CN107096044A - Nuclear medicine and magnetic resonance bimodal imaging medicament, prodrug, preparation method and application - Google Patents
Nuclear medicine and magnetic resonance bimodal imaging medicament, prodrug, preparation method and application Download PDFInfo
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- CN107096044A CN107096044A CN201710279938.5A CN201710279938A CN107096044A CN 107096044 A CN107096044 A CN 107096044A CN 201710279938 A CN201710279938 A CN 201710279938A CN 107096044 A CN107096044 A CN 107096044A
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses a kind of nuclear medicine and magnetic resonance bimodal imaging medicament precursor (DOTA SPIONs PEG FA), such prodrug is using superparamagnetic iron oxide nano-particle as core, in external sheath biocompatible materials and bifunctional chelating agent, folic acid is connected by biocompatible materials with superparamagnetic iron oxide nano-particle.Above-mentioned bimodal imaging medicament precursor is through radioactive metal isotope labeling, so as to obtain the brand-new nuclear medicine of a class and magnetic resonance bimodal imaging medicament (RM DOTA SPIONs PEG FA) first.The vitro Drug stability is good, during applied to folate receptor-positive lesion detection, there is very high initial intake in tumour, good knurl/blood ratio, the longer holdup time, also, there is nano-particle obvious active targeting to act on to tumour, MRI imagings can be effectively applicable to and PET or SPECT is imaged.
Description
Technical field
The invention belongs to molecular image medicine, radiopharmaceutical and nuclear medicine technology field.In particular it relates to which a seed nucleus is cured
Learn and magnetic resonance bimodal imaging medicament precursor.Moreover, it relates to before nuclear medicine and magnetic resonance bimodal imaging medicament
Preparation method, nuclear medicine and the magnetic resonance bimodal imaging medicament of body and its preparing folate receptor-positive tumor imaging medicament
In application.
Background technology
Recent study report points out that newly-increased 14,000,000 cancer patients in the whole world in 2012 simultaneously have 8,200,000 patient deaths.Its
In, newly-increased 3,070,000 cancer patients of China simultaneously there are about 2,200,000 people death.The early diagnosis of cancer and effectively treatment can reduce big
The death of about annual 1/3 to 1/2 (i.e. 240~3,700,000) cancer patient.The design of early diagnosis of tumor and target therapeutic agent is
Using various Tumor biomarkers (such as specific receptor, monoclonal antibody and its fragment, polypeptide etc.) come realizing.
In many tumours (such as oophoroma, cervical carcinoma, carcinoma of endometrium, lung cancer, kidney, breast cancer, colon cancer and the cancer of the brain)
Middle period acid acceptor is overexpressed.Folacin receptor is the target closely related with these tumours.People carried out with folic acid by
Body is the research of the various tumour radiotherapy imaging medicaments targetted.However, either SPECT or PET single mode images skill
Art, although they have the advantages that high sensitivity, its spatial resolution is relatively low.And Magnetic Resonance Imaging (MRI) is with space point
Resolution is high, radiationless but the characteristics of low sensitivity.At present, SPECT/CT, PET/CT and PET/ of two kinds of imaging mode have been merged
MRI is applied in clinic.PET/MRI or SPECT/MRI bimodals imaging technique both had high sensitivity and height soft
Contrast in tissue, and compared with PET/CT or SPECT/CT, also significantly reduce dose of radiation, it has also become with wide application
The bimodal Medical Imaging Technology of prospect.The whole world there are about 70 PET/MRI and put into clinical practice.
Some existing researchs of MRI tumor imagings agent using folacin receptor as targeting, for PET/MRI's or SPECT/MRI
Bimodal imaging medicament is also being researched and developed, but up to the present, at home and abroad there is no official approval, can be in clinic
PET/MRI the or SPECT/MRI bimodal imaging medicaments used.
The content of the invention
Based on above-mentioned technical problem, the present invention is provided before a kind of nuclear medicine and magnetic resonance bimodal imaging medicament first
Body, the precursor obtains PET/MRI or SPECT/MRI bimodal imaging medicaments after radioactive metal isotope labeling, using this
Medicine clearly can effectively detect folate receptor-positive tumour as the active component of imaging medicament.
First aspect is aoxidized there is provided a kind of nuclear medicine and magnetic resonance bimodal imaging medicament precursor, the precursor with superparamagnetic
Fe nanometer particles are core, and in external sheath biocompatible materials and bifunctional chelating agent, folic acid passes through biocompatibility material
Material is connected with superparamagnetic iron oxide nano-particle.
With reference in a first aspect, in a kind of possible implementation of first aspect, using 3- aminopropyl triethoxies
Silane is modified superparamagnetic iron oxide nanoparticle surface, and biocompatible materials and bifunctional chelating agent pass through 3- ammonia
Base propyl-triethoxysilicane is connected with superparamagnetic iron oxide nano-particle.
