CN107308464A - A kind of preparation method and its usage of the T1 T2 bimodal contrast agent with selectively targeted function - Google Patents
A kind of preparation method and its usage of the T1 T2 bimodal contrast agent with selectively targeted function Download PDFInfo
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- CN107308464A CN107308464A CN201710570513.XA CN201710570513A CN107308464A CN 107308464 A CN107308464 A CN 107308464A CN 201710570513 A CN201710570513 A CN 201710570513A CN 107308464 A CN107308464 A CN 107308464A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/16—Antibodies; Immunoglobulins; Fragments thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/143—Peptides, e.g. proteins the protein being an albumin, e.g. HSA, BSA, ovalbumin
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Abstract
The invention provides a kind of preparation method of the T1 T2 bimodal contrast agent with selectively targeted function, with FeCl3•6H2O、FeCl2•4H2O and Gd（NO）3•6H2O and bovine serum albumin(BSA) are raw material, using water as solution, adjust the pH value of reaction system between 10 ~ 13, are reacted under conditions of ultrasound, after reacting 10 ~ 40 minutes, obtain the T1 T2 bimodal contrast agent of Bovine Serum Albumin Modified；CD90 antibody is added in the T1 T2 bimodal contrast agent of Bovine Serum Albumin Modified, CD90 antibody is connected on bovine serum albumin(BSA) by amido link, the T1 T2 bimodal contrast agent with selectively targeted function is obtained.Due to there is the corresponding action target spot of CD90 antibody on fat stem cell, endocytosis of the fat stem cell to resulting T1 T2 bimodal contrast agent can be increased, to reach the purpose that can be marked for a long time.
Description
Technical field
The invention belongs to medical science, it is related to a kind of contrast agent, it is specifically a kind of that there is selectively targeted work(
The preparation method and its usage of the T1-T2 bimodal contrast agent of energy.
Background technology
Fat mesenchymal stem cell, with performances such as differentiation Gegenbaur's cell, cartilage cells, can be made from fat with autologous
With being the stem cell for most promising to be commercialization clinical practice without Ethical Demand.Fat stem cell is in renewable medical science side
The research in face is a big focus of stem-cell research, but fat stem cell is transplanted to migration, the distribution after lesions position
And directed differentiation is still not clear, therefore a kind of fat that can be followed the trail of without invading internal body is needed to do thin before clinical practice
The migration of born of the same parents, cell go back to the nest or transplant fat stem cell destiny in vivo characterization method, it is dry with clear and definite fat mesenchymal
The therapy mechanism of cell.
Magnetic resonance imaging（MRI）Technology has higher spatial imaging resolution, while multi-parameter, multisequencing can be carried out
Imaging, using the teaching of the invention it is possible to provide the information diagnosed at many levels, no ionising radiation, can deep enough organization internal, without invading inside live body
The features such as, thus MRI technique be best suitable for for follow the trail of fat stem cell transplant into vivo after movable means of testing.For
Better discriminate between the fat stem cell to be followed the trail of and other cells, contrast labeled is carried out to fat stem cell so that quilt
The fat stem cell of mark is different from the cell of surrounding.Conventional MRI contrast agent mainly has super suitable based on ferroso-ferric oxide
Magnetic nano-particle and the paramagnetic metal-chelator based on the chelate of gadolinium.Ferroso-ferric oxide can shorten surrounding hydrogen matter
The transverse relaxation efficiency of son, can cause the reduction of MR signals, generation is dark signal in the MRI sequences that T2 is weighted.On the contrary,
The chelating of gadolinium shortens the longitudinal relaxation efficiency of surrounding Hydrogen Proton, in the MRI sequences that T1 is weighted MR signal can be caused to raise,
Produce brighter signal.
Currently used for mark fat stem cell contrast agent be mainly above described in two kinds of contrast agent, T1 and T2
Two kinds of contrast agent are united so that resulting material has the effect of two kinds of weighted imagings simultaneously, can be more by MRI
Accurately judge that survival condition in vivo after fat stem cell transplanting.Introducing the research of contrast labeled stem cell has a lot,
But generally all there is the problem of stem cell is fewer to the endocytosis amount of contrast agent, if stem cell is few to the endocytosis amount of contrast agent, with
The ratio that the amount of the contrast agent in the extension stem cell of time can reduce very fast, do not reach the purpose of long-term labeled stem cells.
The content of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of T1- with selectively targeted function
The preparation method and its usage of T2 bimodal contrast agent, the described this T1-T2 bimodals with selectively targeted function are made
The preparation method and its usage of shadow agent will solve that stem cell of the prior art is fewer to the endocytosis amount of contrast agent, do not reach length
The technical problem of the purpose of phase labeled stem cells.
