CN102688494A - Preparation method of protein drug-carrying magnetic composite nano-material and application thereof - Google Patents
Preparation method of protein drug-carrying magnetic composite nano-material and application thereof Download PDFInfo
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- CN102688494A CN102688494A CN201110070298XA CN201110070298A CN102688494A CN 102688494 A CN102688494 A CN 102688494A CN 201110070298X A CN201110070298X A CN 201110070298XA CN 201110070298 A CN201110070298 A CN 201110070298A CN 102688494 A CN102688494 A CN 102688494A
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Abstract
The invention discloses a preparation method of a protein drug-carrying magnetic composite nano-material and application thereof. The method comprises: adding a surface oleophilic magnetic nanoparticle and a water-soluble protein drug into a methylene chloride solution of a polylactic acid/glycolic acid copolymer (PLGA), conducting mixing and carrying out ultrasonic emulsification at a temperature of 0 DEG C to obtain a preliminary emulsion and then mixing the preliminary emulsion with 1% polyolefin ethanol, carrying out ultrasonic emulsification at a temperature of 0 DEG C to obtain a double emulsion, finally under the stabilizing effect of the polyolefin ethanol, performing evaporation to remove the methylene chloride, performing centrifugation at a temperature of 4DEG C to collect the obtained protein drug-carrying magnetic composite nano-material. Experiments prove that, an interleukin-2 carrying magnetic composite nano-material prepared by the method of the invention can make the drug concentrate in a tumor area under the effect of a magnetic field in vitro, and the interleukin-2 can be released slowly over a period of time and activate T cells, NK cells and other immune cells, and further killing tumor cells.
Description
Technical field
The invention belongs to the controlled preparation and the applied technical field of nano material, particularly prepare the technology that composite magnetic nano material bag carries cytokine with supersound method, and the purposes of this composite magnetic nano material.
Background technology
Magnetic Nano material has huge application potential because of having ferromagnetism and low cytotoxicity on biomedicine, all be widely used like the aspects such as delivery, immune detection and nuclear magnetic resonance at purification, medicine or the gene of albumen or cell.It has the advantage that integrates targeted therapy, imaging, low cytotoxicity etc.Inorganic material exists good dispersion, size and pattern to be prone to the advantages on controllability such as control and homogeneity are good; Organic material has that toxicity is little, degradable in vivo and be easy to the advantage on application such as multifunction, therefore combines both strong point to make up new multifunction magnetic material and will remedy mutual deficiency and expand their application on biomedicine.
Tumor is the principal disease that threatens human health, and at present main treatment means still is limited to operation, radiotherapy and chemotherapy.Along with modern molecular biology, molecular genetics and immunologic developing rapidly, people are to immune mechanism of action, tumor antigen and related gene thereof, the body GVT, and tumor escape mechanism etc. has had more deep understanding.People can discern immune system and killing tumor cells is firmly believe, and have done the trial of many application immunization therapy tumors, have obtained some challenging results, and wherein cytokine therapy is an important component part in this field.The cytokine of treatment tumor commonly used clinically comprises interferon (IFN), interleukin (IL), tumor necrosis factor (TNF), granulocyte-macrophage colony stimutaing factor (GM-CSF).Wherein interleukin-2 (IL-2) is called the T cell growth factor again, is to regulate one of topmost lymphokine of body's immunity.It can promote T, B cell activation, propagation and differentiation, can also activation NK cell and monokaryon-macrophage, and the cytotoxicity of enhanced NK cell killing tumor.Heavy dose of IL-2 induces the NK cell after the activation to be called the LAK cell, thereby produces cytotoxicity.As far back as IL-2 or just begin to be applied to clinical with the LAK cell Combined application eighties in 20th century, especially effect is obviously in the transitivity renal carcinoma.After CD8+T cell, CD4+T cell, monokaryon-macrophage receive the continuous action of IL-2; Its antigen presentation ability, sterilizing power, cytotoxicity all obviously strengthen; The ability of secreting some cytokine is also strengthened, and uses IL-2 treatment tumor to obtain certain curative effect.But these cytokines that are used to treat are the half-life weak point in vivo; Need heavy dose of repeatedly administration, systematicness is used these protide cytokine medicines and is usually caused serious toxic and side effects, and for example IL-2 can cause general symptom such as heating, vomiting; Can cause also that water and salt metabolic disturbance and dysfunctions such as kidney, liver, the heart, lung; The most common, the most serious is the blood capillary leak syndrome, makes the patient have to end treatment, has limited the extensive use of cytokine IL-2.For alleviating the toxic and side effects of IL-2, changing systemic administration is local application, has played certain effect, but targeting is not enough.Nanotechnology is applied to the slow release of medicine and has opened up new approach; Explore a kind of nano material that integrates multiple function; Get final product slow release; But targeting again, the toxic and side effects of bringing greatly because of consumption in the time of can overcoming present cytokine therapy tumor, thus make cytokine effectively bring into play the treatment function of tumor.