With reference to first aspect or above-mentioned some possible embodiments, in a kind of possible implementation of first aspect
In, above-mentioned biocompatible materials includes the polyethylene glycol that molecular weight is 400-20000.
With reference to first aspect or above-mentioned some possible embodiments, in a kind of possible implementation of first aspect
In, above-mentioned bifunctional chelating agent includes DOTA.
With reference to first aspect or above-mentioned some possible embodiments, in a kind of possible implementation of first aspect
In, the precursor is as follows：
Wherein, n=9~454.
Second aspect is cured there is provided a kind of nuclear medicine and magnetic resonance bimodal imaging medicament by any seed nucleus of first aspect
With magnetic resonance bimodal imaging medicament precursor through radioactive metal isotope labeling obtain.
With reference to second aspect, in a kind of possible implementation of second aspect, above-mentioned radioactive metal nucleic includes64Cu、60Cu、61Cu、62Cu、68Ga、66Ga、86Y、44Sc、89Zr、45Ti、55Co、114mIn、94mTc、67Ga、111In、177Lu and99mTc
Any of.
The third aspect is preparing folacin receptor there is provided any nuclear medicine of second aspect and magnetic resonance bimodal imaging medicament
Application in positive tumor imaging medicament.
Fourth aspect is imaged there is provided the nuclear medicine in a kind of possible implementation of first aspect and magnetic resonance bimodal
The preparation method of prodrug, comprises the following steps：
(a) surface modification is carried out to superparamagnetic iron oxide nano-particle using 3- aminopropyl triethoxysilanes, obtained
SPIONs-APTES,
(b) folic acid obtains FA-PEG with polyethylene glycol conjugation,
Wherein, n=9~454；
(c) SPIONs-APTES and FA-PEG reactions obtain SPIONs-PEG-FA, then with Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanes ten
Dioxane-Isosorbide-5-Nitrae, 7,10- tetraacethyls coupling obtains DOTA-SPIONs-PEG-FA, i.e. nuclear medicine and images medicine with magnetic resonance bimodal
Thing precursor.
With reference to fourth aspect, in a kind of possible implementation of fourth aspect, FA-PEG is obtained by following steps：
Folic acid obtains FA-NHS with n-hydroxysuccinimide coupling；FA-NHS and NH2- PEG-COOH reactions obtain FA-PEG,
Above-mentioned nuclear medicine and magnetic resonance bimodal imaging medicament precursor, using superparamagnetic iron oxide nano-particle as core,
In external sheath biocompatible materials, folic acid and bifunctional chelating agent, in use, this precursor is used into radioactive metal core
Element, for example64Cu、94mTc etc. is marked, so as to obtain a kind of brand-new bimodal imaging medicament first.Such vitro Drug is steady
It is qualitative good, during applied to folate receptor-positive lesion detection, there is very high initial intake in tumour, good knurl/blood ratio,
The longer holdup time, also, there is nano-particle obvious active targeting to act on to tumour, can be effectively applicable to MRI and show
Picture and PET or SPECT imaging.
Brief description of the drawings
Fig. 1 is compound FA-PEG in the embodiment of the present invention 11H NMR scheme.
Fig. 2 is the radioactivity TLC figures of label after purification in the step 8 of the embodiment of the present invention 1.
Fig. 3 is (a) blank group in the embodiment of the present invention 4, and (b) blocking group, (c) DOTA-SPIONs-PEG-FA groups are respective
MRI schemes.
Fig. 4 is in the embodiment of the present invention 5 (a)64Cu-DOTA-SPIONs-PEG-OH groups, (b) blocking group, (c)64Cu-
The respective PET/CT figures of DOTA-SPIONs-PEG-FA groups.
Fig. 5 is compound in the embodiment of the present invention 164Cu-DOTA-SPIONs-PEG-FA structural representation.
Embodiment
Technical solution of the present invention is illustrated to be clearer, below in conjunction with skill of the embodiment to the present invention
Art scheme is further elaborated：
There is provided a kind of nuclear medicine and magnetic resonance bimodal imaging medicament precursor in a specific embodiment, before this
Body is using superparamagnetic iron oxide nano-particle as core, and in external sheath biocompatible materials and bifunctional chelating agent, folic acid leads to
Biocompatible materials is crossed to be connected with superparamagnetic iron oxide nano-particle.,
Superparamagnetic iron oxide nano-particle (SPIONs) will be coupled the biocompatibility of folic acid as MRI optical imaging components
Material is connected on SPIONs, and using folic acid as targeting group, bifunctional chelating agent is connected on SPIONs, for connecting conduct
PET or SPECT images the radioactive metal nucleic of composition, in use, this precursor is entered into rower using radioactive metal nucleic
Note, so that the brand-new bimodal imaging medicament of a class is obtained first, including PET/MRI bimodals imaging medicament and SPECT/MRI
Bimodal imaging medicament.The vitro Drug stability is good, during applied to folate receptor-positive lesion detection, there is very high in tumour
Initial intake, good knurl/blood ratio, longer holdup time, also, nano-particle has obvious active target to tumour
To effect, MRI imagings can be effectively applicable to and PET or SPECT is imaged.
