CN101092416A - Derivative of folacin alkylation and application - Google Patents
Derivative of folacin alkylation and application Download PDFInfo
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- CN101092416A CN101092416A CN 200710070005 CN200710070005A CN101092416A CN 101092416 A CN101092416 A CN 101092416A CN 200710070005 CN200710070005 CN 200710070005 CN 200710070005 A CN200710070005 A CN 200710070005A CN 101092416 A CN101092416 A CN 101092416A
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Abstract
This invention provides a folic acid alkylated derivatives, more specifically, folic acid stearyl amine derivative I and folic acid stearic acid derivative II, which are obtained by coupling reaction of folic acid amino and stearic acid carboxyl, or folic acid carboxyl and stearyl amine amino. The folic acid alkylated derivatives can be used to prepare folic acid modified lipid nanoparticles. The alkyl chains of the derivatives have compatibility with lipid nanoparticles, which can accelerate the absorption of lipid nanoparticles, and increase the tumor targeting performance of lipid nanoparticles. The folic acid alkylated derivatives can be used in preparing folic acid modified lipid nanoparticles carrying antitumor drugs. The structural formula of the folic acid alkylated derivatives is shown in this invention.
Description
Technical field
The invention belongs to the synthetic method of compound, relate to the synthetic and application in antineoplaston of derivative of folacin alkylation.
Background technology
Tumour is the major disease that directly threatens human health always, and chemotherapy of tumors is because the molecular targeted property of medicine shortage itself, thereby great treatment problems such as curative ratio is low, toxic side effect is huge occur.By the suitable carriers technology, with the direct target pathological tissues of medicine (organ), cell one of important means that solves the low and toxic side effect of cancer chemotherapy curative ratio.Present scientist both domestic and external has obtained certain progress by carrier technique on the tissue (organ) of tumour medicine and cell-targeting, but the curative effect of making a breakthrough property not, its essence is that the molecularity target spot of most antitumor drugs is positioned at cell, so the research and development of drug molecule action target spot (subcellular organelle) targeting vector material technology are the keys that breaks through the cancer chemotherapy bottleneck in the tumour cell.
The design of targeting vector mainly comprises the focus internal organs target of carrier, and passes through the focus cell-targeting in the focus internal organs on this basis, thereby finishes the subcellular organelle target at molecular drug target.Early stage histoorgan target, the small particle size passive target that utilizes particulate gather tumor tissues etc. to tissues such as livers by " enhanced sees through and retention effect " (enhanced permeability and retention effect).Current, the investigator utilizes the characteristic of some acceptor of tumor cell surface (as folacin receptor) overexpression, ligand modified solid support material is successfully applied to the targeted therapy of tumour.Thereby reach the target of tumour cell, improve intracellular antitumour drug substrate concentration, strengthen the curative effect of antitumor drug itself.
The solid lipid drug delivery system is the new colloidal drug delivery system that grows up early 1990s, and it is after emulsion, liposome, polymer nanoparticle, has the target controlling and releasing drug delivery system of development potentiality.The solid lipid drug delivery system adopts natural or synthetic lipid materials, is carrier as stearic acid, Yelkin TTS, mono-glycerides etc., pharmaceutical pack is wrapped in the lipoid nuclear makes solid micelle drug delivery system.It had both possessed polymeric drug delivery system controlled release, had avoided advantages such as drug leakage, and the toxicity that has had emulsion, liposome again concurrently is low, good biocompatibility, advantage that bioavailability is high.But also there are some potential limitation in the solid lipid drug delivery system, squeezes problems such as phenomenon as limited medicine carrying ability, the medicine of storage process.
The different liquid fatty of mixed form is as mixing lipid matrix in solid lipid, with this prepare New type of S LN-nano structured lipid carrier (nanostructured lipid carrier, NLC).The adding of liquid fatty can be upset the crystalline network of solid lipid rule, increases the ratio of irregular crystal formation in the nanoparticle structure, and the spatial content of carrying fat-soluble medicine is increased, thereby improves the medicine carrying ability of carrier.By controlled liq lipid ratio, also can make NLC under body temperature, keep the solid skeletal structure, realize that the NLC controlled delivery of pharmaceutical agents discharges.
