CN105031665B - Pegylation melanin nano particle and preparation method thereof and purposes - Google Patents
Pegylation melanin nano particle and preparation method thereof and purposes Download PDFInfo
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- CN105031665B CN105031665B CN201510471038.1A CN201510471038A CN105031665B CN 105031665 B CN105031665 B CN 105031665B CN 201510471038 A CN201510471038 A CN 201510471038A CN 105031665 B CN105031665 B CN 105031665B
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Abstract
The invention belongs to pharmaceutical field, and in particular to Pegylation melanin nano particle and preparation method thereof and purposes.The preparation method comprises the following steps：(1) take melanin to be dissolved in the aqueous solution of alkali, stir the lower acid that adds and adjust to pH7.0, centrifuge, wash, freeze-drying, obtain water-soluble black element nano particle, it is standby；(2) the water-soluble black element nano particle is surface-treated with polyethylene glycol of the end containing amino.Pegylation melanin nano particle diameter prepared by the present invention is 1~10nm, and the favorable dispersibility in water equal solvent can be with Fe3+Chelating；ICR Experimental model of small mice results show that there is superpower iron excretion efficiency and good security, long half time to reach 23h, reduce administration number of times, extend dosing interval for it, improve the convenience of medication, can be as the medicine for preparing treatment iron overload disease.
Description
Technical field
The invention belongs to pharmaceutical field, and in particular to Pegylation melanin nano particle and preparation method thereof with
On the way.
Background technology
Iron overload disease, also known as hemochromatosis, be due to prolonged and repeated blood transfusion, thalassemia, marrow hemopoiesis it is active, rich in iron
The diseases caused by factor such as food intake is excessive, it can cause the dysfunction of histoorgan, even threat to life.Iron chelating agent
Or chalybeate is removed by mobilizing reservoir excessive iron is drained from urine or excrement, it can be used for treating iron overload disease.At present, it is existing
More than 100 kinds of iron chelating agent, clinically the most frequently used iron chelating agent is Deferoxamine.Deferoxamine and Fe3+Chelating is than being 1:1, to prescription
Formula is subcutaneous or intravenous injection, but due to half-life short inside Deferoxamine, needs frequent drug administration to can be only achieved therapeutic effect, and pair
Effect is more, is easily caused growth retardation, endocrine dysfunction and peripheral neuropathy etc..
Melanin is a kind of natural pigment, not only universally present in the skin of people and higher mammal, hair and eyeball
In tissue, and can also largely exist in the skin of some plants and insect.At present, studying more has squid ink black pigment
With calm and peaceful melanin of black-bone chicken etc., its good biocompatibility, non-toxic and safe.Squid ink black pigment has very strong cation chelating special
Property, mainly worked by anion such as such as carboxyls and deprotonated hydroxyl group, the combination of melanin and metal ion can play
Protect the function of cell.
But the melanin that nature obtains, although can with the metal ion-chelant such as iron ion, because it is not easy
Water is dissolved in, can not be as the medicine for the treatment of iron overload disease.Therefore, study that new chelation is relatively strong, Half-life in vivo
It is longer, the less iron chelating agent of toxic side effect is significant.
The content of the invention
Therefore, to be solved by this invention is that half-life period is shorter inside existing iron chelating agent, toxic side effect is larger
Technical problem, so as to propose a kind of preparation method of Pegylation melanin nano particle, and then propose above-mentioned preparation method
The Pegylation melanin nano particle and purposes being prepared.
In order to solve the above technical problems, the present invention is achieved through the following technical solutions：
The present invention provides a kind of preparation method of Pegylation melanin nano particle, comprises the following steps：
(1) take melanin to be dissolved in the aqueous solution of alkali, stir the lower acid that adds and adjust to pH7.0, centrifuge, wash, freeze-drying,
Water-soluble black element nano particle is obtained, it is standby；
(2) the water-soluble black element nano particle is surface-treated with polyethylene glycol of the end containing amino；
The alkali is selected from alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline-earth metal carbonic acid
Salt, alkali metal hydrogencarbonate, alkali metal bicarbonates, alkali metal acetate, alkali metal phosphate, alkali metal alcoholates, ammonia,
At least one of ammoniacal liquor, amine；
The acid is selected from least one of halogen acids, sulfuric acid, nitric acid, phosphoric acid, acetic acid.
