CN1679965A - Spleen target directional DNA delivering system - Google Patents
Spleen target directional DNA delivering system Download PDFInfo
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- CN1679965A CN1679965A CN 200510023134 CN200510023134A CN1679965A CN 1679965 A CN1679965 A CN 1679965A CN 200510023134 CN200510023134 CN 200510023134 CN 200510023134 A CN200510023134 A CN 200510023134A CN 1679965 A CN1679965 A CN 1679965A
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Abstract
A spleen-targeting DNA transfer system able to be transferred to spleen by intravenous injection is the nanoparticles prepared from DNA vaccine and one or more high-molecular nanoparticle with a specific hydrophilic material on its surface.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to the nano-drug preparation field, be specifically related to the spleen targeted delivery systems of a kind of DNA of containing, but plasmid DNA is sent in promptly a kind of intravenous injection, at the nanoparticle drug-supplying system of spleen enrichment.
Background technology
Spleen is the peripheral lymphoid organs of whole body maximum, it is the main place of removing blood-borne pathogens and inducing cell and humoral immunization, abundant B, T cell and macrophage, dendritic cell, plasma cell etc. are arranged, with directed spleen and the splenocyte of importing of vaccine, to induce stronger immunoreation, and produce a large amount of effector lymphocytes such as K, NK, CTL cell etc. and various cytokine and antibody.Spleen might become one of main effects organ of immunity inoculation.In amynologic basis research, there is report that multiple vaccination ways inducing specific CTL such as direct injection in the intramuscular injection of naked nucleic acid vaccine, subcutaneous injection and the spleen are replied, find that the CTL when direct injection can induce apparently higher than intramuscular injection and subcutaneous vaccination in the spleen replys level (Vaccine, 1998,16 (2～3): 208～215).Think in view of the above APC is rich in the importing of nucleic acid vaccine targeting
3With the spleen of cytokine, what may help more that CTL replys induces.Discover that the direct injection nucleic acid vaccine has traumaticly in the spleen, and the nucleic acid vaccine that injects is very fast is degraded by enzyme.Still easily vaccine is not imported at present the method for spleen, but spleen target medicine delivery system can be delivered to the nucleic acid vaccine orientation spleen carries out immunity, help induce immune response, also can prevent nucleic acid vaccine degraded in vivo, reduce distribution and toxic and side effects at its hetero-organization.
After the nanoparticle intravenous injection of preparations such as general common high molecular materials such as polylactic acid, the acid of paracyanogen base acrylic acid alkyl, albumin, chitosan, at first by withered Fou Shi (Kupffer) picked-up that cell is held back of liver, and be difficult to be transported to other positions of whole body.But " stealth " of certain physicochemical characteristics of tool (stealth) can evade the picked-up of liver after the nanoparticle intravenous injection, gathering at spleen increases, and has significantly spleen targeting, can be used as carrier (the Pharm Res that bioactive molecule is delivered to spleen, 1999,16 (1): 37～41).Its mechanism is: reticuloendothelial system (reticulo-endothelial system, RES) machine as the macrophage phagocytic nanoparticle of liver spleen etc. causes relevant with opsonic action (opsonization), opsonin in blood plasma or the serum (opsonin) can be attached to dewatering nano grain surface as IgG, C3b etc., the macrophage surface is rich in the receptor of these materials, can discern them, and then they are engulfed in the lump together with nanoparticle.But one or more layers hydrophilic clothing film of invisible nano particle surface adsorption or covalent bond behind poloxamer, poloxamine, PEG etc., makes this opsonic action reduction, can reduce engulfing of macrophage greatly.Liver Kupffer cell reduces therefore and greatly to the picked-up of invisible nano particle, and holding back of spleen do not reduce, and has on the contrary significantly to raise.This is main relevant with the eliminating particle shape foreign body mechanism of spleen uniqueness.Spleen is to open and the upward closed microcirculqtory system of physiology on the anatomy, invisible nano particle can mechanically be filtered to red pulp by reticuloendothelial mesh structure and intercellular substance, and be removed the hydrophilic shell there, then by conditioning with engulf (Adv Drug DelRev, 1995 (16): 183～193).Spleen has substantial connection to the picked-up of invisible nano particle and size, the surface characteristic of nanoparticle.The particle diameter of the quiet notes of rat poloxamine-908 bag quilt is a 220nm pipe/polyhenylethylene nano grain after several hours, and most of " stealth " nanoparticle is carried by spleen and stays (Biochem Biophys Res Comm, 1991,177 (2): 861～866; Biochim Biophys Acta, 1993,1157:233～240).(J ControlRel, 1999,60 (1): such as Peracchia 121～128) with PEGization
14The polybutylcyanoacrylate of C labelling has been material preparation " stealth " nanoparticle of surface exposure PEG group, the radioactive concentration of mouse tail vein injection spleen tissue after 6 hours is more than 5 times of liver, has tangible spleen targeting.
