CN110201179A - A kind of preparation method of the ferric oxide nano particles for the chondroitin sulfate modification that can be distributed in intracerebral space between cells - Google Patents
A kind of preparation method of the ferric oxide nano particles for the chondroitin sulfate modification that can be distributed in intracerebral space between cells Download PDFInfo
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Abstract
The invention discloses the preparation methods that one kind can be distributed in the ferric oxide nano particles of the chondroitin sulfate modification in intracerebral space between cells.Because some special applications of field of biomedicine require ferric oxide nano particles that can be distributed near cell membrane, therefore chondroitin sulfate is modified using physical method and is injected in rat brain behind ferric oxide nano particles surface by the present invention, belong to the function and feature of extracellular matrix using chondroitin sulfate, suitable electrophoresis granularity and zeta current potential in addition, so that modified the ferric oxide nano particles of chondroitin sulfate seldom by intracerebral cell endocytic, and most of it is filled in space between cells in dispersed.
Description
Technical field
The present invention relates to the modification of nano material biology, especially a kind of sulfuric acid that can be distributed in intracerebral space between cells is soft
The preparation method of the ferric oxide nano particles of ossein modification, belongs to Bio-Nano-Materials and application field.
Background technique
Superparamagnetic Iron Oxide nanoparticle (SPIONs) is applied to magnetic resonance imaging with its unusual magnetic property at present
(MRI), target administration, gene delivery, cell marking and separation, organizational project etc..It is modified by surface magnetic oxygenated
Fe nanometer particles, water-soluble, biocompatibility are greatly improved, and extend its circulation time in vivo.By
Surface-functionalized magnetic ferric oxide nano particles can be used as imaging diagnosis contrast medium and pharmaceutical carrier simultaneously, and can be used as
Special targeted system is adhered near cell membrane or cell membrane, or is adhered on tissue barrier.These are distributed in cell membrane
Neighbouring ferric oxide nano particles can be in external magnetic field through fever or disturbance, and the cell opened on intracerebral cell membrane is logical
Road makes cell generate a series of physiological reaction, realizes diagnoses and treatment integration for the Clinics and Practices of lesion tissue
Personalized medicine.Medicament transport and drug can be monitored in real time simultaneously in the distribution situation of target spot and normal organ, monitor medicine
Object metabolic alterations carry out evaluating drug effect.Clinics and Practices are realized to individuation simultaneously to patient, are concerned in recent years, this
It is also a trend of future individualized medical treatment development.
Chondroitin sulfate (Chondroitin sulfate, CS) is a kind of mixing acid mucopolysaccharide, is distributed widely in animal
The extracellular matrix and cell surface of tissue, the sugar chain of the polysaccharide by alternate glucuronic acid and N- acetylgalactosamine (again
Claim N- acetylamino galactosamine) disaccharide unit composition, the serine residue of core protein is connected to like sugared link zone by one
On.The polysaccharide macro-molecular structure mainly by D-Glucose aldehydic acid and N- acetyl group-D-Gal with 1,3- glycosidic bond in conjunction with
Disaccharide be polymerized for basic unit, containing about 50~70 disaccharide basic units greatly, relative molecular mass be 10000~
50000Da.Chondroitin sulfate is white powder, and multiple hydroxyls, sulfate and carboxyl are contained in molecule, soluble easily in water, it and sodium,
The salt that potassium, calcium binding generate has thermal stability, and heated 80 DEG C will not be destroyed, in an acidic solution facile hydrolysis Cheng Dan
Sugared or lesser polysaccharide body.
Black substance is a big core of midbrain, between ventral tegmental area and cerebral peduncle.Dopamine mind abundant in black substance
Animal behavior can be influenced by the dopamine of release through member, the dopaminergic neuron of damage will lead to the hair of Parkinson disease
It is raw.By ferric oxide nano particles surface modification chondroitin sulfate, and it is injected into black substance position, modifies chondroitin sulfate
Ferric oxide nano particles be distributed in space between cells in black substance, i.e., near cell membrane.It is expected to through magnetic fields in these distributions
Ferric oxide nano particles near cell membrane open the ion channel on cell membrane, influence the secretion of dopaminergic neuron,
And then treat Parkinson disease.
