CN103834035A - Cationic laminarin and preparation method and application thereof - Google Patents
Cationic laminarin and preparation method and application thereof Download PDFInfo
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- CN103834035A CN103834035A CN201410095542.1A CN201410095542A CN103834035A CN 103834035 A CN103834035 A CN 103834035A CN 201410095542 A CN201410095542 A CN 201410095542A CN 103834035 A CN103834035 A CN 103834035A
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Abstract
The invention relates to a cationic laminarin and a preparation method and application thereof, the problem about the preparation of the cationic laminarin and the application of the cationic laminarin for preparing the drug for treating cancer can be effectively solved. According to the technical scheme, the cationic laminarin is formed by grafting polyethyleneimine onto the laminarin through a chemical bond, the molecular weight of the laminarin is 10-300kD, the molecular weight of the polyethyleneimine is 600-1200D, the mole ratio of the polyethyleneimine to the laminarin is 1: 3-10; the preparation method is simple, the operation is convenient, the raw material source is wide, the cost is low, the structure is stable, the biocompatibility is good, the cationic laminarin is capable of loading nucleic acid type antitumor drug and efficiently transfecting nucleic acid type antitumor drug to tumor cell so as to treat the tumor.
Description
Technical field
The present invention relates to field of medicaments, particularly a kind of cationization laminarin and its preparation method and application.
Background technology
Research discovery, human diseases is all directly or indirectly relevant to gene, and therefore gene therapy has become one of primary treatment method for the various diseases including cancer.How therapeutic gene being effectively passed to object cell and bringing into play its biological function is the key issue in gene therapy, and the solution of this problem is mainly by means of safety, efficient genophore.At present, be mainly divided into virus vector and non-virus carrier (Curr Drug Deliv, 2004,1:165) for the carrier of gene therapy.Virus vector has higher gene delivery efficiency, but also has the shortcoming that some cannot overcome self, and for example immunogenicity is higher, goal gene loading capacity is less, and expense is higher etc.With respect to virus vector, non-virus carrier has that immunogenicity is low, wide material sources, the advantage such as easy to prepare.Therefore, non-virus carrier receives much concern in recent years, has become the main direction of studying of gene delivery vector.
Polymine (PEI) is that the most representative non-viral gene transmits one of carrier (Journal of Gene Medicine, 2004,7:657).It is by electrostatic interaction and Yeast Nucleic Acid (RNA) or thymus nucleic acid (DNA) formation nano-complex, and then this mixture enters cell by endocytosis, realizes efficient gene transfection.Then utilize " proton sponge effect " to discharge nucleic acid, finally reach the object (BMC Biotechnology, 2004,4:23) for the treatment of disease.Research discovery, the transfection efficiency of PEI and cytotoxicity and its molecular weight are closely related.PEI molecular weight is higher, and the cell transfecting efficiency of therapeutic gene is higher, but cytotoxicity also significantly improves (Bioconjugate Chem.2006,17:152) simultaneously.Higher cytotoxicity has limited the further application of PEI in clinical study, and therefore investigator wishes can obtain having high transfection efficiency, has compared with the novel non-viral gene of low cytotoxicity simultaneously and transmits carrier.
Polysaccharide is a kind of biomacromolecule that occurring in nature extensively exists, a kind of polymeric carbohydrate normally being formed by glycosidic link combination by multiple monose.Original research shows, that polysaccharide has is anti-oxidant, antiviral, improve the multiple physiologically actives (Carbohydrate Polymers, 2012,88:966) such as cellular immunity.Research is subsequently found, polysaccharide not only can form stable nanoparticle with DNA, show good cell transfecting efficiency (Acta Biomater, 2012,8:4224), and can by with cell on the interaction of special receptor, absorbed by specific cells, realize the targeting (Biomaterials, 2011,32:7253) in gene delivery process.Moreover, the poly-hydroxy structure that polysaccharide has, for further structure of modification and modification provide possibility (Biomaterials, 2013,34:5689).Therefore, polysaccharide and derivative thereof become a class have great potential and application prospect non-viral gene transmit carrier.