Three phases has been experienced in the development of vaccine: first generation attenuation, inactivated vaccine have potential pathogenic; There is the immunoreation imperfection in second filial generation subunit vaccine; Abandoned its shortcoming and the dna vaccination that is called as third generation vaccine has the advantage in preceding two generations concurrently,, in the control of infectious disease and tumor, shown huge application potential though have only 10 years short history.But naked DNA vaccine degradation in vivo speed is exceedingly fast, and can not directed transfection antigen-presenting cell, has greatly limited the performance of its immunizing potency, generally imports with the subcutaneous and Intradermal of particle gun mediation at present and the intramuscular injection dna vaccination imports somatic cell.It is generally acknowledged that intravenous injection is unsuitable for doing the dna vaccination inoculation, mainly is because blood volume is relatively large, will be very fast diluted behind the DNA contact blood, and transfection efficiency is low; And DNA will be by the DNA enzymatic degradation in the serum, and bioavailability is very low.Yet the result shows the immanoprotection action that intravenous injection obtains and is only second to intramuscular injection, and reason is antigen presenting cell to the specific recognition of DNA and efficiently offers to remedy the low deficiency of transfection efficiency, still can provide special and immunoprotection efficiently.This expression intravenous injection approach still has the potential to be tapped.Spleen may have been brought into play important function in this process.If can overcome shortcoming diluted and degraded two aspects, by intravenous injection, the dna vaccination targeting is positioned spleen, might induce stronger immune response.Still there is not at present the method for direct inoculation spleen easily.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, provide a kind of DNA is delivered to the drug-supplying system of spleen, native system is " stealth " nanoparticle that contains dna vaccination, makes it behind the quiet notes to assemble in spleen, by endocytosis DNA is imported the spleen endoantigen and is delivery cell.
The present invention contains the spleen targeted delivery systems of DNA, forms nanoparticle by DNA and one or more macromolecular materials, the surface attachment hydrophilic high molecular material.
Spleen targeted nanometer drug delivery system of the present invention, contained DNA are plasmid DNA, especially dna vaccination.
The contained DNA of administration nano-drug administration system of the present invention presses mass ratio and calculates, and accounts for 0.01%～10% of nanoparticle gross weight, is preferably 0.1～1%.
Nanoparticle of the present invention, spleen targeting enrichment is relevant with size, and this particle diameter can be measured with general nanometer particle size analyzer such as laser particle analyzer or scanning electron microscope method.The particle size range of said spleen target directional DNA delivering system is 50～500nm, is preferably 100～400nm.
The specific hydrophilic material of nanoparticle surface attachment of the present invention can be evaded engulfing of macrophage in the organ or tissues such as liver spleen, is commonly referred to as " stealth " nanoparticle.Nanoparticle surface attachment hydrophilic high molecular material can be selected from Polyethylene Glycol, polyoxyethylene, polyoxyethylene propylene copolymer, and the hydrophilic parts molecular weight is decided on chain length, and general molecular weight is big more, and chain length is long more, and spleen targeting effect is good more.Molecular weight can be 400～30000, is preferably 2000～10000.
Spleen targeting drug delivery system of the present invention, the surface attachment hydrophilic high molecular material can be by selecting specific parent material preparation for use when preparing nanoparticle.One of parent material is Polyethylene Glycol and fat-soluble high molecular block copolymer, especially is selected from the Polyethylene Glycol Polyalkylcyanoacrylanano.Described Polyethylene Glycol Polyalkylcyanoacrylanano adopts literature method to make, this method generates the Polyethylene Glycol cyan-acetic ester by cyanoacetic acid and methoxy poly (ethylene glycol) reaction, cyanoacetic acid and carbochain are that the alcohol reaction of 4～37 (being preferably 12～22) generates alkyl cyanoacetates, and two kinds of intermediate generate the Polyethylene Glycol cyanoacrylate by the carbodiimide polymerization.The chain length of Polyethylene Glycol is adjusted by the methoxy poly (ethylene glycol) initiation material of selecting different molecular weight, and the molecular weight of general Polyethylene Glycol is 400～30000, is preferably 200～10000.The ratio of Polyethylene Glycol and alkyl is changed with fat-soluble very important keeping " stealth " in the Polyethylene Glycol Polyalkylcyanoacrylanano, and when the Polyethylene Glycol ratio was too many, the water solublity of macromolecular material own was too strong, is difficult to make nanoparticle; When the alkyl ratio was too high, though can improve fat-solublely, the difficulty when reducing preparation reduced the Polyethylene Glycol density on the nanoparticle surface of making simultaneously, and spleen targeting accumulation ability is reduced.Polyethylene Glycol and alkyl mol ratio are commonly used to be 2: 1～1: 8, is preferably 1: 1～1: 5.