Summary of the invention
The purpose of the present invention is first will be using the ferric oxide nano particles of PEG, PEI modification of high temperature thermal decomposition method synthesis
PEG-PEI-SPIONs, then use physical method modification with chondroitin sulfate C S.The CS-SPIONs of best modification amount is injected separately into
To after rat substantia nigra position, it is distributed by the eucaryotic cell structure that fixed embedding, ultramicrotomy observe particle under the tem.It can
See that the PEG/PEI-SPIONs only a few for having modified CS by endocytosis, is largely filled in space between cells, and it is existing not occur to reunite
As.
Specific steps are as follows:
(1) ferric oxide nano particles (PEG/PEI-SPIONs) that synthesis PEI/PEG first is modified.Weigh 15g PEG and
0.3 g PEI is in three-necked flask, 280 DEG C of reflux 1h in the atmosphere of argon gas.Product is successively cleaned three times with toluene and acetone,
And remaining toluene acetone is cleaned with column magnetic separator, gained sample dispersion arrives PEG/PEI-SPIONs in deionized water.
(2) 10~40mg CS is mixed with the PEG/PEI-SPIONs aqueous dispersions that 20ml concentration is 1mg/ml respectively,
Temperature is 4 DEG C, reacts 5h in the shaking table that revolving speed is 60r/min.Sample after reaction is placed in 4 DEG C of refrigerator overnights, and then sample exists
120h is dialysed in bag filter to get CS-SPIONs is arrived, sample is stored in 4 DEG C of refrigerators.
(3) the healthy adult SD rat of weight about 220~250g is taken, 10% chloral hydrate anesthesia (3.5ml/ is injected intraperitoneally
Kg weight).Then experimental rat head is fixed on micromanipulation instrument.Rat head operative region unhairing, just along head
Middle incision scalp forms notch.Subcutaneous tissue is separated, keeps notch with haemostatic clamp, exposure skull finds bregma and posterior.Use hand
Art knife and operating scissors slowly on mechanically decoupled skull tissue until skull surface, removes broken tissue with deionized water, makes front and back fontanel
Sufficiently exposure.Adjustment rat stereotaxic instrument is in bregma and posterior in same horizontal line, and records corresponding coordinate.Reference
Paxinos map determines left sub antia nigra coordinate.According to syringe needle point pointed location on executor, with scalpel on skull
It marks and cranial drill is used carefully to drill (aperture about 2mm) on skull, it is careful to remove cranium and meninx.With 25 μ l it is micro into
It is 2 μ g/ μ l samples that sample device (0.57 mm internal diameter), which extracts 5 μ l concentration, (sample uses membrane filtration in advance).Microsyringe is fixed on
On micro executor, left sub antia nigra position is slowly injected a sample into.Injection finishes that let the acupuncture needle remain at a certain point 5min, the slow withdraw of the needle, to prevent nanometer
Particle dispersion overflows and is conducive to sample diffusion.Haemostatic clamp is removed, is sewed up the incision skin with surgical thread, penicillin smears notch
Prevention infection.It is marked to rat, puts in animal house and raise after reviving.The CS-SPIONs of best modification amount is infused respectively
Enter to after rat substantia nigra position, is distributed using the eucaryotic cell structure that fixed embedding, ultramicrotomy observe particle under the tem.
Using Malvern laser particle analyzer, PL-GPC 50, FTIR, SQUID, TEM, XPS, XRD and TGA to the sample of preparation
Product are characterized.Using distribution of transmission electron microscope (TEM) observation CS-SPIONs in Nigral Tissue on subcellular scale.
It is had the following beneficial effects: using technical solution of the present invention
Using high temperature thermal decomposition method by Fe (acac)3As source of iron, solvent and modifier when PEG, PEI are as synthesis,
It prepares uniform particle diameter, the PEG-PEI-SPIONs that surface zeta potential current potential (in physiological buffer) is positive, is easy to pass through electrostatic
Effect is in conjunction with CS.To CS physical modification SPIONs, CS and SPIONs ratio is between 1:2~2:1, and physical method grafting amount is more
More, performance is also more stable.For water-soluble good SPIONs, the chemical group of hydrogen bond is easily formed containing S, N etc., simply
Physical mixed method formed hydrogen bond modified it is most simple and effective.