Summary of the invention
The objective of the invention is to the unification in the present nano material application; The method of multi-functional year protein medicaments (cytokine) magnetic composite nano material of a kind of preparation is provided, and prepared drug loaded magnetic composite nano materials can integrate magnetic targeting, slow controlled release and protein medicaments treatment.
The objective of the invention is to the problem that exists in the present oncotherapy; Therapeutic efficiency as producing because of targeting is bad is low, toxic and side effects is big; Propose a kind of preparation and carried protein medicaments magnetic composite nano preparation methods; What obtain carries protein medicaments magnetic composite nano material and can improve targeting and therapeutic efficiency through magnetic target, reduces poisonous side effect of medicine through slow controlled release properties, thereby realizes the treatment of efficient, the low toxicity of tumor.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
A kind of year protein medicaments magnetic composite nano preparation methods comprises the steps:
1) Fe of preparation coated with oleic acid
3O
4Magnetic nanoparticle, perhaps surperficial lipophilic γ-Fe
2O
3, FePt, MgFe
2O
4, MnFe
2O
4Or CoFe
2O
4Magnetic nanoparticle;
2) water-soluble solution of preparation protein medicaments;
3) dichloromethane solution of preparation polylactic acid/ethanol copolymer (PLGA), wherein the concentration of PLGA is 5～200mg/ml;
4) magnetic nanoparticle with the step 1) preparation joins in the PLGA dichloromethane solution of step 3) preparation mixing;
5) the liquid mixing that the water-soluble solution and the step 4) of protein medicaments is made, and 0 ℃ of following ultrasonic emulsification;
6) 1% polyene ethanol (PVA) of 1-3 times of volume of adding in the emulsion of step 5) gained; 0 ℃ of following ultrasonic emulsification; Again the gained emulsion slowly is added among a large amount of 0.1%PVA with stable emulsion; With being placed on the room temperature vibration with volatilization dichloromethane, last 4 ℃ of centrifugal collection drug loaded magnetic composite nano materials.
Above-mentioned steps 1) size (particle diameter) of the magnetic nanoparticle of preparation is preferably 2～20nm, and what said magnetic nanoparticle the most often used is to utilize the synthetic Fe of coprecipitation method
3O
4Magnetic Nano material.Pass through Fe
3+And Fe
2+Coprecipitation method obtains Fe
3O
4Granule is hydrophilic, in order realizing and the mutual fusion of PLGA, need the magnetic particle surface to be carried out modification and make its oleophylic, through oleic acid the particulate surface of magnetic is coated and has realized the particulate lipophile of magnetic.
Above-mentioned steps 2) protein medicaments is water miscible described in, cytokine normally, interleukin-2 for example, the preferred 100-200 μ of its concentration g/ml.
Above-mentioned steps 3) dichloromethane solution of the polylactic acid/ethanol copolymer (PLGA) of preparation, PLGA concentration is preferably 15～150mg/ml.
Above-mentioned steps 5) final concentration of magnetic nanoparticle is preferably 0.01～10mg/ml in the mixed liquor that forms, more preferably 0.05～5mg/ml; The final concentration of pharmaceutical grade protein is preferably 10-20 μ g/ml.
Above-mentioned steps 5) utilize supersound method that water soluble drug and fat-soluble solution are mixed, the process of ultrasonic emulsification can use the cell breakage appearance of band probe under the situation of power 50-100W, ultrasonic 0.5～1min under the condition of ice bath;
Above-mentioned steps 6) adopt the ultrasonic emulsification method to realize carrying the preparation of protein medicaments magnetic Nano material; Employed PVA is a high molecular weight water soluble polymer; Stronger cementability is arranged, and the dispersion film property is arranged, be used to strengthen the parcel of PLGA water-solubility protein class medicine.The emulsion (note is made colostrum) of step 5) preparation mixes the process of back ultrasonic emulsification and can use the cell breakage appearance of being with probe under the situation of power 100W with 1%PVA; Ultrasonic 0.5～2min under the condition of ice bath; Obtain emulsion; Wherein the volume ratio of colostrum and 1%PVA is preferably 1: (1-3), and more preferably 1: 2.Emulsion is slowly added among the 0.1%PVA, the volume ratio of emulsion and 0.1%PVA is preferably 1 again: (30-40), and more preferably 3: 100.Then solution is placed the room temperature shaken overnight, the volatilization dichloromethane, 9000-12000rpm low-temperature centrifugation 5～20min collects the multifunction magnetic composite nano materials that has carried protein medicaments again.