The result of study in our early stage is found solid lipid particulate and nano structured lipid carrier, because the strong-hydrophobicity matter that it is surperficial, have the ability that stronger cellular uptake and cytoplasm are detained, but solid lipid particulate and nano structured lipid carrier itself do not have the target function of tumor tissues and cell.There is the part of some acceptor of overexpression that such carrier is modified if use at tumor cell surface, will improves the application possibility of such carrier in the antineoplastic target treatment greatly.Seal and use such carrier that folic acid is carried out simple physics, understand a large amount of seepages that produce folic acid in the transport process in vivo on the one hand, also calculation may be wrapped in matrix material inside or be distributed in the middle of the matrix material on the other hand, thereby influences the tumour cell target effect of folic acid.
Summary of the invention
First purpose of the present invention provides derivative of folacin alkylation, is specially the stearic aeic derivative I of folic acid and the stearylamine derivative Π of folic acid,, structural formula is respectively:
Derivative of folacin alkylation provided by the invention is realized by the following method:
Precision takes by weighing 20mg stearic acid (or stearylamine) and is dissolved in the 5ml dimethyl formamide (DMF), at magnetic agitation (400rmin
-1) under, add 20mg carbodiimide (EDC), behind the reaction 1h, add 30mg folic acid and 0.5ml pyridine, stirring reaction spends the night under the room temperature.Add elutriation and go out precipitation, after distill water dialysis was removed unreacted free folic acid, lyophilize promptly got the stearylamine derivative of folic acid or the stearic aeic derivative of folic acid.
Another object of the present invention provides derivative of folacin alkylation and uses in the lipid nanoparticle of preparation modified with folic acid.
A further object of the present invention provides the application of derivative of folacin alkylation in the lipid nanoparticle drug delivery system of preparation load antitumor drug.Also promptly in the solid lipid of preparation modified with folic acid and the application in the nano structured lipid carrier drug feeding system.
Derivative of folacin alkylation provided by the present invention can be used for preparing lipid nanoparticle, thereby reach the modified with folic acid purpose of lipid nanoparticle, folacin receptor mediated approach by the tumor cell surface overexpression, quicken the cellular uptake of lipid nanoparticle, thereby improve the antitumor curative effect of the antitumor drug delivery system of lipid nanoparticle.
The invention has the beneficial effects as follows: the present invention is by folic acid and matrix material, chemical grafting as lipid acid or aliphatic amide, synthetic derivative of folacin alkylation with brand-new chemical structure, and by the alkyl chain in this derivative and the affinity of lipid materials, prepare modified with folic acid solid lipid and nano structured lipid carrier drug feeding system, can be applicable to prepare the antineoplaston medicine of cell levels.
Description of drawings
Fig. 1: the nuclear magnetic resonance map of the stearic aeic derivative of folic acid.
Fig. 2: the stearic aeic derivative lipid nanoparticle fluorescence inverted microscope photo that contains folic acid of FITC mark.
Fig. 3: the nuclear magnetic resonance map of the stearylamine derivative of folic acid.
Fig. 4: the stearylamine derivative lipid nanoparticle fluorescence inverted microscope photo that contains folic acid of FITC mark.
Embodiment
The present invention is further described in conjunction with the accompanying drawings and embodiments.
Embodiment 1: the synthetic and application of the stearic aeic derivative of folic acid
1) stearic aeic derivative of folic acid is synthetic
Precision takes by weighing stearic acid 20mg and is dissolved in the 5ml dimethyl formamide (DMF), at magnetic agitation (400rmin
-1) under, add 20mg carbodiimide (EDC), behind the reaction 1h, add 30mg folic acid and 0.5ml pyridine, stirring reaction spends the night under the room temperature.Add elutriation and go out precipitation, after distill water dialysis was removed unreacted free folic acid, lyophilize promptly got the stearic aeic derivative of folic acid.Its nuclear magnetic resonance map is referring to Fig. 1.
