CN101766824A - Mixed copolymer carrier system compound and preparation method thereof - Google Patents
Mixed copolymer carrier system compound and preparation method thereof Download PDFInfo
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- CN101766824A CN101766824A CN200810205366A CN200810205366A CN101766824A CN 101766824 A CN101766824 A CN 101766824A CN 200810205366 A CN200810205366 A CN 200810205366A CN 200810205366 A CN200810205366 A CN 200810205366A CN 101766824 A CN101766824 A CN 101766824A
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Abstract
The invention belongs to the field of biomedicine and provides a new non-viral gene drug carrier-mixed copolymer carrier system, wherein the invention adopts cation dendritic polymer modified by Pluronic, free Pluronic and plasmid DNA to prepare a mixed copolymer carrier system. The vitro assay shows that the copolymer carrier system is an efficient non-viral gene drug carrier, can effectively compress and pack the plasmid DNA, restrain the degradation of DNaseI to the plasmid, and prevent the disaggregation function of liquaemin and blood serum to MCS/DNA. As a new non-viral gene drug carrier, the invention has higher transfection efficiency of cells in vitro.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to cation dendrimer, dendritic polymer (Dendrimer) mixed copolymer carrier system compound of a kind of novel non-viral gene drug administration carrier-modify based on pluronic (Pluronic) and preparation method thereof.
Background technology
Gene therapy technology has become one of hot fields of biological medicine research at present both at home and abroad, and this technology key in application is a kind of safe, drug administration carrier of gene systems efficiently of needs.At present, drug administration carrier of gene mainly is divided into viral vector and non-virus carrier.Wherein, viral vector has very high transfection efficiency, and be a kind of drug administration carrier of gene that is most widely used clinically at present, but viral vector itself has very strong immunogenicity, has the potential danger of integrating with host cell, and lacking targeting, these shortcomings have had a strong impact on the clinical practice of this series products, as U.S.'s recombinant adenovirus " Jesse Gelsinger " incident in 1999 and the French retrovirus inducing leukemia malignant events that take place in 2000 etc.; Thereby the research of non-viral gene drug administration carrier in recent years receives much concern.
The disclosed non-viral gene drug administration carrier of prior art mainly contains cationic-liposome (Dalby B at present, Cates S, etal.Methods, 2004,33:95-103), cationic polymer (Boussif O et al.Proc Nat Acad SciUSA, 1995,92:7297-7301) and nanoparticle (Hu FQ, et al.Inter J Pharm., 2006,315:158-166.) etc.Wherein, cationic-liposome is to use the most a kind of at most non-viral gene drug administration carrier at present, mainly the two is formed by cationic phospholipid and neutral phospholipid DOPE for it, has higher transfection efficiency in vitro, but when having blood plasma to exist, transfection efficiency sharply reduces, and can not be used for intravital gene transfection, seriously limited its clinical practice, and this carrier toxicity is stronger; Cationic polymer is to study another more non-viral gene drug administration carrier at present, as polymine (Polyethylenimine, PEI), stub macromole (PAMAM) and polylysine (PLL) and other polycation protein such as protamine etc., such drug administration carrier of gene also has higher transfection efficiency in vitro, and can promote plasmid to endonuclear transhipment, can be used for intravital gene transfection, but exist toxicity stronger equally, and be easy to accumulative shortcoming; Nanoparticle can overcome the obstacle of tissue, has good cell picked-up effect, and in the plasmid DNA transfered cell can being starched, but transfection efficiency is lower.