Biocompatibility refers to a kind of life entity tissue performance aitiogenic to non-active material or active material, typically
Refer to the compatibility between material and host.Biocompatible materials is generally referred to and the preferable material of host compatibility.
Further, using APTES (APTES) to superparamagnetic iron oxide nanoparticle surface
Modified, biocompatible materials and bifunctional chelating agent are aoxidized by APTES and superparamagnetic
Fe nanometer particles are connected.
Further, biocompatible materials includes the polyethylene glycol that molecular weight is 400-20000, is used in embodiment
Molecular weight polyethylene glycol be 2000.Molecular weight is 400-20000 polyethylene glycol, itself and folic acid and superparamagnetic iron oxide nanometer
The catenation principle and mode of particle are identical for the catenation principle and mode of 2000 polyethylene glycol with molecular weight, therefore, the present invention
The polyethylene glycol that molecular weight is 2000 of being illustrated in embodiment has been enough to support the limit in claims to molecular weight polyethylene glycol
Determine scope.Above-mentioned polyethylene glycol also includes polyethyleneglycol derivative, and the restriction of its middle-molecular-weihydroxyethyl is the molecule to pure polyethylene glycol
The restriction of amount, not other groups including two ends.
Further, bifunctional chelating agent includes DOTA
(DOTA).By above-mentioned bifunctional chelating agent, radioactive metal nucleic can be connected to superparamagnetic iron oxide securely and receive
On rice corpuscles, so that complete nuclear medicine and magnetic resonance bimodal imaging medicament RM-DOTA-SPIONs-PEG-FA are obtained, wherein
RM is radioactive metal nucleic.Bifunctional chelating agent can also use 1,4,8,11- tetraazacyclododecane tetradecanes -1,4,8,11- four
Acetic acid (TETA) or 1,4,7- 7-triazacyclononanes-N, N', N "-triacetic acid (NOTA) etc.；Preferably by DOTA, this is due to
Several bifunctional chelating agents belong to polynitrogen heterocycle class above, and DOTA is classical polynitrogen heterocycle chelating agent more common now.
In another embodiment there is provided a kind of nuclear medicine and magnetic resonance bimodal imaging medicament precursor, before this
Body is as follows：
Wherein, n=9~454.
Foregoing any nuclear medicine is obtained with magnetic resonance bimodal imaging medicament precursor through radioactive metal isotope labeling
Bimodal imaging medicament；Radioactive metal nucleic includes64Cu、60Cu、61Cu、62Cu、68Ga、66Ga、86Y、44Sc、89Zr、45Ti、55Co、114mIn、94mTc、67Ga、111In、177Lu and99mAny of Tc；RM is different, the work of obtained bimodal imaging medicament
With difference, preferably by64Cu or99mTc is marked, when DOTA-SPIONs-PEG-FA connections99mDuring Tc, SPECT/ is obtained
MRI bimodal imaging medicaments；Work as connection64During Cu, then PET/MRI bimodal imaging medicaments are obtained.
Nuclear medicine can be used for preparing folate receptor-positive tumor imaging medicament with magnetic resonance bimodal imaging medicament, and then
Diagnosis for folate receptor-positive tumour.In folate receptor-positive tumor imaging medicament, it can also include necessary medical auxiliary
Material and/or medical solvent.
There is provided the preparation of a kind of nuclear medicine and magnetic resonance bimodal imaging medicament precursor in another embodiment
Method, comprises the following steps：
(a) surface modification is carried out to superparamagnetic iron oxide nano-particle using 3- aminopropyl triethoxysilanes, obtained
SPIONs-APTES；
(b) folic acid obtains FA-PEG with polyethylene glycol conjugation；
(c) SPIONs-APTES and FA-PEG reactions obtain SPIONs-PEG-FA, then with Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanes ten
Dioxane-Isosorbide-5-Nitrae, 7,10- tetraacethyls coupling obtains DOTA-SPIONs-PEG-FA, i.e. nuclear medicine and images medicine with magnetic resonance bimodal
Thing precursor.
Wherein, FA-PEG is obtained by following steps：Folic acid obtains FA- with n-hydroxysuccinimide (NHS) coupling
NHS；FA-NHS and NH2- PEG-COOH reactions obtain FA-PEG.
By above-mentioned synthetic method, then by the mark of radioactive metal nucleic, it is possible to obtain size tunable, magnetics
The PET/MRI bimodal imaging medicaments that matter is stable, top coal drawing is high.
Step (a) in above-mentioned preparation method, (b), the label of (c), which are not used in, limits the suitable of each step in preparation method
Each step in sequence, method, as long as in logic rationally, the order of each step can change.For example, above-mentioned step (a) or
(b) while independent carried out；In another example, step (b) can be placed on step (a) with carrying out before.