It is in the preparation method of the above-mentioned Pegylation melanin nano particle of the present invention, the step of the surface treatment：
The aqueous solution of the water-soluble black element nano particle is taken, adds NH4OH solution is adjusted to pH9.0, adds pH=9
Polyethylene glycol of the end containing amino the aqueous solution, centrifuge, wash, freeze-drying, produce.
In the preparation method of the above-mentioned Pegylation melanin nano particle of the present invention, poly- second two of the end containing amino
Alcohol is NH2-PEG2000-NH2。
In the preparation method of the above-mentioned Pegylation melanin nano particle of the present invention, the alkali is sodium hydroxide, described
Acid is hydrochloric acid.
The present invention also provides a kind of Pegylation melanin nano particle being prepared using above-mentioned preparation method.
In the above-mentioned Pegylation melanin nano particle of the present invention, the grain of the Pegylation melanin nano particle
Footpath is 1~100nm.
In the above-mentioned Pegylation melanin nano particle of the present invention, the grain of the Pegylation melanin nano particle
Footpath is 1~10nm.
In the above-mentioned Pegylation melanin nano particle of the present invention, the Pegylation melanin nano particle is ball
Shape.
Purposes of the above-mentioned Pegylation melanin nano particle of the present invention in metal-chelator is prepared.
Purposes of the above-mentioned Pegylation melanin nano particle of the present invention in the medicine for preparing treatment iron overload disease.
The above-mentioned technical proposal of the present invention has advantages below compared with prior art：
The preparation method of Pegylation melanin nano particle of the present invention, by used in optimum choice surface treatment step
Polyethylene glycol specific species, prepare alkali and acid, the specific behaviour of each step used in water-soluble black element nano particle step
Make etc. so that the particle diameter of prepared Pegylation melanin nano particle is 1~10nm, and dispersiveness is good in water equal solvent
It is good, can be with Fe3+Chelating；ICR Experimental model of small mice results show that it has superpower iron excretion efficiency and good safety
Property, long half time reaches 23h, reduces administration number of times, extend dosing interval, improve the convenience of medication, can be used as and make
The medicine of standby treatment iron overload disease.
Brief description of the drawings
In order that present disclosure is more likely to be clearly understood, specific embodiment and combination below according to the present invention
Accompanying drawing, the present invention is further detailed explanation, wherein：
Fig. 1 (a) is to contain Fe in experimental example of the present invention3+Blood plasma in add melanin after plasma stability effect
Figure；
Fig. 1 (b) is to contain Fe in experimental example of the present invention3+Blood plasma in add Pegylation melanin nano particle after
Plasma stability design sketch；
Fig. 2 (a) is lung's figure of normal mouse in experimental example of the present invention；
Fig. 2 (b) is lung's figure of mouse after injection Pegylation melanin nano particle in experimental example of the present invention；
Fig. 2 (c) is lung's figure of mouse after injection melanin in experimental example of the present invention；
Fig. 3 is the mean plasma concentration time curve map (n of Pegylation melanin nano particle in experimental example of the present invention
=6)；
Fig. 4 is the changes of weight figure of each group mouse in experimental example of the present invention；
Fig. 5 is the urine excrement iron content ratio chart of each group mouse in experimental example of the present invention；
Fig. 6 is the tissues ratio chart of mouse in experimental example of the present invention；
In figure, PEGMN represents Pegylation melanin nano particle, and DFO represents Deferoxamine.
Embodiment
Embodiment 1
A kind of preparation method of Pegylation melanin nano particle of the present embodiment, comprises the following steps：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium hydroxides, stir lower addition 0.1mol/L
Hydrochloric acid is adjusted to pH7.0, is centrifuged with centrifugal filter (MWCO=30kDa), is washed, and freeze-drying, is obtained water-soluble black element and is received
Rice grain, it is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/
The aqueous solution of water-soluble black element nano particle described in mL, add 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9's
NH2-PEG2000-NH2The aqueous solution, stir 12h, with centrifugal filter (MWCO=30kDa) centrifuge, wash, freeze-drying, i.e.,
.
Embodiment 2
A kind of preparation method of Pegylation melanin nano particle of the present embodiment, comprises the following steps：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium carbonate, stir lower addition 0.1mol/L sulphur
Acid regulation is centrifuged with centrifugal filter (MWCO=30kDa), washed, freeze-drying, obtain water-soluble black element nanometer to pH7.0
Particle, it is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/
The aqueous solution of water-soluble black element nano particle described in mL, add 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9's
NH2-PEG2000-NH2The aqueous solution, stir 12h, with centrifugal filter (MWCO=30kDa) centrifuge, wash, freeze-drying, i.e.,
.