In above-mentioned carrier material, dendrimer, dendritic polymer (Dendrimers) is a synthetic, hyperbranched polymer, the molecular structure with monodispersity and complete and homogeneous.The cation dendrimer, dendritic polymer is made up of centronucleus, internal layer repetitive and surperficial end group three parts, compares with the general linear macromole, is characterized in: 1) tactical rule, and highly symmetrical, molecular size and shape and structure can accurately be controlled at molecular level; When 2) algebraically is low is the planar structure configuration, increases with algebraically, and branch also increases, and is spherical three dimensional structure by the loose condition (of surface) transition, and intramolecule has a large amount of holes, and the functional group densities of molecular surface is then dense; 3) reactivity and containing ability are preferably arranged.Intramolecular void structure can hold small-molecule drug, and the functional group on surface then is convenient to further modification (Grayson SM, Fr é chet JM.Chem Rev.2001Dec; 101 (12): 3819-68.).Two dendrimer, dendritic polymers relevant with non-viral gene treatment carrier of suitability for industrialized production are polyamide-amide (polyamidoamine dendrimer at present, PAMAM) and polypropylene imines (poly (propylene imine) denazZdrimers, PPI), wherein the former has the commercialization reagent that is used for in-vitro transfection and sells (SuperFect, QiaGen company).(polyamidoamine dendrimer, PAMAM) in G3 generation when above, molecular structure is spherical to polyamide-amide wherein, better a large amount of active group of receiving surface.The PAMAM that studies show that G6 generation of J.P.Behr all has best transfection efficiency to attached cell and suspension cell, and the PAMAM of low algebraically also has higher transfection efficiency at N/P (6: 1) when higher, but transfection efficiency at this moment can be subjected to influence of serum; The result shows that also the transfection efficiency of PAMAM pair cell is not subjected to the influence of lysosome decomposition agent, think that PAMAM itself has the ability of escaping from lysosome, be that PAMAM itself has very strong proton sponge effect, help complex and flee from out (J.Haensler from lysosomal, F.C.Szoka Jr., Bioconjug.Chem.4 (1993) 372-379.).(poly (propylene imine) dendrimers of polypropylene imines wherein, PPI): Bernd H.Zinselmeyer shows that for the transfection test of PPI on A431 cell line the PPI (G2 and G3) of low algebraically has higher transfection efficiency to 1-5, the transfection efficiency of efficient and cation lipid carrier DOTAP is suitable, the PPI of high algebraically (G4 and G5) can not be used for transfection (Pharmaceutical Research separately because of having bigger cytotoxicity, Vol.19, No.7, July 2002:960-967).The amino of PPI molecular surface has not only reduced cytotoxicity, and has improved the transfection efficiency of inside and outside by after the salinization of iodomethane quaternary ammonium; Have the research in vivo test to show, PPI is as genophore, and the major organs that therapeutic gene is expressed is a liver, rather than cation lipid carrier expressed lungs (Andreas G.Schatzleina, Bernd H.Zinselmeye during as carrier; Journal of Controlled Release 101 (2005) 247-258).
Pluronic is a kind of macromolecule as the pharmaceutical preparation adjuvant that obtains the FDA approval.It is the triblock copolymer that polyoxyethylene (PEO)-polyoxypropylene (PPO)-polyoxyethylene (PEO) constitutes.When concentration when CMC is following, Pluronic exists with unimolecule in water, when concentration was higher than CMC, spontaneous gathering formed micellar structure, hydrophobic block PPO forms micellar kernel, hydrophilic block PEO is positioned at surface composition hydrophilic shell.This distinctive molecular structure makes Pluronic obtain using widely and studying.PPO hydrophobic block among the Pluronic and cell membrane interact, reduce the microviscosity of cell membrane, help allogenic material and enter into (THE JOURNAL OFPHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003,304 (2): 845-854) in the cell.Studies show that Pluronic and naked DNA are expelled in the tissues such as skeletal muscle, cardiac muscle and tumor together, can strengthen expression intensity and the persistent period of transgenic in these tissues; Nguyen is with Pluronic-PEI (2K) compression plasmid DNA, and in system, add free P123, and the result forms the particle of 100-160nm, and these particles are not assembled under the condition that serum exists, for independent PEI, the gene delivery effect of inside and outside all improves.And with the P123 in the hydrophilic Pluronic F127 replacement carrier system, transfection efficiency does not reduce.This polymer supported system is actually electroneutral, and the toxicity of inside and outside is all very little, and (Gene Therapy (2000) 7,126-138).
Summary of the invention
The purpose of this invention is to provide a kind of novel non-viral gene drug administration carrier-mixed copolymer carrier system, be specifically related to cation dendrimer, dendritic polymer (Dendrimer) mixed copolymer carrier system compound of a kind of non-viral gene drug administration carrier-modify based on pluronic (Pluronic) and preparation method thereof.
Cation dendrimer, dendritic polymer, free Pluronic and plasmid DNA co-production mixed copolymer carrier system that the present invention adopts Pluronic to modify as a kind of new non-viral gene drug carrier, have higher transfection efficiency of cells in vitro.