With the raising of CS concentration, modification rate is increase accordingly.Experimental result shows, when CS concentration reach a certain range (and
Nanoparticle similar mass ratio) when, even if being further added by the concentration of CS, modification rate is also improved seldom.In view of the efficiency ratio of experiment,
Under the premise of guaranteeing that modification rate is met the requirements, the modification amount for as making to react required as possible is less, combined reaction condition, CS reaction
After concentration, modification rate meet the requirements (40%, i.e. nanoparticle surface modified 8 an or so functional molecular), it can choose
The mass ratio of CS and SPIONs is between 1:2~2:1, preferably using 1:1 as best modification ratio needed for reaction.
After the CS-SPIONs of best modification amount is injected separately into rat substantia nigra position, using fixed embedding, ultra-thin cut
Chip technology observes the eucaryotic cell structure distribution of particle under the tem.The PEG/PEI-SPIONs of CS has been modified seldom by endocytosis, major part
It is filled in space between cells, and agglomeration does not occur.CS is mainly distributed on extracellular matrix and cell table in animal tissue
Cytoskeleton support is used as in face, and the nanoparticle after modifying CS utilizes the function and feature of this extracellular matrix of CS, in addition
The electrophoresis granularity of CS-SPIONs is greater than 25nm, and zeta current potential is the advantage of negative value, and most of CS-SPIONs is allowed to be filled in two
In the intermembrane space of cell.The result can be advantageously applied to the application field for the treatment of Parkinson's disease, pass through the liter of externally-applied magnetic field
Temperature effect increases temperature or the disturbance of after birth to stimulate the channel TRPV1 to open, promotes the secretion of dopamine, improves Parkinson's disease
Etc. symptoms.
Detailed description of the invention
Fig. 1 is that 20mg CS is mixed with respectively with 20ml concentration for the PEG/PEI-SPIONs aqueous dispersions of 1mg/ml
CS-SPIONs schemes after injecting rat substantia nigra in the TEM of intracerebral subcellular proteomics.
Fig. 2 is that 40mg CS is mixed with respectively with 20ml concentration for the PEG/PEI-SPIONs aqueous dispersions of 1mg/ml
CS-SPIONs, inject rat substantia nigra after intracerebral subcellular proteomics TEM scheme.
Fig. 3 is to scheme after PEG/PEI-SPIONs to be injected to rat substantia nigra in the TEM of intracerebral subcellular proteomics.
Specific embodiment
In order to which the present invention is more clearly understood, with reference to embodiments, the present invention will be described in further detail.This
Place is described, and specific examples are only used to explain the present invention, is not intended to limit the present invention.
Embodiment 1:
(1) ferric oxide nano particles (PEG/PEI-SPIONs) of synthesis PEI/PEG modification.Weigh 15g PEG and 0.3g
PEI is in three-necked flask, 280 DEG C of reflux 1h in the atmosphere of argon gas.Product is successively cleaned three times with toluene and acetone, is used in combination
Column magnetic separator cleans remaining toluene acetone, and gained sample dispersion arrives PEG/PEI-SPIONs in deionized water. PEG-
The average grain diameter of PEI-SPIONs is 9.25 ± 0.36nm.