The present invention has prepared the multifunction magnetic composite nano materials through supersound method, contains magnetic nanoparticle, PLGA and protein medicaments (like cytokine interleukin plain-2) in this nano material.Resulting multi-functional nanometer material monodispersity is better, and granular size differs in size to several microns from tens nanometers, and particle size distribution is at 200nm-2 μ m, and mean diameter is that 697.6 ± 0.51nm is (referring to Fig. 1, Fig. 2).This multifunction magnetic composite nano materials has good magnetic; Can there be better controlled to discharge to medicine; In the PBS of pH7.4, can continue to discharge IL-2; It is about 10% that first Tiantu is released rate, and burst size is more constant after 5 days, discharges about 13.59% (referring to Fig. 3) altogether in 15 days.
Its magnetic intensity of multifunction magnetic composite that the present invention obtains can be regulated through adding the particulate concentration of magnetic, under the effect of externally-applied magnetic field, can realize the location of this Nano medication is controlled.Magnetic Nano material generally is through Fe
3+And Fe
2+Coprecipitation method obtains Fe
3O
4Granule is hydrophilic, in order realizing and the mutual fusion of PLGA, need the magnetic particle surface to be carried out modification and make its oleophylic, through oleic acid the particulate surface of magnetic is coated and has realized the particulate lipophile of magnetic.
The envelop rate of nano material output, distribution of sizes and protein medicaments that the present invention obtains and the consumption of carrying drug ratio and PLGA have important relation.In order to realize the effective coating of PLGA, need suitable PLGA consumption to magnetic granule and protein medicaments.Along with the increase of PLGA amount, envelop rate can improve.And in order to improve carrying drug ratio, PLGA and protein medicaments need a suitable ratio.Because PLGA to the parcel of protein medicaments, makes medicine to obtain discharging through interchain slit or the Degradation of PLGA, thereby can effectively control the concentration of protein medicaments, reduce intravital toxic and side effects.
In some embodiments of the invention; Said multifunction magnetic composite coats mice recombinant il-2 (through the cytokine of gene engineering method synthetic); What obtain carries IL-2 magnetic composite nano material, can prolong the half-life of IL-2, reduces the frequency of heavy dose of administration repeatedly; Under the effect of external magnetic field, can reach targeting, reduce IL-2 systemic toxic side effect.Experiment showed, year IL-2 magnetic composite nano material that the present invention obtains, kept the BA of its cytokine IL-2, promote lymphopoiesis, thereby realize the antitumor immunity of organism effect.
Description of drawings
Fig. 1 is the grain-size graph that carries the IL-2 magnetic nano particle of embodiment 1 preparation.
Fig. 2 is two sem photographs that carry the IL-2 magnetic nano particle of embodiment 1 preparation.
Fig. 3 is year elution profiles figure of IL-2 magnetic nano particle in pH7.4PBS solution of embodiment 1 preparation.
Fig. 4 has shown that the IL-2 that carries IL-2 magnetic nano particle parcel of embodiment 1 preparation is in the lymphopoietic effect of stimulated in vitro T.
Fig. 5 has shown a year IL-2 magnetic nano particle (PLGA/IL-2/Fe
3O
4) be injected to the tumor-bearing mice tumor area, under the external magnetic field effect, the IL-2 of parcel attracts big amount lymphocyte to surround in vivo and soaks into to tumor area (A), and does not add under the situation in magnetic field no lymphocytic infiltration (B) in the tumor area.
Fig. 6 has shown that a year IL-2 magnetic nano particle is injected to the tumor-bearing mice tumor area, and ferrum dyeing sees that under the external magnetic field effect ferrum granule is enriched in tumor area (A), and does not add magnetic field group iron-free particle deposition (B).
The specific embodiment
Through embodiment the present invention is described in further detail below, but the scope that does not limit the present invention in any way.
Embodiment 1PLGA/IL-2/Fe
3O
4The magnetic composite nano material is at stimulated in vitro T lymphopoiesis
One, the supersound method preparation integrates the multifunction magnetic composite nano materials of magnetic, slow release and IL-2.