Laminarin (funcoidan) is a kind of natural polysaccharide being present in Laminariaceae plant sea-tangle or Alariaceae plant kelp, at occurring in nature wide material sources, cheap.Laminarin is the polysaccharide being combined into 1,3-glycosidic link by Glucopyranose, has immunoloregulation function, anti-inflammatory, anticoagulation, antitumor, antiviral and antibacterial etc.For example, laminarin can be combined with heparitinase competitively with heparan, thereby avoids degraded, protecting group counterdie complete of heparitinase, and then stops infiltration and the migration (Int J Cancer, 1999,83:424) of tumour cell; Laminarin can also promote the secretion of interleukin-, thereby promotes hyperplasia, the differentiation of T/B cell, strengthens NK cell self activity, reaches anti-inflammatory object etc.In the molecular structure of laminarin, contain a large amount of active group-OH, therefore can carry out chemical modification by p-OH and realize its different biologic activity, for example laminarin is carried out to sulphating in various degree, can significantly suppress the propagation of human pancreatic cancer cell BxPC-3, reduce the expression of Bcl-2 albumen, the expression that simultaneously improves Bax albumen, the procoagulant activity of inhibition tumor cell, thereby reach the object (Chongqing Medical, 2004,33:417) of oncotherapy.Therefore, laminarin and derivative thereof have the application prospect of good medicine, clinical and medical aspect.But so far there are no to about cationization laminarin and as the open report of gene delivery vector.
Summary of the invention
For above-mentioned situation, for solving the defect of prior art, the present invention's object is just to provide a kind of cationization laminarin and its preparation method and application, can effectively solve the preparation of cationization laminarin and realize the application problem in preparation treatment cancer drug.
The technical scheme that the present invention solves is, this cationization laminarin is to form through chemical bond grafting polyethylene imine on laminarin, laminarin molecular weight is 10-300kD, and polymine molecular weight is 600-1200D, and the mol ratio of polymine and laminarin is 1:3-10; Its preparation method is:
Laminarin is reacted with activating reagent, obtain the laminarin of activation, then the laminarin of activation is reacted with polymine, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
Described activating reagent is the one of potassium periodate, carbonyl dimidazoles, succinyl oxide and maleic anhydride.
Preparation method of the present invention is simple, easy to operate, raw material sources are extensive, with low cost, the cationization laminarin form rule preparing, particle size range 50-250 nm, be evenly distributed, Stability Analysis of Structures, good biocompatibility, can load nucleic acid antitumor drug high-efficiency transfection to tumour cell, realize the treatment of tumour.
Embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is described in further detail.
Embodiment 1
The present invention is in concrete enforcement, this cationization laminarin is, 100mg laminarin is joined in 10mL methyl-sulphoxide, add 400mg maleic anhydride and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then add 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilize, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
Embodiment 2
The present invention is in concrete enforcement, and this cationization laminarin can also be that 100mg laminarin is joined in 10mL deionized water, under agitation condition, add 150mg potassium periodate, lucifuge stirs 48h, then reaction solution is packed into the 2d that dialyses in dialysis tubing, obtains being oxidized laminarin; Oxidation laminarin is added in the 5mL phosphate buffered saline buffer that contains 250mg polymine (PEI), in 1h, dropwise, then stirring at room temperature 36h, finally add 150mg sodium borohydride, stir 72h, through dialysis, lyophilize, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
Embodiment 3