Prepared using chemical coprecipitation in superparamagnetic iron oxide nano-particle, building-up process, reaction condition is to finally receiving
The influence of rice corpuscles pattern is very big.By adjusting reactant ingredient proportion, reacting liquid pH value, drop in specific implementation of the patent mode
Plus alkali lye and stir speed (S.S.), change reaction temperature, the nucleation rate of nano-particle is reduced as far as possible, so as to ferric oxide nano particles
Particle diameter distribution effectively controlled.
By the surface modification to ferric oxide nano particles, its surface is carried active group, can simultaneously with medicine, anti-
The many kinds of substance such as body, gene, enzyme and cell are combined, and are that it realizes that multifunction creates conditions.In this patent embodiment
Carried out using small molecule organic compound APTES (APTES) and organic matter high molecular polymer (PEG)
Surface modification, both provided the active group that can be connected with organic matter for nanoparticle surface, reduced again between nano-particle
Aggregation, make it have good heat endurance and water solubility, biocompatibility is also greatly increased.
In addition, on the basis of above-mentioned bimodal imaging medicament precursor is synthesized, also groping and optimizing64Cu mark and pure
Change condition, establishes the quality control method of correlation, has carried out the evaluation of toy vivo biodistribution, PET and MRI imaging researchs.
Above-mentioned embodiment is further illustrated below by embodiment, but is not therefore limited the present invention to described
Scope of embodiments among.Other in the following example do not do the reagent illustrated, raw material and instrument and equipment can be by business
Industry approach is directly bought.
Embodiment 1PET/MRI bimodal imaging medicament precursor DOTA-SPIONs-PEG-FA and PET/MRI bimodal show
As medicine64Cu-DOTA-SPIONs-PEG-FA preparation
1.SPIONs preparation
Synthetic reaction is in N2Protection is lower to be carried out.By 549mg FeCl3·6H2O and 282mg FeSO4·7H2O is dissolved in 40mL and removed
In oxygen water, stirring and dissolving.Ammoniacal liquor is added dropwise pH is adjusted to 9.Temperature is increased to 50 DEG C again, continues to react 1h.After completion of the reaction, use
50mL deoxygenation water washings, magnet adsorption is toppled over, and is removed ammonium salt, is repeated 3 times.Product is dried in vacuo at 60 DEG C, obtains black block
Shape solid SPIONs 123mg, yield is 53%, in preservation at 4 DEG C.
Product FT-IR (cm-1) (Japanese SHIMADAZU companies IRAffinity-1 types FTIS)：
3419.7,1623.0,576.7.Magnetic measurement (U.S. Quantum Design companies BKT-4500Z type vibrating example magnetic strength
Meter)：Saturation magnetization 35.6emu/g, coercivity 9.3G, remanent magnetism 0.65emu/g.
2.SPIONs-APTES preparation
Pipette 0.5mL deaerated water and mixed with 10mL absolute ethyl alcohols, preparation water content is 3%-5% (v/v) water-ethanol
Mixed solution, and adjust pH (4.5-5.5) with glacial acetic acid.Then, 200 μ L APTESs are added
(APTES) 5min, is activated.86mg SPIONs are added, mechanical agitation, reaction is stayed overnight.After reaction terminates, with the second of 20mL 95%
Alcohol is washed, and magnet adsorption is toppled over, and is removed unreacted APTES, is repeated 5 times.Product is dried in vacuo at 60 DEG C, obtains black grain
Shape solid SPIONs-APTES 100mg, in preservation at 4 DEG C.
Product FT-IR (cm-1)：1525.6,1213.2,1149.5,580.5.Measure (the Britain of hydration kinetics diameter
Malvern companies Nano ZS type dynamic light scattering nano-particle size analysis instrument)：The dynamic optical of intensity weight shine (DLS) image show
It is shown as unimodal, SPIONs-APTES particle diameters are distributed mainly on 86 ± 26nm.
3.FA-NHS preparation
This reaction is in room temperature, N2Carried out under protection and lucifuge.502mg folic acid (FA) is added in the anhydrous DMSO of 10mL,
Stirring is extremely dissolved.Add 250mg DCC reactions 2h.150mg NHS are dissolved in the anhydrous DMSO of 1mL, are then added drop-wise to above-mentioned
In reaction solution, 5min completion of dropping, at room temperature reaction is stayed overnight.Filtration of crude product is removed and precipitated, subtracts filtrate at 40 DEG C
Pressure concentration 30min, then absolute ether is added dropwise into filtrate:Acetone=7:3 mixed liquor, is precipitated as stopping to not regenerating.Filtering,
Gained solid is with 50mL absolute ethers:Acetone=7:3 mixed liquor washing, is repeated 3 times, and in being dried in vacuo at 30 DEG C, obtains yellow
Color granular solids FA-NHS 322mg, yield is 53%, is preserved after bottling sealing at -20 DEG C.