1) 10 μ g IL-2 is prepared into interior water with 100 μ l dissolved in distilled water;
2) PLGA that gets about 118mg is dissolved in the 1ml dichloromethane, with an amount of Fe
3O
4Magnetic-particle mix oil phase;
3) pour oil phase into interior aqueous phase, 50～100W supersound process 30s gets colostrum under the ice bath;
4) colostrum is added among the 2ml 1%PVA, 100W supersound process 30s gets emulsion under ice bath;
5) emulsion is slowly added among the 100ml 0.1%PVA, put on the constant temperature magnetic force agitator and stir, room temperature is placed on the shaking table and is spent the night, and lets its its residual organic solvents of volatilization; At last with emulsion centrifugal 15min (12000r/min, 4 ℃) on refrigerated centrifuge, with distilled water wash 3 times, supernatant is collected its envelop rate to be measured, is precipitated as medicine carrying microballoons, with an amount of sterilized water ultra-sonic dispersion, puts into 4 ℃ of aseptic preservations.
The prepared IL-2 magnetic composite nano material that carries (is expressed as PLGA/IL-2/Fe
3O
4) particle size distribution figure as shown in Figure 1, sem photograph is as shown in Figure 2.Can find out that from Fig. 1 and Fig. 2 the granular size of carrying IL-2 magnetic composite nano material differs in size to several microns from tens nanometers, particle size distribution is at 200nm-2 μ m, and mean diameter is 697.6 ± 0.51nm.
Fig. 3 is PLGA/IL-2/Fe
3O
4Elution profiles figure in the PBS of pH7.4, PLGA/IL-2/Fe
3O
4Granule can continue to discharge IL-2, and it is about 10% that first Tiantu is released rate, and burst size is more constant after 5 days, discharges about 13.59% altogether in 15 days.
Two, PLGA/IL-2/Fe
3O
4The magnetic composite nano material is at stimulated in vitro T lymphopoiesis
Get the spleen of BALB/C mice, shred, sieve is got cell, and Fecol is centrifugal, collects mononuclearcell, and external 1640 training bases are cultivated, and after the grouping, add the PLGA/IL-2/Fe of above-mentioned preparation
3O
4Magnetic composite nano material or simple IL-2 in 24,42, got cell respectively in 72 hours, detected cell number with mtt assay, the result: PLGA/IL-2/Fe
3O
4Magnetic composite nano material and simple IL-2 all have the lymphopoietic effect of obvious stimulation, but PLGA/IL-2/Fe
3O
4The magnetic composite nano material effects is lower than simple IL-2 slightly, because the former has the effect (see figure 4) of slow release.
Embodiment 2PLGA/IL-2/Fe
3O
4The magnetic composite nano material stimulates the T lymphopoiesis in vivo
Get the PLGA/IL-2/Fe of embodiment 1 preparation
3O
4The magnetic composite nano material is tested as follows, observes PLGA/IL-2/Fe
3O
4The magnetic composite nano grain stimulates the T lymphopoiesis in vivo, and assembles lymphocyte in tumor area, has strengthened it and has attacked the effect of tumor.
BALB/C mice subcutaneous vaccination S180 sarcoma cell 5 * 10
4, it is big to treat that tumor is grown to Semen phaseoli radiati, reaches tumor week injection PLGA/IL-2/Fe in the tumor
3O
4The magnetic composite nano material, wherein IL-2 is 20,000 units, and one group adds external magnetic field and is fixed on the tumor after the administration, and magnetic force is 4.0tesla, totally 24 hours.A matched group administration does not add magnetic field, and other establishes not administration group (normal saline injection), merely to the IL-2 group and only to PLGA/Fe
3O
4Group is observed the tumor growth situation after the administration, dead mouse or extremely alive after 20 days is got tumor and liver,spleen,kidney internal organs, carries out pathological observation.PLGA/IL-2/Fe as a result
3O
4After the magnetic composite nano grain was injected into mouse tumor, under the external magnetic field effect, lymphocyte surrounded and soaks into to tumor area; Show that IL-2 concentrates in tumor area, IL-2 discharges the short lymphopoiesis in back, thereby strengthens the killing tumor cells effect; Time spent; IL-2 discharges, and causes spleen to increase, and is 1.5 times of (see figure 5)s of matched group.
Embodiment 3PLGA/IL-2/Fe
3O
4The magnetic composite nano material is under the effect of external magnetic field, and medicine is enriched in tumor area
Get the PLGA/IL-2/Fe of embodiment 1 preparation
3O
4The magnetic composite nano material is tested as follows, can see under the effect of external magnetic field PLGA/IL-2/Fe
3O
4The magnetic composite nano grain is enriched in tumor area.
