CN103745793B - A kind of superparamagnetism fat-PLA targeted nano particle and preparation method - Google Patents
A kind of superparamagnetism fat-PLA targeted nano particle and preparation method Download PDFInfo
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 46
- 235000019152 folic acid Nutrition 0.000 claims abstract description 36
- 239000011724 folic acid Substances 0.000 claims abstract description 36
- 229940014144 folate Drugs 0.000 claims abstract description 19
- 239000003446 ligand Substances 0.000 claims abstract description 19
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical class CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims abstract description 12
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960000304 folic acid Drugs 0.000 claims abstract description 10
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000010410 layer Substances 0.000 claims abstract description 4
- 239000002356 single layer Substances 0.000 claims abstract description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- 239000011553 magnetic fluid Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 6
- 229910021641 deionized water Inorganic materials 0.000 claims description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 3
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 229940083466 soybean lecithin Drugs 0.000 claims description 3
- 239000006228 supernatant Substances 0.000 claims description 3
- 238000000108 ultra-filtration Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 8
- 229940064302 folacin Drugs 0.000 abstract description 7
- 210000004881 tumor cell Anatomy 0.000 abstract description 7
- 239000002245 particle Substances 0.000 abstract description 3
- 238000001179 sorption measurement Methods 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005426 magnetic field effect Effects 0.000 description 1
- 239000002122 magnetic nanoparticle Substances 0.000 description 1
- 239000006148 magnetic separator Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Abstract
The invention discloses a kind of superparamagnetism fat-PLA targeted nano particle, this targeted nano particle is cross-linked by PLA-phosphatide-PEG nano particle and folate ligand and forms; PLA-phosphatide-PEG nano particle wraps up Fe by PLA
3o
4the center that is in as PLA kernel, and is around in this PLA core surface with phosphatide with single layer of rings, and is interspersed in above-mentioned individual layer phosphatide using PEG-DSPE-carboxylic acid and is formed as target shell; Folate ligand is cross-linked to form with folic acid by after certain mol proportion room temperature reaction by DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS.Its preparation method comprises PLA-phosphatide-PEG nano particle, folate ligand preparation and is cross-linked finished product preparation.Particle of the present invention is cross-linked after folate-targeted can at the tumour cell of targets identification folacin receptor process LAN, by magnet adsorption separating tumor cell.
Description
Technical field
The invention belongs to nanosecond medical science field, particularly relate to a kind of superparamagnetic nano particle, specifically a kind of superparamagnetism fat-PLA targeted nano particle and preparation method.
Background technology
Along with the rapid advances of nanometer technology, superparamagnetic nano particle obtains and develops fast in isolated cell, especially nano particle makes it have unique advantage as cell magnetic separating medium because of its superparamagnetism had and surface modificability, by forming biological functional magnetic nano particle at its surperficial immobilizing biologically active molecule, it is made only to have affinity to specific cells, under outside magnetic field effect, can cell directly from primary sample required for specific isolation.The method can save the complex operations such as centrifugal, filtration, and this brings revolutionary development to the separation of target cell.Scientific discovery, some malignant cells of the mankind have the high expressed to folacin receptor.If a kind of target superparamagnetic nano particle just energy well separating tumor cell that there is folate ligand and modify can be prepared.
Summary of the invention
Technical problem to be solved by this invention is for above-mentioned prior art present situation, and provides and have that technique is simple, low cost of manufacture, a kind of superparamagnetism fat-PLA targeted nano particle of tumour cell separator well and preparation method.Wherein: PLA is called for short PLA, DSPE-PEG-carboxyl is called for short DSPE-PEG-COOH, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and is called for short EDC, HOSu NHS abbreviation NHS.
It is a kind of superparamagnetism fat-PLA targeted nano particle that the present invention solves the problems of the technologies described above adopted technical scheme, and this targeted nano particle is cross-linked by PLA-phosphatide-PEG nano particle and folate ligand and forms; PLA-phosphatide-PEG nano particle wraps up Fe by PLA
3o
4the center that is in as PLA kernel, and is around in this PLA core surface with phosphatide with single layer of rings, and is interspersed in above-mentioned individual layer phosphatide using PEG-DSPE-carboxylic acid and is formed as target shell; Folate ligand is cross-linked to form with folic acid by after certain mol proportion room temperature reaction by DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS.