4.FA-PEG synthesis
In room temperature, N2Under protection, by 300mg NH2(molecular weight is 2000 to-PEG-COOH, purchased from Beijing Xi Kai Creative Science and Technology Co. Ltd
Co., Ltd) it is added in 10mL DMSO, then 162mg FA-NHS are dissolved in 2mL DMSO, it is added drop-wise in above-mentioned reaction solution,
5min completion of dropping, adds 150mg N, and N- diisopropyl ethyl amines react 24h under the conditions of lucifuge.Crude product go from
Freezed in sub- water after dialysis (MWCO=1000) 48h, obtain yellow foamy solid FA-PEG 267mg, yield is 76%, filled
Preserved after bottle closure at -20 DEG C.
Product FT-IR (cm-1)：3398.5,2883.3,1689.6,1608.6,1344.3,1109.0,842.8.1H NMR
(DMSO) as shown in Figure 1.δ=8.60 (1H, N=CH-C, pteridine (a))；7.68,6.62(4H,-C4H4-,Ph(c,d))；
4.55(2H,-CH2-(b))；4.31(1H,CH(e))；3.31-3.50(182H,-CH2CH2O-,PEG(h,i))；2.19-2.38
(6H,-CH2-(f,g,j))；2.50(DMSO).
5.SPIONs-PEG-FA preparation
In N2Under protection, 160mg FA-PEG are dissolved in the anhydrous DMSO of 20mL, 84.8mg EDC stirring 10min are added,
Add 24.8mg NHS stirrings 30min.Then, 50mg SPIONs-APTES are dissolved in the anhydrous DMSO of 5mL, added above-mentioned
In reaction solution, reaction is stayed overnight.After reaction terminates, through dialysing (MWCO=8000-14000), freezing, black solid is obtained
SPIONs-PEG-FA 169mg, are preserved after bottling sealing at -20 DEG C.
Product FT-IR (cm-1)：3431.3,2881.6,1631.7,1344.3,1109.0,958.6,840.9,582.5.
DLS images are shown as unimodal, and SPIONs-PEG-FA particle diameters are distributed mainly on 133 ± 78nm.
6.DOTA-SPIONs-PEG-FA preparation
Weigh 50mg DOTA to be dissolved in 5mL water, 9.5mg EDC are dissolved in 1mL water, and both are mixed.Use 0.1mol/
PH value is adjusted to 5 by LNaOH, reacts 10min.Reaction bulb is moved in ice bath, 9mg NHS are added, then will with 0.1mol/LNaOH
PH value is adjusted to 5.5, continues to react 30min.Weigh 25mg SPIONs-PEG-FA to be dissolved in 3mL water, add in above-mentioned reaction solution,
Reacting liquid pH value is adjusted to 8.5 with 0.1mol/LNaOH again, reaction is stayed overnight.Reaction terminate after, through dialysis (MWCO=8000~
14000), freeze, obtain black solid DOTA-SPIONs-PEG-FA28mg, preserved after bottling sealing at -20 DEG C.
Product FT-IR (cm-1)：2877.7,1683.2,1601.7,1346.3,1111.0,842.8,686.3,578.6.
Magnetic measurement：Saturation magnetization 7.9emu/g, remanent magnetism 0.2emu/g.
7. the preparation of radioactive metal nucleic
Radioactive metal nucleic64Cu、60Cu、61Cu、66Ga、86Y、89Zr、45Ti、55Co、114mIn、94mTc、67Ga、111In、44Sc is prepared by cyclotron.68Ga passes through68Ge/68It is prepared by Ga generators.62Cu passes through62Zn/62It is prepared by Cu generators.99mTc passes through99Mo/99mIt is prepared by Tc generators.44Sc passes through44Ti/44It is prepared by Sc generators.177Lu is prepared by nuclear reactor.
Below with64Exemplified by Cu,64Details are as follows for Cu preparation：
The preparation of Ni targets.Uniform in copper target support to plate golden film (11cm × 2cm, 12 μm), W metal target layer is heavy by electricity
Product is plated in golden film.Ni concentration~15mg/mL, electrodeposition temperature is 35-40 DEG C, 350 revs/min of mixing speed, electric current 250mA,
Positive pulsewidth 500mA, bears pulsewidth 40mA, cycle 1.0ms, electroplating time 3h.It is final weigh target layer (Ni) quality is 127mg.
Target piece is fixed in C-30 bevatron solid target systems, with 15.6MeV, 37~70 μ A beam intensities
Proton practiced shooting 2.5~10h with 6 ° of incident angle.After irradiation terminates, 12mL 6mol/L hydrochloric acid and 3mL are added in target groove
H2O2, 95 DEG C of molten targets are heated to, after molten target terminates, molten target liquid is transferred in beaker, heating is evaporated, then uses 5mL 6mol/
L dissolving with hydrochloric acid residues.Molten target liquid is loaded on pretreated AG1-X8 anion-exchange columns, discards efflux.First with
20mL 6mol/L hydrochloric acid elutes exchange column, collects eluent, gained NiCl2Solution can be used for Ni targets next time to prepare.Again with
20mL 4mol/L hydrochloric acid elutes exchange column, discards efflux.Finally, exchange column is eluted with 20mL1mol/L hydrochloric acid, collects elution
Liquid, is obtained64CuCl2Solution, it is standby.
