method may further comprise the steps:
A), with polyethylene glycol diamines one end and folacin coupled, make it have the folic acid residue;
B), with the reaction of chelating agen DTPA and step a products therefrom, the SuO-DTPA-PEG-FA product;
C), step b products therefrom is reacted with PAMAM, the PAMAM-DTPA-PEG-FA product;
D), step c products therefrom and excessive GdCl
3Reactant aqueous solution is got the filtrate dialysis, lyophilization.
4, preparation method as claimed in claim 3 is characterized in that the PAMAM described in the step c is the different integer PAMAM in generation.
5, preparation method as claimed in claim 3 is characterized in that the reaction of step b may further comprise the steps:
I) with H
2N-PEG-FA is dissolved among the dry DMF, is added drop-wise under the condition of ice bath in the DMF solution that contains the two Acibenzolars (SuO-DTPA-SuO) of DTPA, and behind stirring reaction 4～6h under this condition, room temperature reaction 40～60h;
Ii) the reactant liquor molecular cut off is 2000 bag filter, the 60～72h that dialyses in DMF, concentrate, at the ice ether sedimentation, product S uO-DTPA-PEG-FA.
6, preparation method as claimed in claim 3 is characterized in that the reaction of step c may further comprise the steps:
I) SuO-DTPA-PEG-FA is dissolved among the dry DMF, is added drop-wise in the PBS solution that pH7.8～8.0 contain PAMAM stirring reaction 48～60h under the room temperature under the condition of ice bath;
Ii) to concentrate the back be 14000 bag filter, the 60～72h that dialyses in deionized water with molecular cut off to reactant liquor, concentrates, and lyophilization gets product P AMAM-DTPA-PEG-FA.
7,, it is characterized in that two Acibenzolars of DTPA and H as claim 3 or 5 described preparation methoies
2The ratio of N-PEG-FA mole is 1: 1～1.5: 1.
8,, it is characterized in that the SuO-DTPA-PEG-FA and the ratio of PAMAM upper end amido mole are 1: 1～2: 1 as claim 3 or 6 described preparation methoies.
9, preparation method as claimed in claim 3 is characterized in that solvent is the citric acid solution of pH5.5～6.0 in the reaction of steps d.
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