The invention provides a kind of preparation method of the T1-T2 bimodal contrast agent with selectively targeted function, including
Following steps：
1）FeCl3•6H2O、FeCl2•4H2O and Gd（NO）3•6H2O and bovine serum albumin(BSA)（BSA）For raw material, using water as solution,
The pH value for adjusting reaction system using ammoniacal liquor is reacted between 10 ~ 13 under conditions of ultrasound, after reacting 10 ~ 40 minutes,
Obtain the T1-T2 bimodal contrast agent of BSA modifications；
2）CD90 antibody is added to step 1）BSA modification T1-T2 bimodal contrast agent in, CD90 is resisted by amido link
Body is connected on BSA, obtains the T1-T2 bimodal contrast agent with selectively targeted function.
Further, step 1）In reaction system be ice-water bath, be provided with ultrasonic spy in described frozen water bath apparatus
Head.
Further, step 1）In, Iron trichloride hexahydrate is scattered in deionized water, leads to argon gas, four water protochlorides are added
Iron, adds six water gadolinium nitrates after continuing logical argon gas, bovine serum albumin solution is added in above-mentioned solution, and magnetic stirring 40 ~
120min, described Iron trichloride hexahydrate, four water frerrous chlorides, six water gadolinium nitrates, the material of bovine serum albumin(BSA) and deionized water
Than for 180 ~ 220mg：70~75mg：35~45mg：21~82.5mg：15 ~ 40ml, is then transferred into ice-water bath, is put into ultrasonic spy
Head, adds ammoniacal liquor, pH is between 10 ~ 13 for regulation, and 10 ~ 40min of ultrasound obtains Bovine Serum Albumin Modified under conditions of ultrasound
T1-T2 bimodal contrast agent.
Further, the power of ultrasonic probe is that 400W, ultrasonic time are 5s, at intervals of 1s.
In step 2）In, after the T1-T2 bimodal contrast agent phosphate buffer solutions that BSA is modified are diluted, add 1-
(3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and n-hydroxysuccinimide, magnetic are added after stirring 20 ~ 50 minutes
CD90 antibody-solutions, T1-T2 bimodals contrast agent, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides of BSA modifications
Salt (EDC), n-hydroxysuccinimide（NHS）Material ratio with CD90 antibody is 100 μ L：4~6mg:3.5~4mg: 20~50μ
L, magnetic obtains the T1-T2 bimodal contrast agent with selectively targeted function after stirring 16 ~ 40 hours.
Present invention also offers adopt the T1-T2 bimodal radiographies with selectively targeted function that prepare with the aforedescribed process
Agent.
It is dry thin in mark fat present invention also offers the above-mentioned T1-T2 bimodals contrast agent with selectively targeted function
Purposes in born of the same parents.
The present invention utilizes a step coprecipitation, with FeCl3.6H2O、FeCl2.4H2O and Gd（NO）3.6H2O and ox blood are pure
Albumen（BSA）For raw material, using water as solution, the pH value of reaction system is adjusted with ammoniacal liquor, prepare bovine serum albumin(BSA) connection gadolinium and
Ferroso-ferric oxide（IO）Material, obtain T1-T2 bimodal contrast agent of the average grain diameter for the BSA modifications between 85 ~ 95 nanometers
（BSA-Gd+IO）, then CD90 antibody is connected on by amido link the T1-T2 with selectively targeted function pairs is obtained on BSA
Mode contrast agent（CD90-BSA- Gd+ IO）.
Wherein, the reaction equation of IO generations is as follows:
2Fe3++Fe2++8NH3·H2O→Fe3O4+8NH4++4H2O
The present invention obtains dispersed preferably T1-T2 bimodal contrast agent using bovine serum albumin(BSA) and gadolinium source, the step of source of iron one, is
Allow material to carry out specific marker to fat stem cell, CD90 antibody is connect on bovine serum albumin(BSA), obtained material has
The purpose of selectively targeted fat stem cell.Due to there is the corresponding action target spot of CD90 antibody on fat stem cell, it can improve
Fat stem cell, to the endocytosis of resulting T1-T2 bimodal contrast agent, is that fat is dry thin to reach the purpose marked for a long time
The differentiation mechanism of born of the same parents and clinical practice provide reliable theories integration.