Particularly, the present invention modifies the cation dendrimer, dendritic polymer with Pluronic, prepare the mixed copolymer carrier system by coacervation, with GFP egfp grain (pEGFP-N2) and luciferase plasmid (pLuc-promotor) as reporter gene, a large amount of different high molecular transfection efficiency in vitro have been tested, especially investigate this carrier system to SPC-A1, CHO, the isocellular transfection efficiency of 293T, the result shows, it is less that Pluronic modifies PPI dendrimer, dendritic polymer toxicity, transfectional cell very efficiently is especially to SPC-A1, CHO, cells such as 293T have the higher transfection efficiency of ratio.
The present invention has synthesized the PPI cation dendrimer, dendritic polymer that a series of Pluronic modifies, and PluronicL61, P123 and F123 and PPI react respectively, obtains the Pluronic-PPI macromolecule of different modifying degree.
Pluronic in the described mixed copolymer carrier system mainly contains: P123, P85, P84, P103, P104, L61, L62, L64, L81 and L92 or any two or more mixture wherein.Preferred P123, P84, L64 or two or more mixture arbitrarily wherein.
Cation dendrimer, dendritic polymer Dendrimer in the described mixed copolymer carrier system mainly contains PPI (polypropylene imines), PAMAM (polyamide-amide) and PLL (polylysine).
Mixed copolymer carrier system compound of the present invention can prepare by coacervation.
The present invention combines the advantage of cation dendrimer, dendritic polymer and Pluronic, modifies the cation dendrimer, dendritic polymer as the non-viral gene drug administration carrier with Pluronic, brings into play two kinds of macromolecules advantage separately and mutual synergism.Pluronic wherein can increase flowability of cell membranes, being beneficial to carrier system enters in the kytoplasm, can reduce simultaneously the interaction of carrier system and plasma protein, protection pDNA is not subjected to nuclease degradation, prolong the time of carrier system in blood circulation, EPR (permeability strengthens and the is detained) effect of performance nano-carrier systematic treating tumor; Dendrimer, dendritic polymer compression, parcel plasmid DNA, enter lysosome after, its intensive proton sponge effect is beneficial to it and flees from out and avoid degraded.
Description of drawings
Figure l is a reversing tumor MDR mixed copolymer carrier system schematic diagram.
Fig. 2 is a mixed copolymer carrier system sketch map.
Fig. 3 is P123-2.5g-PPI at N/P than 5 and 10 o'clock, adds the influence of inequality P123 to the enzyme action protection.
Fig. 4 be P123-2.5g-PPI N/P than 10, add inequality P123 to the dissociated resistant function of serum.
Fig. 5 be P123-2.5g-PPI/P123 N/P than 10, add the dissociation of inequality P123 antagonism heparin sodium.
Fig. 6 is whether different N/P exists transfection SPC-A1 cell under the condition at serum than P123-2.5g-PPI/DNA a transfection efficiency.
Whether be P123-2.5g-PPI exist fluorescence pattern under the condition at N/P 20 and 30 o'clock serum to Fig. 7.
Whether be N/P exist the transfection efficiency of transfection SPC-A1 cell under the condition than 20 o'clock MCS to Fig. 8 at serum.
Fig. 9 is whether P123-2.5g-PPI exists transfection SPC-A1 under the condition at N/P10 and 20, serum a luciferin enzymatic activity.
Figure 10 is the influence of FBS to the transfection efficiency of P123-2.5g-PPI/3P123/DNA N/P20.
Figure 11 is the fluorescence pattern of P123-2.5g-PPI/3P123/DNA N/P20 transfection SPC-A1 cell under inequality FBS condition.
The specific embodiment
Further set forth the present invention below in conjunction with specific embodiment, should be understood that these embodiment only are used to the present invention is described and are not used in to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.