The preparation method of superparamagnetism fat-PLA targeted nano particle, the method comprises the following steps:
A), in four neck flasks, 30mL deionized water is first added, logical N
210min, takes 6.7573gFeCl fast
36H
2o and 3.4753gFeSO
47H
2o, joins in reaction bulb, stirring and dissolving, slowly drips ammoniacal liquor by constant pressure funnel, and in temperature 20
oc to 30
ounder C condition, mechanical vigorous stirring, to pH9 ~ pH11, drip ammoniacal liquor 24mL altogether, solution colour gradually becomes black by rufous, then after at room temperature stirring 25min to 35min, is warming up to 55
oc to 65
oc, reaction 25min to 35min, cooling, is separated with magnet, outwells supernatant, and wash three times with each 70mL of deionized water, and disperse with ultrasonic wave, then wash three times with each 70mL of ethanol, finally add 45mL Tetramethylammonium hydroxide and dissolve, then add redistilled water to 250mL, filter with sand core funnel thus obtain magnetic fluid;
B), get PLA and be dissolved in second cyanogen, then add the magnetic fluid in 1mL step a, the obtained PLA second cyanogen solution containing magnetic fluid;
C), get 0.06mg DSPE-PEG-carboxyl, 0.24mg soybean lecithin, be added in the ethanol water of 3ml, heating is stirred to 55 DEG C to 70 DEG C, the obtained mixed ethanol aqueous solution;
D), by PLA second cyanogen dropwise obtained in 1ml step b add in the obtained mixed ethanol aqueous solution of 3ml step c, under the condition of uniform temperature, stirring 1 is little of 3 hours continuously, and period allows solvent evaporates, the PLA-phosphatide-PEG nano particle obtained;
E), by DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS in molar ratio 1:1:2 after room temperature reaction a period of time, add folic acid, obtain folate ligand;
F), hand over the folate ligand obtained in PLA-phosphatide-PEG nano particle obtained in steps d and step e to be cross-linked, ultrafiltration washes three times, i.e. this product obtained.
When in above-mentioned step a, constant pressure funnel slowly drips ammoniacal liquor, in temperature 25
ounder C condition, mechanical vigorous stirring is to pH10.
After at room temperature stirring 30min again in above-mentioned step a, be warming up to 60
oc, reaction 30min, cooling.
PLA concentration in above-mentioned step b in PLA second cyanogen solution is 2mg/mL.
In above-mentioned step c, the concentration of ethanol water is 4%, and heating is stirred to 65
oc.
Temperature conditions in above-mentioned steps d is 65 DEG C, and continuous mixing time is 2 hours.
In above-mentioned step e, DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS are after room temperature reaction 15min, add folic acid.
In above-mentioned step f, the mol ratio of PLA-phosphatide-PEG nano particle and folate ligand is 1:1.
Compared with prior art, the present invention has following characteristics:
1, PLA, phosphatide have good biocompatibility, biodegradable and excreted by normal physiological pathway.
2, simultaneously particle be cross-linked after folate-targeted can at the tumour cell of targets identification folacin receptor process LAN, by magnet adsorption separating tumor cell.
3, this particle low cost of manufacture, convenient operation is promoted.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
A kind of superparamagnetism fat-PLA targeted nano particle of the present invention, this targeted nano particle is cross-linked by PLA-phosphatide-PEG nano particle and folate ligand and forms; PLA-phosphatide-PEG nano particle wraps up Fe by PLA
3o
4the center that is in as PLA kernel, and is around in this PLA core surface with phosphatide with single layer of rings, and is interspersed in described individual layer phosphatide using PEG-DSPE-carboxylic acid and is formed as target shell; Folate ligand is cross-linked to form with folic acid by after certain mol proportion room temperature reaction by DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS.