The present invention is compared with prior art, and its technological progress is significant.It is of the invention to use a step coprecipitation for the first time
The T1-T2 bimodal contrast agent of Bovine Serum Albumin Modified is prepared, operating method is simple, and water dispersible is good.The present invention is in ox blood
CD90 antibody is connect on pure albumen, the selectively targeted ability of fat stem cell is improved, contrast agent is added dry to fat thin
The mark of born of the same parents, improves endocytosis of the fat stem cell to contrast agent, so as to increase the mark time, realizes long-term mark, is fat
The clinical conversion of fat stem cell provides support.
Brief description of the drawings
Fig. 1 is BSA-Gd+IO and CD90-BSA-Gd+IO transmission electron microscope picture.
Fig. 2 is BSA-Gd+IO and CD90-BSA-Gd+IO DLS.
Fig. 3 is BSA-Gd+IO and CD90-BSA-Gd+IO Zeta potential.
Fig. 4 is commercial T1, T2 contrast agent and CD90-BSA-Gd+IO relaxation rate measure.
Fig. 5 is CD90-BSA-Gd+IO MR imaging effects.
Fig. 6 is phagocytosis situation of the fat stem cell to CD90-BSA-Gd+IO, a:Blank；b:BSA-Gd+IO (100μg/
mL Fe)； c: CD90-BSA-Gd+IO(100μg/mL Fe)；d: BSA-Gd+IO (400μg/mL Fe) ； e: CD90-
BSA-Gd+IO (400μg/mL Fe)。
Fig. 7 is the reacting flow chart of the present invention.
Embodiment
The step coprecipitation of embodiment 1 one prepares BSA-Gd+IO aqueous dispersions
194.4mg Iron trichloride hexahydrates are scattered in 20mL deionized waters, lead to argon gas 10min, the water protochlorides of 71.2mg tetra- are added
Iron, adds the water gadolinium nitrates of 40mg six after continuing logical argon gas 10min, takes 21mgBSA to be dissolved in 0.5mL deionized waters, dissolved
It is added to after complete in above-mentioned solution, magnetic stirring 80min.It is then transferred in ice-water bath, is put into ultrasonic probe regulation power and is 400W, surpasses
The sound time is 5s, at intervals of 1s, and ammoniacal liquor is added under conditions of ultrasound, adjusts pH, ultrasonic 20min.Obtain the T1- of BSA modifications
T2 bimodal contrast agent, the material average grain diameter obtained by transmission electron microscope observing is in 90nm or so, and measuring result by DLS can
The hydration particle diameter for obtaining resulting materials is 156.2nm, and current potential is 25.8mV, as shown in Figure 1 to Figure 3.
The CD90-BSA-Gd+IO of embodiment 2 preparation
Take the aqueous dispersions for the BSA-Gd+IO that 100 μ L embodiments 1 obtain, 2mL be diluted to 1X PBS, add 5mgEDC and
After 3.75mgNHS, magnetic stirring 15min, 20 μ L are added（0.5mg/μL）CD90 antibody-solutions, magnetic stirring 24h, obtain have spy
The T1-T2 bimodal contrast agent of different in nature target function.
The material average grain diameter obtained by transmission electron microscope observing is measured obtained by result can obtain as DLS in 105nm or so
The hydration particle diameter of material is 252.8nm, and current potential is 10.2mV, decreases compared with Example 1 compared with can obtain current potential, illustrates CD90
Modify successfully, as shown in Figure 1 to Figure 3.
As shown in figure 4, the relaxivity of test CD90-BSA-Gd+IO and business contrast agent can be obtained, CD90-BSA-Gd+IO
R1 be 6.65mM-1.s-1, more than the r1 values 3.89mM of commercial contrast agent magnevist-1.s-1, CD90-BSA-Gd+IO r2 is
231.45mM-1.s-1, the r2 values 72.84mM more than commercial iron supplementary Ferumoxytol-1.s-1。
As shown in figure 5, with the increase of concentration, the effect of CD90-BSA-Gd+IO T1 weighted imagings is more and more brighter, together
When its T2 weighted imaging effect be that darkness deepens, the effect being imaged with preferable T1-T2 bimodals these results suggest that this
Contrast agent obtained by patent has very big application value.
Phagocytosis of the fat stem cell of embodiment 3 to CD90-BSA-Gd+IO
The present invention carries out culture sorting by the SVF mixed liquor isolated to people's fat and obtains fat stem cell, training used
Foster base is DMEM low sugar basis training base, 10% hyclone and the 1% dual anti-mixed liquor now matched somebody with somebody, just after passage fat stem cell every
Change liquid within 1 day, change a not good liquor every 2 days afterwards.