2) lung cancer A549 cell that contains the stearic aeic derivative lipid nanoparticle of folic acid is transported
The present invention adopts the stearic aeic derivative lipid nanoparticle of the folic acid that contains fluorescein isothiocyanate (fitc) (FITC) and stearylamine chemistry grafting to carry out the transhipment research of lung cancer A549 cell.The stearic aeic derivative lipid nanoparticle that contains the folic acid of fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting mark prepares by the following method: precision takes by weighing 27mg matrix material (oleic acid, 1/1/8) and 4.5mg fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting the stearic aeic derivative of folic acid and the ratio of mono-glycerides are:, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With distilled water is disperse phase, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical stirring condition, organic phase is injected the 30ml disperse phase, stir 5min, obtain the dispersion liquid of the stearic aeic derivative lipid nanoparticle of FITC mark folic acid.The dispersion liquid 3molL of the stearic aeic derivative lipid nanoparticle of resultant FITC mark folic acid
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.The gained dispersion liquid is used for lung cancer A549 cell transhipment research.
Get the A549 cell, in the RPMI RPMI-1640 that contains 10% calf serum of having an appointment, cultivate (5%CO
2, 37 ℃ of incubators).When cell reaches logarithmic phase, can inoculate.The cell in vegetative period of taking the logarithm after the PBS rinse, adds trysinization and with the nutrient solution dilution, by every hole 1 * 10
5The density of individual cell is inoculated in 24 well culture plates, after the growth of cell attachment in 24 well culture plates, adds the lipid nanoparticle of FITC mark respectively or contain the stearic aeic derivative lipid nanoparticle of folic acid that (final concentration is 100 μ gmL
-1), hatch 1,2,4,12, behind the 24h, wash cell 3 times with PBS, the fluorescence inverted microscope is observed also and is taken pictures.The result is referring to Fig. 2, and wherein A is the lipid nanoparticle of FITC mark, and B contains the stearic aeic derivative lipid nanoparticle of folic acid for the FITC mark.The result shows, the A549 cellular uptake of stearic aeic derivative lipid nanoparticle that contains folic acid is obviously faster than non-modified with folic acid lipid nanoparticle.
3) the paclitaxel loaded preparation that contains the stearic aeic derivative lipid nanoparticle drug delivery system of folic acid
Precision takes by weighing the 30mg matrix material (ratio of oleic acid and mono-glycerides is: 1/9 respectively; Or the ratio of the stearic aeic derivative of oleic acid/mono-glycerides/folic acid is 1/8/1) and the 1.5mg taxol, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With distilled water is disperse phase, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical stirring condition, organic phase is injected the 30ml disperse phase, stir 5min, obtain paclitaxel loaded lipid nanoparticle and the paclitaxel loaded dispersion liquid that contains the stearic aeic derivative lipid nanoparticle of folic acid respectively.Resultant nanoparticle dispersion liquid 3molL
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.Promptly obtain paclitaxel loaded lipid nanoparticle and the paclitaxel loaded stearic aeic derivative lipid nanoparticle drug delivery system that contains folic acid.
Table 1 is preparation-obtained paclitaxel loaded lipid nanoparticle and the paclitaxel loaded physico-chemical properties such as particle diameter, surface potential and entrapment efficiency that contain the stearic aeic derivative lipid nanoparticle of folic acid.