The preparation method of a kind of superparamagnetism fat-PLA targeted nano particle of the present invention, the method comprises the following steps:
A), in four neck flasks, 30mL deionized water is first added, logical N
210min, takes 6.7573gFeCl fast
36H
2o and 3.4753gFeSO
47H
2o, joins in reaction bulb, stirring and dissolving, slowly drips ammoniacal liquor by constant pressure funnel, and in temperature 20
oc to 30
ounder C condition, mechanical vigorous stirring, to pH9 ~ pH11, drip ammoniacal liquor 24mL altogether, solution colour gradually becomes black by rufous, then after at room temperature stirring 25min to 35min, is warming up to 55
oc to 65
oc, reaction 25min to 35min, cooling, is separated with magnet, outwells supernatant, and wash three times with each 70mL of deionized water, and disperse with ultrasonic wave, then wash three times with each 70mL of ethanol, finally add 45mL Tetramethylammonium hydroxide and dissolve, then add redistilled water to 250mL, filter with sand core funnel thus obtain magnetic fluid;
B), get PLA and be dissolved in second cyanogen, then add the magnetic fluid in 1mL step a, the obtained PLA second cyanogen solution containing magnetic fluid;
C), get 0.06mg DSPE-PEG-carboxyl, 0.24mg soybean lecithin, be added in the ethanol water of 3ml, heating is stirred to 55 DEG C to 70 DEG C, the obtained mixed ethanol aqueous solution;
D), by PLA second cyanogen dropwise obtained in 1ml step b add in the obtained mixed ethanol aqueous solution of 3ml step c, under the condition of uniform temperature, stirring 1 is little of 3 hours continuously, and period allows solvent evaporates, the PLA-phosphatide-PEG nano particle obtained;
E), by DSPE-PEG-COOH, EDC, NHS in molar ratio 1:1:2 after room temperature reaction a period of time, add folic acid, obtain folate ligand;
F), hand over the folate ligand obtained in PLA-phosphatide-PEG nano particle obtained in steps d and step e to be cross-linked, ultrafiltration washes three times, i.e. this product obtained.Detect with DelsaTMNanoC sedimentograph, average grain diameter is between 50-300nm.
When in above-mentioned step a, constant pressure funnel slowly drips ammoniacal liquor, in temperature 25
ounder C condition, mechanical vigorous stirring is to pH10.
After at room temperature stirring 30min again in above-mentioned step a, be warming up to 60
oc, reaction 30min, cooling.
PLA concentration in above-mentioned step b in PLA second cyanogen solution is 2mg/mL.
In above-mentioned step c, the concentration of ethanol water is 4%, and heating is stirred to 65
oc.
Temperature conditions in above-mentioned steps d is 65 DEG C, and continuous mixing time is 2 hours.
In above-mentioned step e, DSPE-PEG-COOH, EDC, NHS are after room temperature reaction 15min, add folic acid.
In above-mentioned step f, the mol ratio of PLA-phosphatide-PEG nano particle and folate ligand is 1:1.
The Validation in vitro of folacin receptor cancer target effect
The MCF-7 cell of folacin receptor process LAN is inoculated in blake bottle, treats that Growth of Cells is to exponential phase, discards culture medium, wash 2-3 time with PBS buffer solution, with trypsinization liquid digestion cell dispersion, collected by centrifugation number reaches 10
4the all cells of individual/mL is placed in centrifuge tube.Adding 100 μ L superparamagnetism fat-PLA folate-targeted nanoparticulate dispersion joins in cell suspending liquid, and hatch 30min altogether for 37 DEG C, centrifuge tube is placed in magnetic separator and carries out Magneto separate, isolated cell number reaches 91% of initial incremental amount.And the low compared with control cells A549 of folacin receptor expression is through same operation, isolated cell quantity is only 10% of initial incremental amount.The tumour cell of visible superparamagnetism fat-PLA folate-targeted nano particle specific isolation folacin receptor process LAN.
Claims (8)
1. a preparation method for superparamagnetism fat-PLA targeted nano particle, is characterized in that: described targeted nano particle is cross-linked by PLA-phosphatide-PEG nano particle and folate ligand and forms; Described PLA-phosphatide-PEG nano particle wraps up Fe by PLA
3o
4the center that is in as PLA kernel, and is around in this PLA core surface with phosphatide with single layer of rings, and is interspersed in described individual layer phosphatide using PEG-DSPE-carboxylic acid and is formed as target shell; Described folate ligand is cross-linked to form with folic acid by after certain mol proportion room temperature reaction by DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS; The preparation method of superparamagnetism fat-PLA targeted nano particle comprises the following steps:
A), in four neck flasks, 30mL deionized water is first added, logical N
210min, takes 6.7573gFeCl fast
36H
2o and 3.4753gFeSO
47H
2o, joins in reaction bulb, stirring and dissolving, slowly drips ammoniacal liquor by constant pressure funnel, and in temperature 20
oc to 30
ounder C condition, mechanical vigorous stirring, to pH9 ~ pH11, drip ammoniacal liquor 24mL altogether, solution colour gradually becomes black by rufous, then after at room temperature stirring 25min to 35min, is warming up to 55
oc to 65
oc, reaction 25min to 35min, cooling, is separated with magnet, outwells supernatant, and wash three times with each 70mL of deionized water, and disperse with ultrasonic wave, then wash three times with each 70mL of ethanol, finally add 45mL Tetramethylammonium hydroxide and dissolve, then add redistilled water to 250mL, filter with sand core funnel thus obtain magnetic fluid;
B), get PLA and be dissolved in second cyanogen, then add the magnetic fluid in 1mL step a, the obtained PLA second cyanogen solution containing magnetic fluid;
C), get 0.06mg DSPE-PEG-carboxyl, 0.24mg soybean lecithin, be added in the ethanol water of 3ml, heating is stirred to 55 DEG C to 70 DEG C, the obtained mixed ethanol aqueous solution;
D), by PLA second cyanogen dropwise obtained in 1ml step b add in the obtained mixed ethanol aqueous solution of 3ml step c, under the condition of uniform temperature, stirring 1 is little of 3 hours continuously, and period allows solvent evaporates, the PLA-phosphatide-PEG nano particle obtained;
E), by DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS in molar ratio 1:1:2 after room temperature reaction a period of time, add folic acid, obtain folate ligand;
F), hand over the folate ligand obtained in PLA-phosphatide-PEG nano particle obtained in steps d and step e to be cross-linked, ultrafiltration washes three times, i.e. this product obtained.