The present invention is in concrete enforcement; this cationization laminarin can also be; 100m g laminarin is joined in 8mL dimethyl sulfoxide (DMSO); under nitrogen protection condition; add successively 100 μ L triethylamines; 30mg carbonyl dimidazoles; lucifuge vigorous reaction 4h; then to the dimethyl sulphoxide solution 6mL that drips 100mg polymine in reaction solution; finally add 50 μ L triethylamines, lucifuge reaction 24h, reaction solution is through dialysis, lyophilize; obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
Embodiment 4
The present invention is in concrete enforcement, this cationization laminarin can also be, 100mg laminarin is joined in 10mL methyl-sulphoxide, add 400mg succinyl oxide and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then add 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilize, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
Cationization laminarin prepared by the present invention is through repeatedly experiment repeatedly, and its effect is very good, has obtained satisfied useful technique effect, and related tests data is as follows:
Experiment one: the cationization laminarin of different mass is joined in 20 μ L deionized waters, add 2 μ g plasmid pEGFP-C1, room temperature is placed 30min, carry out 0.7% agarose gel electrophoresis detection, experimental result shows, in the time adding the above cationization laminarin of 2 μ g, the completely dissolve of DNA band, this explanation is when positively charged ion laminarin is during greater than or equal to plasmid DNA, load DNA completely, and experimental result shows that positively charged ion laminarin has good nucleic acid carrying capacity; Human cervical carcinoma cell Hela is at the DMEM substratum that contains 10% foetal calf serum and 37 DEG C, 5%CO
2cellar culture under condition, front 16 h of transfection are according to 1.2 × 10
4individual/hole is inoculated in 96 orifice plates, 8 μ g positively charged ion laminarins are joined in 2 μ g ultrapure waters, add 2 μ g plasmid pEGFP-C1, transfectional cell after room temperature placement 30min, after transfection 48h, the expression amount of cells were tested by flow cytometry green fluorescent protein, experimental result shows that the expression amount of green fluorescent protein is 78.2%, experimental result shows that positively charged ion laminarin can enter cell by plasmid pEGFP-C1 transfection, and efficiently gives expression to green fluorescent protein.
Experiment two: human liver cancer cell SMMC-7721 is at the DMEM substratum that contains 10% foetal calf serum and 37 DEG C, 5%CO
2cellar culture under condition, according to 1.2 × 10
4individual/hole is inoculated in 96 orifice plates, the positively charged ion laminarin of different mass is joined in substratum, after 24h, tetramethyl-azo azoles salt colorimetry (MTT) is measured cell proliferation, and experimental result shows, along with the increase of positively charged ion laminarin content, cell survival rate slightly declines, but in the scope of 0-100 μ g/mL, cationization laminarin cell growth does not have restraining effect, and test-results shows that positively charged ion laminarin has good biocompatibility.
Experiment three: human breast cancer cell MCF-7 is at the DMEM substratum that contains 10% foetal calf serum and 37 DEG C, 5%CO
2cellar culture under condition, front 16 h of transfection are according to 1.2 × 10
4individual/hole is inoculated in 96 orifice plates, be 4/1 to mix the siRNA of positively charged ion laminarin and target c-fos according to mass ratio, transfectional cell after room temperature incubation 30 min, after transfection 48 h, MTT detects cell proliferation, experimental result shows, inhibitory rate of cell growth is 46%, adopt Trizol method to extract cell total rna, carry out RT-PCR reaction with specificity c-fos primer and specific beta-actin primer, experimental result shows, expression of target gene inhibiting rate is 75%, experimental result shows that positively charged ion laminarin/siRNA system can effectively induce RNA interference effect, suppress tumor growth.