Table 1: particle diameter, surface potential and the entrapment efficiency of paclitaxel loaded mono-glycerides oleic acid lipid nanoparticle.
| Drug delivery system | Particle diameter (nm) | Surface potential (mV) | Entrapment efficiency (%) |
| Lipid nanoparticle | 561.7 | 37.4 | 68.7 |
| The stearic aeic derivative lipid nanoparticle that contains folic acid | 501.6 | 38.7 | 80.2 |
4) the paclitaxel loaded anti-tumor activity that contains the stearic aeic derivative lipid nanoparticle of folic acid
With the lung cancer A549 cell is model, and the IC50 value (the half lethality rate of cell) after the paclitaxel loaded antitumor curative effect that contains the stearic aeic derivative lipid nanoparticle drug delivery system of folic acid is hatched altogether by drug delivery system and cell is estimated.The cell survival rate test adopts tetrazolium salts colorimetry (MTT Assay) to measure.After 24 orifice plates are cultivated the growth of 24h cell attachment in advance, add the suspension of the blank lipid nanoparticle of different concns respectively; The paclitaxel loaded lipid nanoparticle of paclitaxel solution of different concns (solvent is Cremophor: dehydrated alcohol 1: 1 (V/V)) and different concns and contain the suspension of the stearic aeic derivative lipid nanoparticle of folic acid, and establish control wells, every group is repeated 3 times; After hatching 48h, every hole adds MTT solution 60 μ L and hatches abandoning supernatant behind the 4h, PBS solution flushing 2 times, and every hole adds DMSO 500 μ L, termination reaction.With culture plate level vibration 10min, measure optical density at the 570nm place with enzyme connection detector, calculate cell survival rate by (1) formula:
Cell survival rate (%)=A
570(sample)/A
570(contrast) * 100% (1)
A wherein
570(sample) is the optical density of the cell behind the adding suspension, A
570(contrast) is the optical density of the cell of blank.
The blank lipid nanoparticle of being measured, paclitaxel solution and paclitaxel loaded lipid nanoparticle and the IC50 value that contains the stearic aeic derivative lipid nanoparticle of folic acid the results are shown in Table 2
Table 2: blank lipid nanoparticle, paclitaxel solution and paclitaxel loaded lipid nanoparticle and contain the IC50 value of the stearic aeic derivative lipid nanoparticle of folic acid
| Drug delivery system | The IC50 (μ g/ml) of blank carrier | The IC50 of drug delivery system (μ g/ml) |
| The paclitaxel solution lipid nanoparticle | / 315.2 | 1.72 0.25 |
| The stearic aeic derivative lipid nanoparticle that contains folic acid | 308.7 | 0.02 |
The result shows that mono-glycerides oleic acid lipid nanoparticle and the stearic aeic derivative lipid nanoparticle that contains folic acid are the low cytotoxicity solid support material; Taxol height after mono-glycerides oleic acid lipid nanoparticle is sealed can improve the curative effect about 5.88 times; Lipid nanoparticle can further improve the curative effect of medication of taxol after the stearic aeic derivative of folic acid is modified, compare the curative effect that can improve about 86 times with free drug.
Embodiment 2: the synthetic and application of the stearylamine derivative of folic acid
1) the stearylamine derivative of folic acid is synthetic
Precision takes by weighing stearylamine 20mg and is dissolved in the 5ml dimethyl formamide (DMF), at magnetic agitation (400rmin
-1) under, add 20mg carbodiimide (EDC), behind the reaction 1h, add 30mg folic acid and 0.5ml pyridine, stirring reaction spends the night under the room temperature.Add elutriation and go out precipitation, after distill water dialysis was removed unreacted free folic acid, lyophilize promptly got the stearylamine derivative of folic acid.The nuclear magnetic resonance map of the stearylamine derivative of folic acid is referring to Fig. 3.
2) lung cancer A549 cell that contains the stearylamine derivative lipid nanoparticle of folic acid is transported
The present invention adopts the stearylamine derivative lipid nanoparticle of the folic acid that contains fluorescein isothiocyanate (fitc) (FITC) and stearylamine chemistry grafting to carry out the transhipment research of lung cancer A549 cell.The stearylamine derivative lipid nanoparticle that contains the folic acid of fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting mark prepares by the following method: precision takes by weighing 27mg matrix material (oleic acid, 1/1/8) and 4.5mg fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting the stearylamine derivative of folic acid and the ratio of mono-glycerides are:, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With distilled water is disperse phase, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical stirring condition, organic phase is injected the 30ml disperse phase, stir 5min, obtain the dispersion liquid of the stearylamine derivative lipid nanoparticle of FITC mark folic acid.The dispersion liquid 3molL of the stearylamine derivative lipid nanoparticle of resultant FITC mark folic acid
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.The gained dispersion liquid is used for lung cancer A549 cell transhipment research.