64Cu feature energy peak is 1345.8keV, β+Decay energy peak is 511.0keV, and gamma ray spectrometer measurement result is shown,64Cu
Radionuclide purity be more than 99.0%.IRIS Advantage spectrophotometers64In Cu metal impurities (Ni, Co, Fe and
Au) concentration is respectively less than 0.05mg/L.
8.64Cu mark and purifying
Take 5mg DOTA-SPIONs-PEG-FA to be dissolved in 500 μ L ammonium acetate buffer solutions (pH=6.5), be added to 2mL
In EP pipes, add64CuCl2(~296MBq), is vortexed and mixes, 45min is incubated under the conditions of 60 DEG C.
Purified using the method that centrifuge tube centrifugation is concentrated by ultrafiltration.Label is moved into ultrafiltration concentration centrifuge tube upper strata,
Centrifuge 10min under conditions of 5000 revs/min, discard lower floor's liquid, upper strata residue respectively with 500 μ L 10mM DTPA and
The washing of 1mM DTPA solution is each once, centrifugation, to the substantially "dead" activity detection of lower floor's filtrate, then collects upper strata remaining
Thing.
Determined using instant thin-layer chromatography method (Instant thin layer chromatography, ITLC)64Cu-
DOTA-SPIONs-PEG-FA mark rate and top coal drawing.Take 2 μ L to react liquid spotting on No. 1 chromatographic paper of Whatman, use
(volume ratio is 50 to 10% ammonium acetate/methyl alcohol mixed liquor：50) the 15mM EDTA solution prepared deploys for solvent and uses radial pattern
Thin-layer chromatogram scanner (German Eckert Ziegler companies AR-2000 type radial patterns thin-layer chromatogram scanner) is scanned, according to not isolabeling
Product Rf value (R in paper chromatography expansion systemf) difference so as to calculating mark rate or top coal drawing.Label concentrates on original
Near point, Rf=0-0.1, dissociates64Cu Rf=0.6-0.7.
As a result show, under above-mentioned flag condition, its mark rate is up to 23%.By centrifuge tube purifying is concentrated by ultrafiltration, put
Change is pure more than 98%, and specific activity is up to 1.7 μ Ci/ μ g.
The stabilization in vitro Journal of Sex Research of embodiment 2
By 100 μ L64Cu-DOTA-SPIONs-PEG-FA labels (~0.37MBq), are added to 200 μ L phosphate-buffereds
In solution PBS (pH=7.4), incubate, be incubated after 0h, 4h, 12h at 37 DEG C, sample and determined with instant thin-layer chromatography method and put
Change pure.
As a result show, label still keeps preferable top coal drawing stability when 4h is incubated in PBS, maintain 93% with
On.And after a half-life period (12h), top coal drawing is down to 85%.This shows that the label is basicly stable in 4h.
Embodiment 3：Biodistribution research in mice with tumor body
Animal selection lotus KB cell Balb/c nude mices (female, 18-20g), are purchased from Tumour Inst., Chinese Medical Academy.
Take 4-5 week old Balb/c Female nude mices, right fore oxter inoculation 5 × 106Individual KB (human mouth epidermoid carcinoma) cell, treats that tumour is put down
Equal diameter reaches to be used to test during 8-10mm.
Respectively through the μ L of tail vein injection 10064Cu-DOTA-SPIONs-PEG-FA (30 μ g ,~0.37MBq) and64Cu-
DOTA-SPIONs-PEG-OH (30 μ g ,~0.37MBq) normal saline solution, and after injection 1,3,6h when, to every group 3
Nude mice progress plucks eyeball and takes blood, and the neck that then breaks is put to death.Core, liver, spleen, lung, kidney, stomach, small intestine, muscle, femur, blood, knurl are weighed,
And determine radiocounting with gamma counter (Perkin Elmer companies of U.S. Wallace 1470-002 types gamma counter).Meter
Calculate the percentage injection dose rate (%ID/g) and tumour/non-tumour (tumour/blood) ratio of per gram of tissue.
Label64Cu-DOTA-SPIONs-PEG-FA and64Lifes of the Cu-DOTA-SPIONs-PEG-OH in mice with tumor body
Thing distribution results are respectively as shown in table 2 and table 3：
Table 2.64Bio distribution (mean ± SD, %ID/g, n=s of the Cu-DOTA-SPIONs-PEG-FA in mice with tumor body
3)
Table 3.64Bio distribution (mean ± SD, %ID/g, n=s of the Cu-DOTA-SPIONs-PEG-OH in mice with tumor body
3)
As shown in Table 2：Target label64Cu-DOTA-SPIONs-PEG-FA (21.04%ID/g, 6h) in liver
Intake is very big, and the intake in spleen (15.04%ID/g, 6h) and lung (29.83%ID/g, 6h) is also larger.64Cu-DOTA-
SPIONs-PEG-FA is mainly relevant with the phagocytosis of macrophage in the high intake of liver, spleen and lung.Internal reticular endothelium system
System (RES, including the tissue such as liver, spleen, lung and marrow) has abundant phagocyte, can using a certain size nano particle as
Foreign matter and absorb, larger particle is retained in some positions due to that can not filter capillary.