Experiment four: 8 μ g positively charged ion laminarins are joined in 2 μ g ultrapure waters, add 2 μ g plasmid pAIRM-cmv-shT, room temperature is placed 30min, the solution of positively charged ion laminarin and pAIRM-cmv-shT mixture is dropped on the required copper mesh of electron microscopy observation, after solution dries with 2% phospho-wolframic acid dyeing 2min, after solution dries again, with projection electron microscopic observation, experimental result shows, positively charged ion laminarin/pAIRM-cmv-shT mixture is a kind of spherical or dense granule that class is spherical, median size 198nm; By human lung adenocarcinoma epithelial cell A549 at the DMEM substratum that contains 10% foetal calf serum and 37 DEG C, 5%CO
2cellar culture under condition, collects logarithmic phase cell, adjusts concentration of cell suspension as 2 × 10 taking physiological saline
7individual/mL, subcutaneous vaccination, to male BALB/c nude mice (4-6w, 18-22g) right fore top, treats that gross tumor volume is more than or equal to 60mm
3by positively charged ion laminarin/pAIRM-cmv-shT mixture of above-mentioned preparation by tail vein injection to Mice Body, every 5d is administered once, administration 3 times altogether, using injecting normal saline as blank group, in experimentation, observe mouse animation, detect Mouse Weight and gross tumor volume, experimental result shows, compared with physiological saline control group, Mouse Weight does not have notable difference, but gross tumor volume changes slowly, inhibition rate of tumor growth is 64.7%, and this explanation positively charged ion laminarin/pAIRM-cmv-shT mixture has significantly suppressed the growth of tumour.
In above-mentioned experiment, cell strain used, plasmid, nucleotide sequence is:
1, cell strain: liver cancer cell SMMC-7721, mammary cancer MCF-7, cervical cancer cell Hela, adenocarcinoma of lung epithelial cell A549 is all purchased from Chinese Academy of Sciences's cell bank.
2, plasmid: the egfp expression plasmid pEGFP-C1(GenBank number of logging in U55763) purchased from BD Biosciences Clontech company; The RNA interference plasmid pAIRM-cmv-shT of targeted human reverse transcriptase of telomere (hTERT) is built by this laboratory, and Xueling Ren is shown in concrete operations, et al.Plasmid, 2011,65:42-50.
3, nucleotide sequence:
(1) siRNA (siRNA) sequence:
The siRNA sequence of targeted cells proto-oncogene c-fos: positive-sense strand, 5 '-GCGGAGACAGAUCAACUUGTT-3 '; Antisense strand, 5 '-CAAGUUGAUCUGUCUCCGCTT-3 '.
(2) for the primer of reverse transcriptase polymerase chain reaction (RT-PCR)
Specificity c-fos primer: upstream primer, 5 '-CCGACTCCTTCTCCAGCAT-3 '; Downstream primer 5 '-TCACCGTGGGGATAAAGTTG-3 '.
Specific actin (β-actin) primer: upstream primer, 5 '-CTGGGACGACATGGAGAAAA-3 '; Downstream primer 5 '-AAGGAAGGCTGG AAG AGTGC-3 '.
But cell strain used, carrier DNA and nucleic acid are not for limiting the scope of the invention, but for useful technique effect of the present invention is described as embodiment.
In experiment, the application in oncotherapy as gene delivery vector of described cationization laminarin, also comprises Antioncogene medicine is mixed with cationization laminarin, then carries out the biological assessment of antitumor cell and anti-tumor in vivo.
Described Antioncogene medicine is: be mounted with one or more in the plasmid DNA of therapeutic gene, the virus vector DNA that is mounted with therapeutic gene, antisense oligonucleotide, siRNA.
Described tumour cell behaviour organ surface or the inner various solid tumor cells that occur, comprise the one in breast cancer cell, lung carcinoma cell, liver cancer cell, nasopharyngeal carcinoma cell, esophageal cancer cell, ovarian cancer cell, prostate cancer cell, kidney cancer cell, stomach cancer cell, penile cancer cell, testicular cancer cell, skin cancer cell, leukemia cell, pancreatic cancer cell, Human Tongue Carcinoma Lines, malignant melanoma cell.
Described tumour behaviour organ surface or the inner various solid tumors that occur, comprise the one in mammary cancer, lung cancer, liver cancer, nasopharyngeal carcinoma, the esophageal carcinoma, ovarian cancer, prostate cancer, kidney, cancer of the stomach, penile cancer, carcinoma of testis, skin carcinoma, leukemia, carcinoma of the pancreas, tongue cancer, malignant melanoma.