Spleen targeting drug delivery system of the present invention, the parent material of surface attachment hydrophilic high molecular material can also be a Myrj 45, is commonly referred to as Myrij, the molecular weight of polyoxyethylene part is 400～10000, is preferably 2000～10000.When preparing this parent material is sneaked into preparation in other macromolecular materials such as polylactic acid, the Polyalkylcyanoacrylanano etc. with certain proportion by nanoparticle.
Spleen targeting drug delivery system of the present invention, the parent material of surface attachment hydrophilic high molecular material can also be a poloxalkol, be commonly referred to as poloxamer, the molecular weight of polyoxyethylene polyoxypropylene part is 1000～10000, is preferably 2000～10000.When preparing this parent material is sneaked into preparation in other macromolecular materials such as polylactic acid, the Polyalkylcyanoacrylanano etc. with certain proportion by nanoparticle.
The said plasmid DNA of the present invention, or dna vaccination can be by prior art for preparing, report and the disclosed technical scheme of patent as known references: Norman JA, Montgomery DL and Hartikka J (Norman JA, et al.Vaccine.1997,15:8:801-803; Montgomery DL, et al.DNA and CellBiology.1993,12:9:777-783; Hartikka J, et al.Human Gene Therapy.1996,7:1205-1217), and patent No. PCT WO97/28259, patent No. PCT WO98/52581, patent No. PCT WO98/06863, or " nucleic acid vaccine " (Sun Shuhan work) etc.
Description of drawings
Fig. 1 is a Polyethylene Glycol cetyl cyanoacrylate spleen targeting invisible nano particle in-vivo tissue scattergram.
Fig. 2 is an intravenous injection plasmid DNA copolymerization collection microphotograph,
Wherein, left figure is 2 hours results, and right figure is 4 hours results.
The specific embodiment
Embodiment 1: Polyethylene Glycol cetyl cyanoacrylate spleen target directional DNA nanoparticle
Smart methoxy poly (ethylene glycol) 2000 11g (5.5mmol) and the cyanoacetic acid 0.935g (11mmol) of claiming, placing volume is the three-necked bottle of 250ml, adds the 30ml dichloromethane, ultrasonicly makes its dissolving.Then under the condition of magnetic agitation, add 2.27g (11mmol) condensing agent carbodiimide, feed nitrogen a little, continuous stirring is 6 hours under the room temperature.Filter, filtering residue is given a baby a bath on the third day after its birth inferior with the 15ml dichloromethane, and merging filtrate is concentrated into filtrate decompression thick, solidifies under the room temperature, promptly gets the Polyethylene Glycol cyan-acetic ester.Get light yellow waxy solid.
Smart hexadecanol 1.33g (5.5mol) or the docosanol 1.85g (5.5mol) and cyanoacetic acid 0.935g (11mmol) of claiming, placing volume is the three-necked bottle of 250ml, adds the 30ml dichloromethane, ultrasonicly makes its dissolving.Then magnetic agitation condition under, add 2.27g (11mmol) condensing agent carbodiimide, feed nitrogen a little, continuous stirring is 6 hours under the room temperature.After adding the 25ml normal hexane, filter, filtering residue is given a baby a bath on the third day after its birth inferior with the 15ml dichloromethane, and merging filtrate is concentrated into filtrate decompression thick, solidifies under the room temperature, promptly gets cetyl or docosane ethyl-cyanacetic ester.Get Off-white solid.
Essence deserves to be called states synthetic Polyethylene Glycol cyan-acetic ester and cetyl cyan-acetic ester, respectively with 1: 1; 1: 2; 1: 3; 1: 4; Different rate of charges fed intake in 1: 5, and placing volume is the three-necked bottle of 250ml, added the mixed solution of ethanol and dichloromethane (1: 1), the ultra-sonic dispersion dissolving.Inject 37% (w/v) formalin (7.5mmol) and 33% (w/v) dimethylamine solution (7.5mmol), under the condition of logical nitrogen, reaction is 8 hours under the room temperature.Concentrating under reduced pressure washs in the concentrated solution impouring water, and the reuse dichloromethane extracts, isolate organic facies, add anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated into thick, places under the room temperature vacuum and solidifies, and promptly gets Polyethylene Glycol cetyl cyanoacrylate.