According to above-mentioned method, primary acquisition human adipose-derived stem cell was cultivated to 2 ~ 3 generations, fat stem cell is seeded in 24
On orifice plate, it is incubated in 37 DEG C of incubator after 24h, adds 50 ~ 200 μ g/mL（Calculated with Fe amount）BSA-Gd+IO and
The mixed liquors of CD90-BSA-Gd+IO respectively with culture medium, continuation is incubated 24h in 37 DEG C of incubator, is washed with PBS three times
Afterwards, with prussian blue staining, the distribution situation of magnetic material in the cell is observed under the microscope.As shown in fig. 6, comparing BSA-
Gd+IO and CD90-BSA-Gd+IO is measured to the mark situation of fat stem cell with ferro element, chooses 100 μ g/mL and 400 μ
Two concentration of g/mL, it can be seen that fat stem cell substantially wants unnecessary to BSA-Gd+IO's to CD90-BSA-Gd+IO endocytosis
Endocytosis, and the comparison assembled around fat stem cell with the increasing CD90-BSA-Gd+IO of concentration is more, it may be possible to
There is interaction in CD90 antibody and the CD90 marks on fat stem cell surface, illustrate that the addition of CD90 antibody can be improved and make
Mark of the shadow agent to fat stem cell.
Claims (7)
1. a kind of preparation method of the T1-T2 bimodal contrast agent with selectively targeted function, it is characterised in that including as follows
Step：
1) with FeCl3·6H2O、FeCl2·4H2O and Gd (NO)3·6H2O and bovine serum albumin(BSA) are raw material, using water as solution,
The pH value for adjusting reaction system using ammoniacal liquor is reacted between 10~13 under conditions of ultrasound, is reacted 10~40 minutes
Afterwards, the T1-T2 bimodal contrast agent of Bovine Serum Albumin Modified is obtained；
2) CD90 antibody is added to step 1) Bovine Serum Albumin Modified T1-T2 bimodal contrast agent in, pass through acid amides
Key is connected on CD90 antibody on bovine serum albumin(BSA), obtains the T1-T2 bimodal contrast agent with selectively targeted function.
2. a kind of preparation method of T1-T2 bimodal contrast agent with selectively targeted function according to claim 1,
It is characterized in that：Step 1) in reaction system be ice-water bath, have ultrasonic probe in described frozen water bath apparatus.
3. a kind of preparation method of T1-T2 bimodal contrast agent with selectively targeted function according to claim 1,
It is characterized in that：Step 1) in, Iron trichloride hexahydrate is scattered in deionized water, leads to argon gas, four water frerrous chlorides are added, continued
Six water gadolinium nitrates are added after logical argon gas, bovine serum albumin solution is added in above-mentioned solution, magnetic stirs 40~120min, described
Iron trichloride hexahydrate, four water frerrous chlorides, six water gadolinium nitrates, the material ratio of bovine serum albumin(BSA) and deionized water for 180~
220mg：70~75mg：35~45mg：21~82.5mg：15~40ml, is then transferred into ice-water bath, is put into ultrasonic probe,
Ammoniacal liquor is added under conditions of ultrasound, pH is between 10~13 for regulation, and 10~40min of ultrasound obtains Bovine Serum Albumin Modified
T1-T2 bimodal contrast agent.
4. a kind of preparation method of T1-T2 bimodal contrast agent with selectively targeted function according to claim 3,
It is characterized in that：The power of ultrasonic probe is that 400W, ultrasonic time are 5s, at intervals of 1s.
5. a kind of preparation method of T1-T2 bimodal contrast agent with selectively targeted function according to claim 1,
It is characterized in that：In step 2) in, the T1-T2 bimodal contrast agent of Bovine Serum Albumin Modified is dilute with phosphate buffer solution
After releasing, addition 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and n-hydroxysuccinimide, magnetic stirring 20~
CD90 antibody-solutions, T1-T2 bimodals contrast agent, 1- (3- dimethylamino-propyls) -3- ethyls of BSA modifications are added after 50 minutes
The material ratio of carbodiimide hydrochloride, n-hydroxysuccinimide and CD90 antibody is 100 μ L：4~6mg:3.5~4mg:20~
50 μ L, magnetic obtains the T1-T2 bimodal contrast agent with selectively targeted function after stirring 16~40 hours.
6. the T1-T2 bimodal contrast agent with selectively targeted function prepared using the method described in claim 1.
7. the T1-T2 bimodals contrast agent with selectively targeted function described in claim 6 is in mark fat stem cell
Purposes.
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| CN114042172A (en) * | 2021-11-11 | 2022-02-15 | 上海市第一人民医院 | PH-responsive T1-T2 dual-activation nanoprobe and preparation method and application thereof |
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