With the label of not connected folic acid64Cu-DOTA-SPIONs-PEG-OH is compared,64Cu-DOTA-SPIONs-PEG-
Intakes of the FA in tumour is substantially increased.64Cu-DOTA-SPIONs-PEG-FA and64Cu-DOTA-SPIONs-PEG-OH to
Medicine 1h uptake ratio is respectively 9.76 ± 5.27%ID/g and 1.41 ± 0.36%ID/g；The uptake ratio that 3h is administered is respectively 8.81
± 8.30%ID/g and 1.52 ± 0.60%ID/g；Administration 6h uptake ratio be respectively 8.90 ± 3.32%ID/g and 2.09 ±
0.63%ID/g.This shows after connection folic acid that there is nano-particle obvious active targeting to act on to KB cytomas.
In administration 1,3,6h,64Cu-DOTA-SPIONs-PEG-FA tumor/blood is than respectively 6.82,6.67,
6.74；And64Cu-DOTA-SPIONs-PEG-OH tumor/blood ratio respectively 0.65,0.52,0.68.It is connected with folic acid nanoparticle
The tumor/blood of son is than apparently higher than the nano-particle connected without folic acid, and in 1-6h, T/B is all higher than 6, and this shows64Cu-
DOTA-SPIONs-PEG-FA has the longer holdup time in tumour, and target is obvious with non-target tissue's contrast, can be wider
Tumour is imaged in time range.
Embodiment 4：The MRI imaging researchs of mice with tumor
Lotus KB cell Balb/c nude mices 3 are taken, one is only used as blank group；One is only used as blocking group, first through tail vein injection
50 μ L FA-PEG (200 μ g) inject 100 μ L DOTA-SPIONs-PEG-FA (20 μ again after carrying out folacin receptor blocking, 30min
g)；One is only used as experimental group, through the μ L DOTA-SPIONs-PEG-FA (20 μ g) of tail vein injection 100.4h is carried out upon administration
MRI imagings (imaging instrument is U.S.'s Varian companies 7.0T toys magnetic resonance imager).SPIO nanoparticle
Son, as T2 contrast agent, makes corresponding area in MRI imagings after swallowing SPIONs by the phagocyte in reticuloendothelial system
Domain signal weakens.
As a result it is as shown in Figure 3.Tumor locus is the brightest in Fig. 3 (a), blank group.Enter when to folacin receptor
After row is blocked (Fig. 3 (b)), image is also slightly dimmed, and this may be relevant with the Thief zone and retention effect of solid tumor, nano-particle quilt
Tumour is absorbed on a small quantity.Fig. 3 (c) shows that tumor locus is most dark.This shows that DOTA-SPIONs-PEG-FA has maximum in tumor locus
Intake, its intake is closely related with folacin receptor, and DOTA-SPIONs-PEG-FA can be used as folacin receptor active targeting
KB tumour MRI contrast agents.
Embodiment 5：The PET/CT imaging researchs of mice with tumor
Lotus KB cells nude mice 3 is taken, one is only used as non-targeted group, through the μ L non-folate receptor target marks of tail vein injection 100
Remember thing64Cu-DOTA-SPIONs-PEG-OH (~18.5MBq)；One is only used as blocking group, first through the μ LFA-PEG of tail vein injection 50
(200 μ g) injects 100 μ L again after carrying out folacin receptor blocking, 30min64Cu-DOTA-SPIONs-PEG-FA (~18.5MBq)；
One is only used as experimental group, through the μ L of tail vein injection 10064Cu-DOTA-SPIONs-PEG-FA (~18.5MBq).4h upon administration
Carry out PET/CT imagings (imaging instrument is Siemens companies of Germany Inveon small animal position emission tomography (PET)s/CT imagers).
As a result it is as shown in Figure 4.As shown in Figure 4, non-targeted group (Fig. 4 (a)) and blocking group (Fig. 4 (b)), medicine is in tumour
The intake at position is less, and big difference is not shown compared with muscle.And direct injection folacin receptor targeting label64After Cu-DOTA-SPIONs-PEG-FA, medicine substantially increases (Fig. 4 (c)) in the intake of tumor locus.This explanation64Cu-
DOTA-SPIONs-PEG-FA has targeting to KB cell tumours, and this targeting is realized by the effect with folacin receptor
, it is active targeting.
Illustrated by embodiment 2-5 detection data,64Cu-DOTA-SPIONs-PEG-FA can be used as PET/MRI bimodulus
State imaging medicament, the application prospect with the imaging medicament as folate receptor-positive tumour (such as KB cell tumours).