Get synthetic Polyethylene Glycol cetyl cyanoacrylate; be dissolved in the 10ml oxolane; GFP egfp grain DNA concentrated solution is scattered in above-mentioned tetrahydrochysene furan feeds in the solution; under 1000 rev/mins of churned mechanically conditions; inject the 50ml ultra-pure water, stir 2h under the room temperature, promptly get the nanoparticle suspension; in nanoparticle and 1: 5 ratio of freeze drying protectant mannitol with existing current techique lyophilization, the nanoparticle freeze-dried preparation.With commercially available Pico
The Green test kit is measured the content that carries DNA that wraps, and drug loading is between 0.1～1%.
Embodiment 2: Polyethylene Glycol docosyl cyanoacrylate spleen target directional DNA nanoparticle
Synthesizing of Polyethylene Glycol docosyl cyanoacrylate with Polyethylene Glycol cetyl cyanoacrylate among the embodiment 1.The main distinction is to replace hexadecanol with docosanol.
The preparation of nanoparticle replaces Polyethylene Glycol cetyl cyanoacrylate with method among the embodiment 1 with Polyethylene Glycol docosyl cyanoacrylate.
Embodiment 3: stealthy solid lipid nanoparticle spleen target directional DNA delivering system
High temperature evaporation-low-temperature setting method: get the hard ester acid of 0.1g, ultrasonic slight fever is dissolved in 5mL acetone, and GFP egfp grain DNA concentrated solution is scattered in this acetone soln, constitutes organic facies; Other gets 0.1g wheat pool 59 and is dissolved in the 30mL water and constitutes water; Organic facies is injected (75 ± 2) that 1000r/min stirs ℃ with the 6# syringe needle, stirs 3h, and organic facies is evaporated fully, and the about 20mL solution of gained is poured into rapidly in the 30mL water (ice-water bath) that another 1000rpm stirs, and stirs 1h, gets sodium stearate grain of rice colloidal suspension.Get stealthy solid lipid nanoparticle through the universal method lyophilization.
Embodiment 4: hepatitis B DNA vaccine spleen targeting Polyethylene Glycol cetyl alpha-cyanoacrylate ester nanoparticles delivery system
Press the method for embodiment 1.Substitute GFP egfp grain DNA with known hepatitis B DNA vaccine, make spleen targeting hepatitis B DNA vaccine nanoparticle delivery system in the same way.
Embodiment 5: hepatitis B DNA vaccine spleen targeting Polyethylene Glycol docosyl alpha-cyanoacrylate ester nanoparticles delivery system
Press the method for embodiment 2.Substitute GFP egfp grain DNA with known hepatitis B DNA vaccine, make spleen targeting hepatitis B DNA vaccine nanoparticle delivery system in the same way.
Embodiment 6: hepatitis B DNA vaccine spleen targeting solid lipid nanoparticle delivery system
Press the method for embodiment 3.Substitute GFP egfp grain DNA with known hepatitis B DNA vaccine, make spleen targeting hepatitis B DNA vaccine nanoparticle delivery system in the same way.
Embodiment 7: spleen targeting invisible nano particle spleen gathering and measuring
For the enrichment of checking spleen targeting invisible nano particle, with 3-at spleen
14To be initiation material have radioactive macromolecular material by the operating procedure among the embodiment 1 is synthetic to the cyanoacetic acid of C labelling, and make radiolabeled spleen targeted nano granule, behind the mouse tail vein injection, measure radioactivity in the tissues such as the heart, liver, spleen, lung, kidney with liquid sudden strain of a muscle method, to judge the spleen enrichment of spleen targeted nano granule.The result shows that the spleen targeted nano granule is significantly higher than in other tissue in the picked-up of spleen.
Embodiment 8: the expression in vivo of spleen target directional DNA invisible nano particle
With spleen targeting GFP egfp grain DNA nanoparticle mouse tail vein injection, promptly to get spleen ethanol behind the execution mice and fix, pathological section is observed down in Laser Scanning Confocal Microscope, and the result shows that after injection 2 hours, green fluorescent protein is great expression in spleen.
Claims (20)
1. a spleen target directional DNA delivering system contains DNA, it is characterized in that described delivery system forms nanoparticle by DNA and one or more macromolecular materials, its surface attachment hydrophilic high molecular material.
2. by the described spleen target directional DNA delivering system of claim 1, it is characterized in that the wherein contained DNA of described delivery system is 0.01%～10% of a nanoparticle gross weight.
3, by claim 1 or 2 described spleen target directional DNA delivering systems, it is characterized in that the wherein contained DNA of described delivery system is 0.1～1% of a nanoparticle gross weight.