(2) 20mg CS is mixed with the PEG/PEI-SPIONs aqueous dispersions that 20ml concentration is 1mg/ml respectively, in temperature
It is 4 DEG C, reacts 5h in the shaking table that revolving speed is 60r/min.Sample after reaction is placed in 4 DEG C of refrigerator overnights, and then sample is being dialysed
Bag in dialysis 120h to get arrive CS-SPIONs, the electrophoresis granularity of CS-SPIONs in water be 30.9nm, zeta current potential be-
15.3mV.Thermogravimetric analysis shows that modification amount of the CS on SPIONs is 37.0wt%
(3) the healthy adult SD rat of weight about 220~250g is taken, 10% chloral hydrate anesthesia (3.5ml/ is injected intraperitoneally
Kg weight).Then experimental rat head is fixed on micromanipulation instrument.Rat head operative region unhairing, just along head
Middle incision scalp forms notch.Subcutaneous tissue is separated, keeps notch with haemostatic clamp, exposure skull finds bregma and posterior.Use hand
Art knife and operating scissors slowly on mechanically decoupled skull tissue until skull surface, removes broken tissue with deionized water, makes front and back fontanel
Sufficiently exposure.Adjustment rat stereotaxic instrument is in bregma and posterior in same horizontal line, and records corresponding coordinate.Reference
Paxinos map determines left sub antia nigra coordinate.According to syringe needle point pointed location on executor, with scalpel on skull
It marks and cranial drill is used carefully to drill (aperture about 2mm) on skull, it is careful to remove cranium and meninx.With 25 μ l it is micro into
Sample device (0.57 mm internal diameter) extracts the CS-SPIONs sample that 5 μ l concentration are 2mg/ml (sample uses membrane filtration in advance).It is micro
Sample injector is fixed on micro executor, slowly injects a sample into left sub antia nigra position.Injection finishes that let the acupuncture needle remain at a certain point 5min, is slowly moved back
Needle overflows to prevent nanoparticle dispersion liquid and is conducive to sample diffusion.Haemostatic clamp is removed, is sewed up the incision skin with surgical thread, it is green
Mycin smears notch prevention infection.It is marked to rat, puts in animal house and raise after reviving.
It is about 1mm that rat substantia nigra site tissue, which is cut into volume,3The particulate samples of size are put into EP pipe, the penta 2 of 3% are added
4 DEG C of aldehyde solution overnight, are outwelled 3% glutaraldehyde solution, embathe sample repeatedly three times with 0.1M, the PBS of pH 7.0, removing remains in
Glutaraldehyde in tissue, each 15min, this process are preceding fixation；Sample is fixed in the case where being protected from light with 1% osmic acid solution
1~2h, this process are fixed after being known as；The osmic acid solution for outwelling 1% embathes sample three times with 0.1M, the PBS of pH 7.0 repeatedly,
Each 15min, in this way can be to avoid reacting between fixer and dehydrating agent.Sample successively use 50%, 70%, 80%, 90% with
And 100% ethanol solution is dehydrated sample step by step, every kind of concentration handles 10~15min of time, then with volume ratio is 1:1
Ethyl alcohol and acetone treatment sample 30min, finally use acetone treatment sample 20min；With the mixed liquor (volume of embedding medium and acetone
Than handling sample 1h (37 DEG C) for 1:1)；Sample 3h (37 DEG C) are handled with the mixed liquor (volume ratio 3:1) of embedding medium and acetone；
Final sample embedding medium at 37 DEG C is impregnated with overnight；Sample is neatly put into receiving hole one end of embedding plate, is poured slowly into embedding
Agent is put into air dry oven.Programming setting acid extraction (37 DEG C of 12h, 45 DEG C of 12h, 60 DEG C of 48h) keeps sample poly-
Conjunction is fixed in the embedding medium of solidification.After obtaining sample embedding fastly, block is first repaired, using semithin section, last ultra-thin section is cut
Lower thickness is about 70nm thin slice.Thin slice is placed in the support grid (carbon support film) of 200 mesh using Special-purpose forceps.Contain sample sheet
Support grid spontaneously dry after, dye 7~9min with the uranium acetate prepared in advance, finally dye 2~3min with lead citrate,
Sample is placed under mercury lamp after drying again, is sliced with tem observation, the PEG/PEI-SPIONs only a few for having modified CS is interior
It gulps down, is largely filled in space between cells, and agglomeration (Fig. 1) does not occur.
Embodiment 2:
(1) ferric oxide nano particles (PEG/PEI-SPIONs) of synthesis PEI/PEG modification.Weigh 15g PEG and 0.3g
PEI is in three-necked flask, 280 DEG C of reflux 1h in the atmosphere of argon gas.Product is successively cleaned three times with toluene and acetone, is used in combination
Column magnetic separator cleans remaining toluene acetone, and gained sample dispersion arrives PEG/PEI-SPIONs in deionized water. PEG-
The average grain diameter of PEI-SPIONs is 9.25 ± 0.36nm.