2. the preparation method of a kind of superparamagnetism fat-PLA targeted nano particle according to claim 1, is characterized in that: when in described step a, constant pressure funnel slowly drips ammoniacal liquor, in temperature 25
ounder C condition, mechanical vigorous stirring is to pH10.
3. the preparation method of a kind of superparamagnetism fat-PLA targeted nano particle according to claim 1, is characterized in that: after at room temperature stirring 30min again in described step a, be warming up to 60
oc, reaction 30min, cooling.
4. the preparation method of a kind of superparamagnetism fat-PLA targeted nano particle according to claim 1, is characterized in that: the PLA concentration in described step b in PLA second cyanogen solution is 2mg/mL.
5. the preparation method of a kind of superparamagnetism fat-PLA targeted nano particle according to claim 1, is characterized in that: in described step c, the concentration of ethanol water is 4%, and heating is stirred to 65
oc.
6. the preparation method of a kind of superparamagnetism fat-PLA targeted nano particle according to claim 1, it is characterized in that: the temperature conditions in described steps d is 65 DEG C, continuous mixing time is 2 hours.
7. the preparation method of a kind of superparamagnetism fat-PLA targeted nano particle according to claim 1; it is characterized in that: in described step e, DSPE-PEG-carboxyl, 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimides and HOSu NHS are after room temperature reaction 15min, add folic acid.
8. the preparation method of a kind of superparamagnetism fat-PLA targeted nano particle according to claim 1, is characterized in that: in described step f, the mol ratio of PLA-phosphatide-PEG nano particle and folate ligand is 1:1.
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| CN112717844B (en) * | 2020-12-10 | 2021-07-23 | 南京紫金山分子医学技术研究院有限公司 | Magnetic nano material for extracellular vesicle enrichment, preparation method and application thereof, and extracellular vesicle enrichment material |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010048623A8 (en) * | 2008-10-26 | 2010-08-19 | Board Of Regents, The University Of Texas Systems | Medical and imaging nanoclusters |
| CN102145177A (en) * | 2011-04-13 | 2011-08-10 | 南方医科大学 | Method for preparing folate molecular targeted magnetic nanometer medicine carrier and targeting gene medicine |
| CN103040724A (en) * | 2012-12-22 | 2013-04-17 | 中国科学院深圳先进技术研究院 | Nano drug delivery system containing polymer and phospholipid and preparation method thereof |
| CN103126990A (en) * | 2011-11-23 | 2013-06-05 | 苏州苏大赛尔免疫生物技术有限公司 | Preparation method of targeting magnetic drug loaded liposome |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010048623A8 (en) * | 2008-10-26 | 2010-08-19 | Board Of Regents, The University Of Texas Systems | Medical and imaging nanoclusters |
| CN102145177A (en) * | 2011-04-13 | 2011-08-10 | 南方医科大学 | Method for preparing folate molecular targeted magnetic nanometer medicine carrier and targeting gene medicine |
| CN103126990A (en) * | 2011-11-23 | 2013-06-05 | 苏州苏大赛尔免疫生物技术有限公司 | Preparation method of targeting magnetic drug loaded liposome |
| CN103040724A (en) * | 2012-12-22 | 2013-04-17 | 中国科学院深圳先进技术研究院 | Nano drug delivery system containing polymer and phospholipid and preparation method thereof |
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