Shown by above-mentioned, positively charged ion laminarin of the present invention is through repeated tests, all obtain satisfied useful technique effect, fully prove, the present invention is by being connected to laminarin by polymine, overcome the known shortcoming of laminarin, positively charged ion laminarin good water solubility in the present invention, physics and stable chemical nature, preparation condition easily meets, material source is abundant, preparation cost is low, good biocompatibility, nucleic acid carrying capacity is strong, cationization laminarin is as a kind of good Antioncogene treatment carrier, and use it for field of gene, effectively realize the application in anti-tumor medicine as gene delivery vector of cationization laminarin, preparation method is simple, open up the medicine new way of oncotherapy, there is huge economic and social benefit.
Claims (7)
1. a cationization laminarin, it is characterized in that, this cationization laminarin is to form through chemical bond grafting polyethylene imine on laminarin, laminarin molecular weight is 10-300kD, polymine molecular weight is 600-1200D, and the mol ratio of polymine and laminarin is 1:3-10.
2. the preparation method of cationization laminarin claimed in claim 1, is characterized in that, laminarin is reacted with activating reagent, the laminarin that must activate, again the laminarin of activation is reacted with polymine, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin; Described activating reagent is the one of potassium periodate, carbonyl dimidazoles, succinyl oxide and maleic anhydride.
3. the preparation method of cationization laminarin according to claim 2, it is characterized in that, 100mg laminarin is joined in 10mL methyl-sulphoxide, add 400mg maleic anhydride and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then add 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilize, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
4. the preparation method of cationization laminarin according to claim 2, it is characterized in that, 100mg laminarin is joined in 10mL deionized water, under agitation condition, add 150mg potassium periodate, lucifuge stirs 48h, then reaction solution is packed into the 2d that dialyses in dialysis tubing, obtain being oxidized laminarin; Oxidation laminarin is added in the 5mL phosphate buffered saline buffer that contains 250mg polymine, in 1h, dropwise, then stirring at room temperature 36h, finally add 150mg sodium borohydride, stir 72h, through dialysis, lyophilize, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
5. the preparation method of cationization laminarin according to claim 2; it is characterized in that; 100mg laminarin is joined in 8mL dimethyl sulfoxide (DMSO); under nitrogen protection condition; add successively 100 μ L triethylamines; 30mg carbonyl dimidazoles; lucifuge vigorous reaction 4 h; then to the dimethyl sulphoxide solution 6mL that drips 100mg polymine in reaction solution; finally add 50 μ L triethylamines, lucifuge is reacted 24 h, and reaction solution is through dialysis, lyophilize; obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
6. the preparation method of cationization laminarin according to claim 2, it is characterized in that, 100mg laminarin is joined in 10mL methyl-sulphoxide, add 400mg succinyl oxide and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then add 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilize, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
7. the application of the cationization laminarin described in claim 1 or 2-6 any one in anti-tumor medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106692981A (en) * | 2017-01-10 | 2017-05-24 | 郑州大学 | Preparation method and application of cationization lentinan |
| CN111358955A (en) * | 2020-04-01 | 2020-07-03 | 重庆理工大学 | Inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases, and preparation method and application thereof |
| CN113501889A (en) * | 2021-07-06 | 2021-10-15 | 郑州大学 | Preparation method and application of pseudo-ginseng polysaccharide cationic derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102665686A (en) * | 2009-09-09 | 2012-09-12 | 药明公司 | Anionic-core composition for delivery of therapeutic agents, and methods of making and using the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102665686A (en) * | 2009-09-09 | 2012-09-12 | 药明公司 | Anionic-core composition for delivery of therapeutic agents, and methods of making and using the same |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106692981A (en) * | 2017-01-10 | 2017-05-24 | 郑州大学 | Preparation method and application of cationization lentinan |
| CN111358955A (en) * | 2020-04-01 | 2020-07-03 | 重庆理工大学 | Inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases, and preparation method and application thereof |
| CN113501889A (en) * | 2021-07-06 | 2021-10-15 | 郑州大学 | Preparation method and application of pseudo-ginseng polysaccharide cationic derivative |
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