4. by the described spleen target directional DNA delivering system of claim 1, it is characterized in that described nanoparticle particle diameter is 50～500nm.
5, by claim 1 or 4 described spleen target directional DNA delivering systems, it is characterized in that described nanoparticle particle diameter is 100～400nm.
6. by the described spleen target directional DNA delivering system of claim 1, it is characterized in that described nanoparticle surface attachment hydrophilic high molecular material is selected from Polyethylene Glycol, polyoxyethylene or polyoxyethylene propylene copolymer, molecular weight is 400～30000.
7, by the described spleen target directional DNA delivering system of claim 6, it is characterized in that described nanoparticle surface attachment hydrophilic high molecular material molecular weight is 2000～10000.
8. by the described spleen target directional DNA delivering system of claim 1, it is characterized in that described DNA is a plasmid DNA.
9. by the described spleen target directional DNA delivering system of claim 1, the parent material that it is characterized in that described its surface attachment hydrophilic high molecular material of spleen targeting drug delivery system is Polyethylene Glycol and fat-soluble high molecular block copolymer.
10, by the described spleen target directional DNA delivering system of claim 9, the parent material that it is characterized in that described its surface attachment hydrophilic high molecular material of spleen targeting drug delivery system is the Polyethylene Glycol Polyalkylcyanoacrylanano.
11. by the described spleen target directional DNA delivering system of claim 10, it is characterized in that described Polyethylene Glycol Polyalkylcyanoacrylanano wherein the molecular weight of Polyethylene Glycol be 400～30000.
12, by the described spleen target directional DNA delivering system of claim 10, it is characterized in that described Polyethylene Glycol Polyalkylcyanoacrylanano wherein the molecular weight of Polyethylene Glycol be 200～10000.
13. by the described spleen target directional DNA delivering system of claim 10, it is characterized in that in the described Polyethylene Glycol Polyalkylcyanoacrylanano that alkyl carbon chain is 4～37 in the acid of paracyanogen base acrylic acid alkyl.
14,, it is characterized in that in the described Polyethylene Glycol Polyalkylcyanoacrylanano that alkyl carbon chain is 12～22 in the acid of paracyanogen base acrylic acid alkyl by the described spleen target directional DNA delivering system of claim 10.
15,, it is characterized in that Polyethylene Glycol and alkyl mol ratio are 2: 1～1: 8 in the described Polyethylene Glycol Polyalkylcyanoacrylanano by the described spleen target directional DNA delivering system of claim 10.
16,, it is characterized in that Polyethylene Glycol and alkyl mol ratio are 1: 1～1: 5 in the described Polyethylene Glycol Polyalkylcyanoacrylanano by the described spleen target directional DNA delivering system of claim 10.
17. by the described spleen target directional DNA delivering system of claim 9, the parent material that it is characterized in that described surface attachment hydrophilic high molecular material can also be a Myrj 45, wherein the molecular weight of polyoxyethylene part is 400～10000.
18, by the described spleen target directional DNA delivering system of claim 9, it is characterized in that the parent material Myrj 45 of described surface attachment hydrophilic high molecular material, wherein the molecular weight of polyoxyethylene part is 2000～10000.
19. by the described spleen target directional DNA delivering system of claim 9, the parent material that it is characterized in that described surface attachment hydrophilic high molecular material can also be a poloxalkol, wherein the hydrophilic segment molecular weight is 1000～10000.
20, by the described spleen target directional DNA delivering system of claim 9, it is characterized in that the parent material poloxalkol of described surface attachment hydrophilic high molecular material, wherein the hydrophilic segment molecular weight is 2000～10000.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100358483C (en) * | 2005-12-28 | 2008-01-02 | 中国医学科学院生物医学工程研究所 | Implanting device carried with plasmid DNA nanometer particle and its prepn. method |
| CN114887071A (en) * | 2022-06-06 | 2022-08-12 | 郑州大学第一附属医院 | Spleen-targeting nano delivery carrier |
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2005
- 2005-01-05 CN CN 200510023134 patent/CN1679965A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100358483C (en) * | 2005-12-28 | 2008-01-02 | 中国医学科学院生物医学工程研究所 | Implanting device carried with plasmid DNA nanometer particle and its prepn. method |
| CN114887071A (en) * | 2022-06-06 | 2022-08-12 | 郑州大学第一附属医院 | Spleen-targeting nano delivery carrier |
| CN114887071B (en) * | 2022-06-06 | 2023-09-22 | 郑州大学第一附属医院 | Spleen-targeting nano delivery carrier |
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