Get the A549 cell, in the RPMI RPMI-1640 that contains 10% calf serum of having an appointment, cultivate (5%CO
2, 37 ℃ of incubators).When cell reaches logarithmic phase, can inoculate.The cell in vegetative period of taking the logarithm after the PBS rinse, adds trysinization and with the nutrient solution dilution, by every hole 1 * 10
5The density of individual cell is inoculated in 24 well culture plates, after the growth of cell attachment in 24 well culture plates, adds the lipid nanoparticle of FITC mark respectively or contain the stearylamine derivative lipid nanoparticle of folic acid that (final concentration is 100 μ gmL
-1), hatch 1,2,4,12, behind the 24h, wash cell 3 times with PBS, the fluorescence inverted microscope is observed also and is taken pictures.The result is referring to Fig. 4.Wherein: A is the lipid nanoparticle of FITC mark, and B contains the stearylamine derivative lipid nanoparticle of folic acid for the FITC mark.The result shows, the A549 cellular uptake of stearylamine derivative lipid nanoparticle that contains folic acid is obviously faster than non-modified with folic acid lipid nanoparticle.
3) the paclitaxel loaded preparation that contains the stearylamine derivative lipid nanoparticle drug delivery system of folic acid
Precision takes by weighing the 30mg matrix material (ratio of oleic acid and mono-glycerides is: 1/9 respectively; Or the ratio of the stearylamine derivative of oleic acid/mono-glycerides/folic acid is 1/8/1) and the 1.5mg taxol, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With distilled water is disperse phase, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical stirring condition, organic phase is injected the 30ml disperse phase, stir 5min, obtain paclitaxel loaded lipid nanoparticle and the paclitaxel loaded dispersion liquid that contains the stearylamine derivative lipid nanoparticle of folic acid respectively.Resultant nanoparticle dispersion liquid 3molL
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.Promptly obtain paclitaxel loaded lipid nanoparticle and the paclitaxel loaded stearylamine derivative lipid nanoparticle drug delivery system that contains folic acid.
Table 3 is preparation-obtained paclitaxel loaded lipid nanoparticle and the paclitaxel loaded physico-chemical properties such as particle diameter, surface potential and entrapment efficiency that contain the stearylamine derivative lipid nanoparticle of folic acid.
Table 3: particle diameter, surface potential and the entrapment efficiency of paclitaxel loaded mono-glycerides oleic acid lipid nanoparticle.
| Drug delivery system | Particle diameter (nm) | Surface potential (mV) | Entrapment efficiency (%) |
| Lipid nanoparticle | 561.7 | 37.4 | 68.7 |
| The stearylamine derivative lipid nanoparticle that contains folic acid | 512.4 | 37.5 | 78.5 |
4) the paclitaxel loaded anti-tumor activity that contains the stearylamine derivative lipid nanoparticle of folic acid
With the lung cancer A549 cell is model, and the IC50 value (the half lethality rate of cell) after the paclitaxel loaded antitumor curative effect that contains the stearylamine derivative lipid nanoparticle drug delivery system of folic acid is hatched altogether by drug delivery system and cell is estimated.The cell survival rate test adopts tetrazolium salts colorimetry (MTT Assay) to measure.After 24 orifice plates are cultivated the growth of 24h cell attachment in advance, add the suspension of the blank lipid nanoparticle of different concns respectively; The paclitaxel loaded lipid nanoparticle of paclitaxel solution of different concns (solvent is Cremophor: dehydrated alcohol 1: 1 (V/V)) and different concns and contain the suspension of the stearylamine derivative lipid nanoparticle of folic acid, and establish control wells, every group is repeated 3 times; After hatching 48h, every hole adds MTT solution 60 μ L and hatches abandoning supernatant behind the 4h, PBS solution flushing 2 times, and every hole adds DMSO 500 μ L, termination reaction.With culture plate level vibration 10min, measure optical density at the 570nm place with enzyme connection detector, calculate cell survival rate by (1) formula:
Cell survival rate (%)=A
570(sample)/A
570(contrast) * 100% (1)
A wherein
570(sample) is the optical density of the cell behind the adding suspension, A
570(contrast) is the optical density of the cell of blank.