Embodiment 3
A kind of preparation method of Pegylation melanin nano particle of the present embodiment, comprises the following steps：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium acid carbonates, stir lower addition 0.1mol/L
Acetic acid is adjusted to pH7.0, is centrifuged with centrifugal filter (MWCO=30kDa), is washed, and freeze-drying, is obtained water-soluble black element and is received
Rice grain, it is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/
The aqueous solution of water-soluble black element nano particle described in mL, add 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9's
NH2-PEG2000-NH2The aqueous solution, stir 12h, with centrifugal filter (MWCO=30kDa) centrifuge, wash, freeze-drying, i.e.,
.
Embodiment 4
A kind of preparation method of Pegylation melanin nano particle of the present embodiment, comprises the following steps：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium phosphates, stir lower addition 0.1mol/L phosphorus
Acid regulation is centrifuged with centrifugal filter (MWCO=30kDa), washed, freeze-drying, obtain water-soluble black element nanometer to pH7.0
Particle, it is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/
The aqueous solution of water-soluble black element nano particle described in mL, add 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9's
NH2-PEG2000-NH2The aqueous solution, stir 12h, with centrifugal filter (MWCO=30kDa) centrifuge, wash, freeze-drying, i.e.,
.
Experimental example
1st, instrument and reagent
BH5300S types Atomic Absorption Spectrometer (Bohui Innovation Photoelectric Technology Co. Ltd., Beijing)；
Milli-Q Advantage A10 ultrapure water systems (U.S. Millipore)；
5415R type low temperature ultracentrifuge (German Eppendorf)；
Melanin (Sigma-Aldrich)；
Iron-dextrin (Sigma-Aldrich)；
FeCl3、HNO3It is that analysis is pure, and water is ultra-pure water；
ICR small white mouses (this experimental animal Co., Ltd of changzhou Cavan).
2nd, experimental method
2.1 plasma stabilities are tested
The blood plasma of two part of 200 μ L normal mouse is taken, adds a certain amount of FeCl3Make Fe in blood plasma3+Concentration be 100 μ
G/mL, being then respectively adding a certain amount of melanin and Pegylation melanin nano particle makes its concentration in blood plasma be
100 μ g/mL, shake, centrifugation.
2.2 biocompatibility experiment
ICR mouse 6 are taken, it is small that the μ L/20g of tail vein injection iron-dextrin (150mg/kg) 200 establish iron overload model
Mouse, it is divided into after one week two groups (N=3), respectively tail vein injection melanin and Pegylation melanin nano particle (100mg/
Kg) 200 μ L/20g, observation.
The measure of 2.3 half-life period
Take ICR mouse 6, tail vein injection89The melanin solution (200 μ L/20g) of Zr marks, makes dosage reach 25mg/
kg.Then the μ L of blood 20 are taken by docking in Each point in time (0.25,0.5,1,1.5,2.5,3.5,4,6,15,24 and 48h), with
The radioactive activity of gamma counter measure Each point in time calculates the blood concentration at each time point, with pharmacokinetics software
DAS2.0 analyzes pharmacokinetic parameters.
The excretion of 2.4 iron and the measure of tissues
50 ICR mouse are taken, wherein 40 are established by the μ L/20g of tail vein injection iron-dextrin (150mg/kg) 200
Iron overload model, four groups are only randomly divided into every group 10 after one week：Pegylation melanin nano particle low dose group, poly- second
Diolation melanin nano particle high dose group, Deferoxamine group and model group, 10 are only used as normal group in addition.
The disposable tail vein injection Pegylation melanin nanometer of Pegylation melanin nano particle low dose group
The μ L/20g of particle (35mg/kg) 200, the poly- second two of the Pegylation disposable tail vein injection of melanin nano particle high dose group
Refine melanin nano particle (100mg/kg) 200 μ L/20g；Deferoxamine group injects Deferoxamine (150mg/kg) 200 μ L/20g,
It is administered every other day totally 5 times, administration accumulated dose is 750mg/kg；Model group and normal group inject isometric physiological saline.
Record each group mouse weight daily, start within the 8th day to collect urine and excrement with metabolic cage；Posterior orbit blood sampling in 21 days,
Separation serum and blood plasma are stored in -20 DEG C, and dissection each group mouse is raw to collect each organ (heart, liver, spleen, lung, kidney, pancreas)
Normal saline washing is managed, weighs, is stored in 10% formalin.