Embodiment 1 synthetic P123-PPI
Claim 2.0 gram Pluronic in the 50ml round-bottomed flask, spend the night in 50 ℃ of baking oven vacuum dryings, add the 20ml anhydrous acetonitrile, fully after the dissolving, under the condition of 40 ℃ of oil baths, magnetic agitation, slowly drip the equimolar CDI that is dissolved in the 10ml anhydrous acetonitrile, within 30min, dropwise, then in the conditioned response 10hr of 40 ℃ of oil baths, magnetic agitation.After reaction finishes, add isopyknic pure water in reaction system, dialyse then (dialysis medium 20% alcoholic solution, molecular cut off 3500) is to remove micromolecular imidazoles.After dialysis finished, the graft reaction of beginning and PPI reacted 48hr under the room temperature.The Pluronic of different model is because of the water solublity difference, so the graft reaction system is also different.
The result shows that the rate of charge of graft reaction obtains the PPI macromolecule of different modifying degree not simultaneously, as on average connecing 1 or 2 P123 molecules on the PPI molecule.
Embodiment 2 coacervations prepare the mixed copolymer carrier system
Preparation process is as follows:
(1) in 5 0.5ml EP pipes, each adds 135 μ l plasmid DNA (100 μ g/ml), adds pure water 160,156,148,124 and 87 μ l and 50mg/ml P123 solution 0,4.1,12.2,36.5 and 73 μ l more respectively, and mixing.
(2) in 5 0.5ml EP pipes, respectively add P123-2.5g-PPI 81 μ l (2.5mg/ml) and pure water 40 μ l respectively, and mixing.
(3) with in (2) disposable adding (1), mix homogeneously is hatched 15min under room temperature immediately, measures particle diameter and ξDian Wei then.
The particle diameter and the ξDian Wei characterization result of the mixed copolymer carrier system that obtains are as shown in the table:
The particle diameter of table 1, mixed copolymer carrier system and zeta current potential
The external opposing of embodiment 3 mixed copolymer carriers DNaseI enzymolysis, serum dissociates and the heparin sodium dissociation
This series with experiment in vitro investigated mixed copolymer carrier system opposing DNaseI enzymolysis respectively, serum dissociates and the heparin sodium dissociation, predicts that with this it is applied to intravital probability.The result shows:
N/P is than 5 o'clock, and the adding of free P123 can increase the enzyme action protective effect of P123-2.5g-PPI, but and the P123 amount how much do not have an obvious relation; N/P is than 10, and the adding of free P123 does not change the enzyme action protective effect of P123-2.5g-PPI.The electrophoresis behavior that shows complex is not subjected to influence of serum, and promptly described carrier material can protect plasmid DNA not to be subjected to the dissociation of serum.On the other hand, serum can mutually combine with naked DNA, causes the remarkable change of DNA electrophoresis behavior.
The experimental result explanation of the anti-DNaseI enzymolysis of mixed copolymer carrier system of the present invention, serum and heparin sodium dissociation, when quiet notes are used in the body transfection, this system can overcome influence of serum to a certain extent, has transfection efficiency in the higher body.
The transfection material and the instrument of carrier mediated green fluorescent protein reporter gene of embodiment 4 mixed copolymers and luciferase reporter gene:
NIKON Eclipse TS100 is inverted optical microscope; NIKON TE-2000 inverted fluorescence microscope; MicroplateLuminometer TR717 type luminescence assays instrument (Applied Biosystems); Fluorescence spectrophotometer (LS55, PerkinElmer company); TECAN Safire2 microplate reader;
Cell culture consumptive material (BD Falcon company); Hyclone (Hyclone); Pancreas enzyme-EDTA (Gibco company); Lipofectamine
TM2000 (Invitrogen companies); DMEM culture fluid (Gibco company); Luciferin enzymatic determination test kit (BioTherm company); BCA protein quantification test kit (Shanghai is friendship chemical industry company limited still)
Experimental technique:
A. prepare various PPI/DNA, Plu-PPI/DNA complex
Than 20, the preparation process of adding the MCS of 0,1,3,9,18 times of free P123 is an example, is described as follows with the N/P of P123-2.5g-PPI/DNA:
(1) in 5 0.5ml EP pipes, each adds 20 μ l plasmid DNA (100 μ g/ml), adds pure water 39.3,38.1,35.7,28.5 and 17.7 μ l and 50mg/ml P12 3 solution 0,1.2,3.6,10.8 and 21.6 μ l more respectively, and mixing.
(2) in other 5 0.5ml EP pipes, respectively add P123-2.5g-PPI 24 μ l (2.5mg/ml) and pure water 50 μ l respectively, and mixing.