The blank lipid nanoparticle of being measured, paclitaxel solution and paclitaxel loaded lipid nanoparticle and the IC50 value that contains the stearylamine derivative lipid nanoparticle of folic acid the results are shown in Table 4
Table 4: blank lipid nanoparticle, paclitaxel solution and paclitaxel loaded lipid nanoparticle and contain the IC50 value of the stearylamine derivative lipid nanoparticle of folic acid
| Drug delivery system | The IC50 (μ g/ml) of blank carrier | The IC50 of drug delivery system (μ g/ml) |
| The paclitaxel solution lipid nanoparticle | / 315.2 | 1.72 0.25 |
| The stearylamine derivative lipid nanoparticle that contains folic acid | 297.5 | 0.03 |
The result shows that mono-glycerides oleic acid lipid nanoparticle and the stearylamine derivative lipid nanoparticle that contains folic acid are the low cytotoxicity solid support material; Taxol height after mono-glycerides oleic acid lipid nanoparticle is sealed can improve the curative effect about 5.88 times; Lipid nanoparticle can further improve the curative effect of medication of taxol after the stearylamine derivative of folic acid is modified, compare the curative effect that can improve about 57 times with free drug.
Claims (4)
1. derivative of folacin alkylation is characterized in that: be specially the stearic aeic derivative I of folic acid and the stearylamine derivative ∏ of folic acid, have following structural formula:
2. derivative of folacin alkylation according to claim 1, amino and stearic carboxyl by folic acid, or the coupling reaction of the amino of the carboxyl of folic acid and stearylamine is synthetic obtains, it is characterized in that realizing by following steps: precision takes by weighing 20mg stearic acid or stearylamine, be dissolved in the 5ml dimethyl formamide, at 400rmin
-1Under the magnetic agitation, add the 20mg carbodiimide, react after 1 hour, add 30mg folic acid and 0.5ml pyridine, stirring reaction spends the night under the room temperature, adds elutriation and goes out precipitation, and after distill water dialysis was removed unreacted free folic acid, lyophilize promptly got derivative of folacin alkylation.
3. the application of derivative of folacin alkylation according to claim 1 in the lipid nanoparticle of preparation modified with folic acid.
4. derivative of folacin alkylation according to claim 1 is in the solid lipid of the modified with folic acid of preparation load antitumor drug and the application in the nano structured lipid carrier drug feeding system.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105008930A (en) * | 2012-12-27 | 2015-10-28 | 生物梅里埃公司 | Folate derivatives, useful in particular in the context of the folate assay |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105008930A (en) * | 2012-12-27 | 2015-10-28 | 生物梅里埃公司 | Folate derivatives, useful in particular in the context of the folate assay |
| US9926323B2 (en) | 2012-12-27 | 2018-03-27 | Biomerieux | Folate derivatives, useful in particular in the context of the folate assay |
| CN105008930B (en) * | 2012-12-27 | 2018-05-29 | 生物梅里埃公司 | The particularly useful folic acid derivatives in the situation for measuring folic acid |
| US10640505B2 (en) | 2012-12-27 | 2020-05-05 | bioMérieux | Folate derivatives, useful in particular in the context of the folate assay |
| US11535620B2 (en) | 2012-12-27 | 2022-12-27 | bioMérieux | Folate derivatives, useful in particular in the context of the folate assay |
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