The content of iron is determined with atomic absorption spectrography (AAS) in urine, excrement and each organ.Take each organ part
Weigh, then add 500 μ LPBS homogenate, be subsequently added into 800 μ L concentrated nitric acids on electric hot plate in 70 DEG C of resolutions.It is ultimately used to survey
HNO in fixed sample (5mL)3Concentration be 1%, HNO in iron standard liquid3Concentration also be 1%.
3rd, experimental result and analysis
3.1 plasma stability experimental results
Containing Fe3+Blood plasma in be separately added into after melanin and Pegylation melanin nano particle and shake centrifugation.
As shown in Fig. 1 (a), the plasma uniform of Pegylation melanin nano particle group is present；It is black as shown in Fig. 1 (b)
The blood plasma of pigment group produces precipitation.
3.2 biocompatibility experiment results
Fig. 2 (a) show the lung of normal mouse；Fig. 2 (b) is mouse after injection Pegylation melanin nano particle
Lung figure；Fig. 2 (c) show lung's figure of mouse after injection melanin.
Upon administration, melanin group mouse is dead at once for each group iron overload model mouse, Pegylation melanin nanometer
Particle group mouse is without exception.Melanin group mouse lung blackening is found after dissection, it may be possible to die due to embolism.
3.3 Drug-time curve and main pharmacokinetic parameters
Blood concentration-time curve is obtained according to the blood concentration of Each point in time, as shown in Figure 3.
Plasma drug concentration data is fitted with DAS2.0 programs, determines that it meets two compartment model in vivo, main medicine moves
It is as shown in table 1 to learn parameter.
From Fig. 3 and table 1, the elimination half-life period t of Pegylation melanin nano particle1/2βFor 23.803 ±
1.735h, far above the 5min of Deferoxamine.
The main pharmacokinetic parameters of the Pegylation melanin nano particle of table 1
Note：t1/2αRepresent for distribution half-life, t1/2βRepresent for eliminate half-life period.
The changes of weight of 3.4 each group mouse
The changes of weight of each group mouse is as shown in Figure 4.As a result show, the body weight of each group mouse before administration after 21 days in
There is the trend of growth, without significance difference (P between each group>0.05).
The urine excrement iron excretion of 3.5 mouse
Iron content in each group mouse urine and excrement is determined with atomic absorption spectrography (AAS), using model group as standard
(1.0) ratio of each group iron content is calculated, as a result as shown in Figure 5.As a result show, compared with model group, Deferoxamine and poly- second two
The urine excrement iron content of alcoholization melanin nano particle treatment group significantly improves, and Pegylation melanin nano particle high dose
Group urine excrement iron content is significantly higher than Deferoxamine group.
The iron content of 3.6 different tissues
The iron content of each tissue (heart, liver, spleen, lung, kidney, pancreas) of each group mouse is determined with atomic absorption spectrography (AAS),
The ratio of each group iron content is calculated using model group as standard (1.0), as a result as shown in Figure 6.
As a result show, compared to model group, the Iron In Tissue of Deferoxamine and Pegylation melanin nano particle treatment group
Content is remarkably decreased, and the iron content of Pegylation melanin nano particle high dose group is markedly inferior to Deferoxamine group.
4th, experiment conclusion
Pegylation melanin nano particle good biocompatibility, non-toxic and safe, its plasma half-life are up to 23h, phase
Than being significantly improved in the half-life period 5min of traditional medicine Deferoxamine.
Understand that Pegylation melanin nano particle can significantly reduce tissue with the experimental result of iron overload mouse model
Iron content and the notable rise for urinating excrement iron content, it is internal to illustrate that Pegylation melanin nano particle can be removed effectively
Iron.Compared with Deferoxamine needs frequent drug administration to can be only achieved therapeutic effect, (dosage is more than Pegylation melanin nano particle
The effect of 35mg/kg) only needing single administration to can reach better than Deferoxamine and without obvious toxic side effect, it can be used as and prepare
Treat the medicine of iron overload disease.
Obviously, above-described embodiment is only intended to clearly illustrate example, and is not the restriction to embodiment.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of change or
Change.There is no necessity and possibility to exhaust all the enbodiments.And the obvious change thus extended out or
Among changing still in the protection domain of the invention.