(3) with in (2) disposable adding (1), vortex 20s is hatched 15min under room temperature immediately, and the every hole of 24 orifice plates adds 50 μ l complex solutions (containing plasmid 0.75 μ g) then.
The preparation method of other complex by that analogy, the complex solution volume that every hole adds when guaranteeing transfection as far as possible is 50 μ l, and the amount that contains plasmid is 0.75 μ g.
B. cell culture
SPC-A1, CHO, 293T be culture fluid (not containing two resisting) to contain 10%FBS (V/V) DMEM (high sugar) all, and (37 ℃, 5%CO2, saturated humidity) continuous culture goes down to posterity or bed board when growing to the 80-90% degrees of fusion in CO2 gas incubator.With pancreatin (0.1%Trypsin+0.02%EDTA) digestion, went down to posterity when going down to posterity with 1: 3.
C. the transfection of cell
Transfection the previous day, peptic cell, counting is with 2 * 10
5Individual/1.0ml/ hole evenly is inoculated in 24 orifice plates, second day when the cell fusion degree reaches 80-90%, beginning transfection operation, old culture fluid is abandoned in suction, every hole adds the fresh culture fluid of 0.45ml, then the complex for preparing is added (about 50 μ l), plasmid is 0.75 μ g in every hole, and every kind of prescription is done two or three multiple holes.Shaking 24 orifice plates gently evenly is present in the hole complex.After cultivating 4hr in the incubator, inhale and abandon the culture fluid that contains complex, PBS washs one time gently, changes the complete cell culture fluid that contains 10%FBS.Change every day with fresh culture fluid, continue to cultivate 48hr; Operate cationic-liposome Lipofectamine simultaneously
TM2000 as positive control.
D. flow cytometer method and spectrofluorophotometer method are estimated green fluorescent protein reporter gene transfection efficiency of cells in vitro flow cytometer method and are estimated green fluorescent protein reporter gene transfection efficiency of cells in vitro:
Behind the transfection 48hr, inhale and abandon culture fluid, PBS washs twice gently, and every hole adds 2 PBS and 1 trypsin digestion cell.With cell harvesting to 1.5ml EP pipe, 1500rpm, 5min is centrifugal, supernatant discarded: if flow measurement formula at once adds an amount of PBS in every pipe, make cell concentration greatly about 5 * 10
5Individual/ml, cell resuspended evenly after, the test that promptly is available on the machine, 30,000 cells of test count at every turn; Wait a period of time could flow measurement formula (above 1 day) if desired, abandon the paraformaldehyde that in every pipe, adds 0.8ml 2.5% behind the supernatant, fixing 30min under the room temperature of resuspended even back, behind the recentrifuge, abandon behind the supernatant with an amount of PBS re-suspended cell, be positioned over 4 ℃ of refrigerators, treat the machine test.
The spectrofluorophotometer method is estimated green fluorescent protein reporter gene transfection efficiency of cells in vitro:
Behind the transfection 48hr, inhale and abandon culture fluid, PBS washs twice gently, and every hole adds 2 PBS and 1 trypsin digestion cell.With cell harvesting to 1.5ml EP pipe, 1500rpm, 5min is centrifugal, supernatant discarded, every pipe adds 0.2mlPBS, resuspendedly all is drawn in 96 orifice plates of White-opalescent after even, set excitation wavelength 490nm, emission wavelength 509nm measures the fluorescence intensity of green fluorescent protein.
E. the evaluating combined thing transfection efficiency of cells in vitro of luciferin enzymatic activity method
Behind the transfection 48hr, culture fluid is abandoned in suction, PBS washs twice gently, every hole adds 100 μ l cell pyrolysis liquids, under the room temperature condition, sway 30min on the shaking table, make the abundant cracking of cell, centrifugal (4 ℃, 8000rpm, 15min), get supernatant 10 μ l, on the luminescence assays instrument with the activity of luciferase kit measurement luciferase, parameter is set to delay time 2s, and measure interval 10s is simultaneously with Protein content in the BCA kit measurement cell pyrolysis liquid, calculate every mg total protein relative light unit (relative luminescence units, RLU).