BALB/C mice subcutaneous vaccination S180 sarcoma cell 5 * 10
4, it is big to treat that tumor is grown to Semen phaseoli radiati, reaches tumor week injection PLGA/IL-2/Fe in the tumor
3O
4The magnetic composite nano material, wherein IL-2 is 20,000 units, and one group adds external magnetic field and is fixed on the tumor after the administration, and magnetic force is 4.0tesla, totally 24 hours.A matched group administration does not add magnetic field, and other establishes not administration group (normal saline injection), merely to the IL-2 group and only to PLGA/Fe
3O
4Group is observed the tumor growth situation after the administration, dead mouse or extremely alive after 25 days is got tumor and liver,spleen,kidney internal organs, carries out the dyeing of pathology and ferrum and observes.Result: PLGA/IL-2/Fe
3O
4After the magnetic composite nano grain is injected into mouse tumor, medicine is concentrated in tumor area, ferrum dyeing sees that the ferrum granule is enriched in tumor area, and does not add the PLGA/IL-2/Fe in magnetic field
3O
4Group and PLGA/Fe
3O
4Organize equal iron-free particle deposition (see figure 6).
Though description has been done detailed description through generality explanation and specific embodiments to the present invention, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, modification of being made or improvement without departing from theon the basis of the spirit of the present invention all belongs to the scope of protection of present invention.
Claims (10)
1. one kind carries protein medicaments magnetic composite nano preparation methods, comprises the steps:
1) Fe of preparation coated with oleic acid
3O
4Magnetic nanoparticle, perhaps surperficial lipophilic γ-Fe
2O
3, FePt, MgFe
2O
4, MnFe
2O
4Or CoFe
2O
4Magnetic nanoparticle;
2) water-soluble solution of preparation protein medicaments;
3) dichloromethane solution of polylactic acid/ethanol copolymer of preparation 5～200mg/ml;
4) magnetic nanoparticle of step 1) preparation is joined in the dichloromethane solution of polylactic acid/ethanol copolymer of step 3) preparation mixing;
5) the liquid mixing that the water-soluble solution and the step 4) of protein medicaments is made, and 0 ℃ of following ultrasonic emulsification;
6) 1% polyene ethanol of 1-3 times of volume of adding in the emulsion of step 5) gained; 0 ℃ of following ultrasonic emulsification; Again the gained emulsion slowly is added in a large amount of 0.1% polyene ethanol with stable emulsion; With being placed on the room temperature vibration with volatilization dichloromethane, last 4 ℃ of centrifugal collection drug loaded magnetic composite nano materials.
2. method for preparing as claimed in claim 1 is characterized in that, the particle diameter of the magnetic nanoparticle of step 1) preparation is 2～20nm.
3. method for preparing as claimed in claim 1 is characterized in that step 2) said protein medicaments is cytokine.
4. method for preparing as claimed in claim 3 is characterized in that step 2) said protein medicaments is interleukin-2, its solution concentration is 100-200 μ g/ml.
5. method for preparing as claimed in claim 1 is characterized in that, the dichloromethane solution concentration of the polylactic acid/ethanol copolymer of step 3) preparation is 15～150mg/ml.
6. method for preparing as claimed in claim 1 is characterized in that, the concentration of magnetic nanoparticle is 0.01～10mg/ml in the mixed liquor that step 5) forms, and the concentration of protein medicaments is 10-20 μ g/ml.
7. method for preparing as claimed in claim 1 is characterized in that the ultrasonic emulsification of step 5) and step 6) is carried out under condition of ice bath, ultrasonic time is 0.5～2min.
8. method for preparing as claimed in claim 1 is characterized in that, in step 6), the used alcoholic acid volume of 0.1% polyene of stable emulsion is 20～40 times of emulsion volume.
9. year protein medicaments magnetic composite nano material for preparing according to the arbitrary described method for preparing of claim 1～8.
10. said year protein medicaments magnetic composite nano of claim 9 material is used in the medicine of preparation treatment tumor.
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| CN103601900A (en) * | 2013-11-15 | 2014-02-26 | 无锡中科光远生物材料有限公司 | Preparation method of nano particle with targeting effect |
| CN113521033A (en) * | 2021-08-03 | 2021-10-22 | 西北大学 | PHA magnetic nanoparticles containing protein shells as well as preparation method and application thereof |
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Application publication date: 20120926 |