Claims (4)
1. purposes of the Pegylation melanin nano particle in the medicine for preparing treatment iron overload disease, the polyethylene glycol
Change melanin nano particle, which is prepared by the following method, to be formed：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium hydroxides, stir lower addition 0.1mol/L hydrochloric acid
Regulation is centrifuged with MWCO=30kDa centrifugal filter, washed, freeze-drying, obtain water-soluble black element nanometer to pH7.0
Grain, it is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/mL institutes
The aqueous solution of water-soluble black element nano particle is stated, adds 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9 NH2-
PEG2000-NH2The aqueous solution, stir 12h, centrifuged with MWCO=30kDa centrifugal filter, washed, freeze-drying, produced.
2. purposes of the Pegylation melanin nano particle in the medicine for preparing treatment iron overload disease, the polyethylene glycol
Change melanin nano particle, which is prepared by the following method, to be formed：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium carbonate, stir lower addition 0.1mol/L sulfuric acid and adjust
Save to pH7.0, centrifuged, washed with MWCO=30kDa centrifugal filter, freeze-drying, obtain water-soluble black element nano particle,
It is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/mL institutes
The aqueous solution of water-soluble black element nano particle is stated, adds 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9 NH2-
PEG2000-NH2The aqueous solution, stir 12h, centrifuged with MWCO=30kDa centrifugal filter, washed, freeze-drying, produced.
3. purposes of the Pegylation melanin nano particle in the medicine for preparing treatment iron overload disease, the polyethylene glycol
Change melanin nano particle, which is prepared by the following method, to be formed：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium acid carbonates, stir lower addition 0.1mol/L acetic acid
Regulation is centrifuged with MWCO=30kDa centrifugal filter, washed, freeze-drying, obtain water-soluble black element nanometer to pH7.0
Grain, it is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/mL institutes
The aqueous solution of water-soluble black element nano particle is stated, adds 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9 NH2-
PEG2000-NH2The aqueous solution, stir 12h, centrifuged with MWCO=30kDa centrifugal filter, washed, freeze-drying, produced.
4. purposes of the Pegylation melanin nano particle in the medicine for preparing treatment iron overload disease, the polyethylene glycol
Change melanin nano particle, which is prepared by the following method, to be formed：
(1) take 20mg melanin to be dissolved in the aqueous solution of 10mL 0.1mol/L sodium phosphates, stir lower addition 0.1mol/L phosphoric acid and adjust
Save to pH7.0, centrifuged, washed with MWCO=30kDa centrifugal filter, freeze-drying, obtain water-soluble black element nano particle,
It is standby；
(2) NH is used2-PEG2000-NH2The water-soluble black element nano particle is surface-treated, that is, takes 5mL1mg/mL institutes
The aqueous solution of water-soluble black element nano particle is stated, adds 28wt%NH4OH solution is adjusted to pH9.0, adds pH=9 NH2-
PEG2000-NH2The aqueous solution, stir 12h, centrifuged with MWCO=30kDa centrifugal filter, washed, freeze-drying, produced.
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| CN109329929A (en) * | 2018-10-29 | 2019-02-15 | 福建农林大学 | A method of preparing water-soluble Boletus aereus melanin |
| CN109370250A (en) * | 2018-10-29 | 2019-02-22 | 福建农林大学 | A method of preparing water-soluble Phellinus melanin |
| CN110898233B (en) * | 2019-12-12 | 2022-04-05 | 北京肿瘤医院(北京大学肿瘤医院) | Three-modal prostate cancer targeted nanoparticle imaging agent and preparation method thereof |
| CN116919886B (en) * | 2023-07-21 | 2024-01-30 | 中国海洋大学 | Injectable photo-thermal hydrogel based on black pigment, and preparation method and application thereof |
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| CN104017202A (en) * | 2009-10-23 | 2014-09-03 | 首尔大学校产学协力团 | Nano-sized melanin particles and method of producing same |
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| In vitro chelating, cytotoxicity, and blood compatibility of degradable poly(ethylene glycol)-based macromolecular iron chelators;Nicholas A.A. Rossi et al;《Biomaterials》;20081101;第30卷;第638–648页 * |
| Transferring Biomarker into Molecular Probe: Melanin Nanoparticle as a Naturally Active Platform for Multimodality Imaging;Quli Fan et al.;《J. Am. Chem. Soc.》;20141007;第136卷;第15185-15194页，尤其是第15187页右栏第2段，第15192页左栏第2-3段及图1 * |
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