(2) 40mg CS is mixed with the PEG/PEI-SPIONs aqueous dispersions that 20ml concentration is 1mg/ml respectively, in temperature
It is 4 DEG C, reacts 5h in the shaking table that revolving speed is 60r/min.Sample after reaction is placed in 4 DEG C of refrigerator overnights, and then sample is being dialysed
Bag in dialysis 120h to get arrive CS-SPIONs, the electrophoresis granularity of CS-SPIONs in water be 28.1nm, zeta current potential be-
23.6mV.Thermogravimetric analysis shows that modification amount of the CS on SPIONs is 41.3wt%
Other zooperies and tissue sample making step and characterization are the same as embodiment 1, the CS- for being 2mg/ml by 5 μ l concentration
SPIONs sample is injected into after rat substantia nigra position, observes the thin of particle under the tem using fixed embedding, ultramicrotomy
Born of the same parents' structure distribution.The PEG/PEI-SPIONs only a few for having modified CS is largely filled in space between cells by endocytosis, and is not sent out
It is raw to reunite (Fig. 2).
Embodiment 3 (comparative example):
(1) ferric oxide nano particles (PEG/PEI-SPIONs) of synthesis PEI/PEG modification.Weigh 15g PEG and 0.3g
PEI is in three-necked flask, 280 DEG C of reflux 1h in the atmosphere of argon gas.Product is successively cleaned three times with toluene and acetone, is used in combination
Column magnetic separator cleans remaining toluene acetone, and gained sample dispersion arrives PEG/PEI-SPIONs in deionized water. PEG-
The average grain diameter of PEI-SPIONs is 9.25 ± 0.36nm.
5 μ l concentration are 2mg/ml's with embodiment 1 by other zooperies and tissue sample making step and characterization
PEG/PEI-SPIONs sample is injected into after rat substantia nigra position, is observed under the tem using fixed embedding, ultramicrotomy
The eucaryotic cell structure of particle is distributed.PEG/PEI-SPIONs is mostly phagocytized by cells in intracerebral, is distributed in reunion state intracellular
On myelin or mitochondria, but seldom it is distributed in space between cells or cell membrane nearby (Fig. 3).
Claims (2)
1. the preparation side that one kind can be distributed in the ferric oxide nano particles of chondroitin sulfate (CS) modification in intracerebral space between cells
Method, it is characterised in that specific steps are as follows:
(1) 15g polyethylene glycol PEG and 0.3g polyethyleneimine PEI is weighed in three-necked flask, in 280 DEG C in argon atmosphere
Flow back 1h, and product is successively cleaned three times with toluene and acetone, and cleans remaining toluene acetone, gained sample dispersion with column magnetic separator
To get the ferric oxide nano particles PEG/PEI- modified jointly to polyethyleneimine and polyethylene glycol in deionized water
SPIONs；
(2) by 10~40mg CS respectively with 20ml concentration be 1mg/ml the step of (1) synthesis PEG/PEI-SPIONs moisture
The weight ratio of dispersion liquid mixing, i.e. CS and PEG/PEI-SPIONs are 4 DEG C in temperature between 1:2 to 2:1, revolving speed 60r/min
Shaking table in react 5h, the sample after reaction is placed in 4 DEG C, 12h, and then sample dialyses 120h in bag filter to get to CS-
SPIONs, sample are stored in 4 DEG C；
(3) the CS-SPIONs sample that 5 μ l concentration are 2mg/ml is extracted with 25 μ l microsyringes (0.57mm internal diameter), in rat
Under stereotaxic instrument auxiliary, SD rats with left black substance position, rat substantia nigra portion are slowly injected a sample into using microsyringe
Distribution of the transmission electron microscope observing ferric oxide nano particles in brain tissue, CS- are used in bit organization sampling after fixation, embedding, slice
SPIONs is largely filled in space between cells, and agglomeration does not occur；
Polyethylene glycol in the step (1) is cetomacrogol 1000, polyethylene glycol 2000, Macrogol 3000 and polyethylene glycol
One of 4000, polyethyleneimine is polyethyleneimine 600, polyethyleneimine 1800, polyethyleneimine 3000 and polyethylene
One of imines 4000.
2. preparation method according to claim 1, which is characterized in that CS-SPIONs obtained in the step (2),
Electrophoresis granularity is between 30~50nm, and zeta current potential is in -10~-40mV, and CS modification amount is in 15wt%~45wt%.
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| CN112717955A (en) * | 2020-12-31 | 2021-04-30 | 武汉理工大学 | Preparation method and application of surface sulfur modified iron oxide nanodisk |
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