Finally it should be noted that：Various embodiments above only to help to understand technical scheme and core concept,
Rather than its limitations；Although the present invention is described in detail with reference to foregoing embodiments, the ordinary skill people of this area
Member should be understood：It can still modify to the technical scheme described in foregoing embodiments, or to which part or
Person's all technical characteristic carries out equivalent substitution, and these modifications or replacement also fall into the protection domain of the claims in the present invention
It is interior.
Claims (10)
1. a kind of nuclear medicine and magnetic resonance bimodal imaging medicament precursor, it is characterised in that with superparamagnetic iron oxide nano-particle
For core, in external sheath biocompatible materials and bifunctional chelating agent, folic acid passes through biocompatible materials and superparamagnetic
Ferric oxide nano particles are connected.
2. nuclear medicine according to claim 1 and magnetic resonance bimodal imaging medicament precursor, it is characterised in that use 3- ammonia
Base propyl-triethoxysilicane is modified superparamagnetic iron oxide nanoparticle surface, biocompatible materials and difunctional chela
Mixture is connected by APTES with superparamagnetic iron oxide nano-particle.
3. nuclear medicine according to claim 1 and magnetic resonance bimodal imaging medicament precursor, it is characterised in that the biology
Compatibility material includes the polyethylene glycol that molecular weight is 400-20000.
4. nuclear medicine according to claim 1 and magnetic resonance bimodal imaging medicament precursor, it is characterised in that described pair of work(
Energy chelating agent includes DOTA.
5. nuclear medicine according to claim 1 and magnetic resonance bimodal imaging medicament precursor, it is characterised in that the precursor is such as
Under：
Wherein, n=9~454.
6. a kind of nuclear medicine and magnetic resonance bimodal imaging medicament, it is characterised in that as described in any one of Claims 1 to 5
Nuclear medicine is obtained with magnetic resonance bimodal imaging medicament precursor through radioactive metal isotope labeling.
7. nuclear medicine according to claim 6 and magnetic resonance bimodal imaging medicament, it is characterised in that the radiogold
Category nucleic includes64Cu、60Gu、61Cu、62Cu、68Ga、66Ga、86Y、44Sc、89Zr、45Ti、55Co、114mIn、94mTc、67Ga、111In
、177Lu and99mAny of Tc.
8. nuclear medicine described in claim 6 or 7 and magnetic resonance bimodal imaging medicament show preparing folate receptor-positive tumour
As the application in medicine.
9. nuclear medicine and the preparation method of magnetic resonance bimodal imaging medicament precursor described in a kind of claim 5, its feature exist
In comprising the following steps：
(a) surface modification is carried out to superparamagnetic iron oxide nano-particle using 3- aminopropyl triethoxysilanes, obtains SPIONs-
APTES,
(b) folic acid obtains FA-PEG with polyethylene glycol conjugation,
Wherein, n=9~454；
(c) SPIONs-APTES and FA-PEG reactions obtain SPIONs-PEG-FA, then with Isosorbide-5-Nitrae, 7,10- tetraazacyclododecanands-
Isosorbide-5-Nitrae, 7,10- tetraacethyls coupling, is obtained before DOTA-SPIONs-PEG-FA, i.e. nuclear medicine and magnetic resonance bimodal imaging medicament
Body.
10. nuclear medicine according to claim 9 and the preparation method of magnetic resonance bimodal imaging medicament precursor, its feature exist
In FA-PEG is obtained by following steps：Folic acid obtains FA-NHS with n-hydroxysuccinimide coupling；FA-NHS and NH2-
PEG-COOH reactions obtain FA-PEG；
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| CN113877421A (en) * | 2021-08-20 | 2022-01-04 | 苏州爱索拓普智能科技有限公司 | Medical isotope separation and purification process |
| US11964948B2 (en) | 2022-06-07 | 2024-04-23 | Actinium Pharmaceuticals, Inc. | Bifunctional chelators and conjugates |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109626439A (en) * | 2018-12-11 | 2019-04-16 | 中国科学院宁波材料技术与工程研究所 | A kind of metal-doped ferrite nano material, comprising its magnetic nano-particle preparation method and applications |
| CN109626439B (en) * | 2018-12-11 | 2024-05-07 | 中国科学院宁波材料技术与工程研究所 | Metal-doped ferrite nano material, preparation method of magnetic nano particles containing metal-doped ferrite nano material and application of magnetic nano particles |
| CN113877421A (en) * | 2021-08-20 | 2022-01-04 | 苏州爱索拓普智能科技有限公司 | Medical isotope separation and purification process |
| US11964948B2 (en) | 2022-06-07 | 2024-04-23 | Actinium Pharmaceuticals, Inc. | Bifunctional chelators and conjugates |
| US11975081B2 (en) | 2022-06-07 | 2024-05-07 | Actinium Pharmaceuticals, Inc. | Bifunctional chelators and conjugates |
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