The result shows:
Along with the increase of N/P ratio, the transfection efficiency of P123-2.5g-PPI progressively improves, and reaches platform status during N/P 20.When the N/P ratio was lower than 20, the adding of serum obviously reduced transfection efficiency; When the N/P ratio was higher than 20, the adding of serum was not obvious to the transfection efficiency influence.
During transfection, the adding of P123 has all reduced transfection efficiency under the serum-free condition, and amount and reduction degree that P123 adds do not have dependency; Under the serum existence condition during transfection, the adding of the P123 transfection efficiency that is significantly increased, when the amount of P123 1 times and 3 times of quality than the time, the raising degree is the most obvious, when the amount of P123 9 times and 18 times of quality than the time, decrease with raising degree to transfection efficiency.
The concentration of serum is very big to the transfection efficiency influence of MCS in the rotaring redyeing system, and when hyclone content was less than 25% (V/V), transfection efficiency was all higher, when hyclone content is 50%, seriously undermined the transfection ability of MCS.Lipofectamine
TM2000 in the presence of 50% hyclone obvious transfection SPC-A1 still.
Experimental result has proved that Pluronic modifies the mixed copolymer carrier system transfection GFP egfp grain of PPI dendrimer, dendritic polymer preparation and the efficient of luciferase reporter plasmid all is higher than positive control Lipofectamine2000, and promptly the mixed copolymer carrier system has higher transfection efficiency in vitro.
Claims (7)
1. a mixed copolymer carrier system compound is characterized in that being made up of the cation dendrimer, dendritic polymer of polyoxyethylene-poly-oxypropylene polyoxyethylene copolymer Pluronic modification, free polyoxyethylene-poly-oxypropylene polyoxyethylene copolymer and plasmid DNA.
2. by the described mixed copolymer carrier system compound of claim 1, it is characterized in that described polyoxyethylene-poly-oxypropylene polyoxyethylene copolymer Pluronic is selected from: P123, P85, P84, P103, P104, L61, L62, L64, L81 or L92 or two or more mixture arbitrarily wherein; Described cation dendrimer, dendritic polymer Dendrimer is selected from polypropylene imines PPI, polyamide-amide PAMAM or polylysine PLL.
3. by the described mixed copolymer carrier system compound of claim 1, it is characterized in that described polyoxyethylene-poly-oxypropylene polyoxyethylene copolymer, Pluronic is P123, P84, L64 or two or more mixture arbitrarily wherein.
4. by the described mixed copolymer carrier system compound of claim 2, it is characterized in that the cation dendrimer, dendritic polymer that described polyoxyethylene-poly-oxypropylene polyoxyethylene copolymer is modified is respectively Pluronic L61, P123 and F123 and PPI reaction, obtains the Pluronic-PPI macromolecule of different modifying degree.
5. the preparation method of a mixed copolymer carrier system compound, it is characterized in that adopting coacervation, cation dendrimer, dendritic polymer Pluronic-PPI that Pluronic is modified and free Pluronic are with after the plasmid DNA that contains therapeutic gene is mixed in pure water, vortex, hatch 15min under the room temperature, obtain non-viral gene treatment carrier system.
6. by the preparation method of claim 5, it is characterized in that the particle diameter and the ξDian Wei of the mixed copolymer carrier system that makes characterizes as shown in the table:
7. the purposes of the described mixed copolymer carrier system compound of claim 1 in preparation non-viral gene drug administration carrier.
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Cited By (2)
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|---|---|---|---|---|
| CN106496585A (en) * | 2016-10-21 | 2017-03-15 | 浙江大学 | Sensitive graphene oxide based nano-materials of a kind of ROS and its preparation method and application |
| CN111317720A (en) * | 2018-12-13 | 2020-06-23 | 复旦大学 | Leukocyte-simulated pluronic-lipid nano hybrid drug delivery carrier and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106496585A (en) * | 2016-10-21 | 2017-03-15 | 浙江大学 | Sensitive graphene oxide based nano-materials of a kind of ROS and its preparation method and application |
| CN106496585B (en) * | 2016-10-21 | 2019-02-19 | 浙江大学 | A kind of graphene oxide based nano-material and its preparation method and application of ROS sensitivity |
| CN111317720A (en) * | 2018-12-13 | 2020-06-23 | 复旦大学 | Leukocyte-simulated pluronic-lipid nano hybrid drug delivery carrier and application thereof |
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