CN103834035B - A kind of cationization laminarin and its preparation method and application - Google Patents
A kind of cationization laminarin and its preparation method and application Download PDFInfo
- Publication number
- CN103834035B CN103834035B CN201410095542.1A CN201410095542A CN103834035B CN 103834035 B CN103834035 B CN 103834035B CN 201410095542 A CN201410095542 A CN 201410095542A CN 103834035 B CN103834035 B CN 103834035B
- Authority
- CN
- China
- Prior art keywords
- laminarin
- cationization
- polymine
- preparation
- polyethylene imine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to cationization laminarin and its preparation method and application, effectively can solve the preparation of cationization laminarin and realize preparing the application problem in Therapeutic cancer medicine, its technical scheme solved is, this cationization laminarin forms 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; Preparation method of the present invention is simple, easy to operate, and raw material sources are extensive, with low cost, Stability Analysis of Structures, good biocompatibility, can load nucleic acid antitumor drug high-efficiency transfection to tumor cell, realize the treatment of 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 finds, human diseases is all directly or indirectly relevant to gene, and therefore gene therapy has become one of the primary treatments for the various diseases comprising cancer.How therapeutic gene being effectively passed to object cell and playing its biological function is key issue in gene therapy, and the solution of this problem is mainly by means of safety, efficiently genophore.At present, the carrier for gene therapy is mainly divided into viral vector and non-virus carrier (CurrDrugDeliv, 2004,1:165).Viral vector has higher gene transfer efficiency, but also has some shortcomings that self cannot overcome, and such as immunogenicity is higher, genes of interest useful load is less, costly etc.Relative to viral 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 representational non-viral gene of most transmits one of carrier (JournalofGeneMedicine, 2004,7:657).It forms nano-complex by electrostatic interaction and ribonucleic acid (RNA) or DNA (deoxyribonucleic acid) (DNA), and then this complex enters cell by endocytosis, realizes efficient gene transfection.Then utilize " proton sponge effect " to discharge nucleic acid, finally reach the object (BMCBiotechnology, 2004,4:23) of disease therapy.Research finds, the transfection efficiency of PEI and cytotoxicity and its molecular weight closely related.PEI molecular weight is higher, and the cell transfecting efficiency of therapeutic gene is higher, but cytotoxicity also significantly improves (BioconjugateChem.2006,17:152) simultaneously.Higher cytotoxicity limits PEI further application in clinical studies, and therefore researcher wishes to obtain having high transfection efficiency, has simultaneously and transmits carrier compared with the novel non-viral gene of low cytotoxicity.
Polysaccharide is a kind of biomacromolecule that occurring in nature extensively exists, and is normally combined by glycosidic bond by multiple monosaccharide and a kind of polymeric carbohydrate formed.Original research shows, polysaccharide has the multiple physiologically actives (CarbohydratePolymers, 2012,88:966) such as antioxidation, antiviral, raising cellular immunity.Research subsequently finds, polysaccharide not only can form stable nanoparticle with DNA, show good cell transfecting efficiency (ActaBiomater, 2012,8:4224), and can by the interaction with special receptor on cell, absorbed by specific cells, realize the targeting (Biomaterials, 2011,32:7253) in gene delivery process.Moreover, the polyhydroxy structure that polysaccharide has, for further structure of modification and modification provide possibility (Biomaterials, 2013,34:5689).Therefore, many carbohydrates and their derivative have become the non-viral gene transmission carrier that a class has great potential and application prospect.
Laminarin (funcoidan) is present in a kind of natural polysaccharide in Laminariaceae plant Thallus Laminariae (Thallus Eckloniae) or Alariaceae plant Thallus Laminariae (Thallus Eckloniae), at occurring in nature wide material sources, cheap.Laminarin is the polysaccharide be combined into 1,3-glycosidic bond by Glucopyranose., has immunoloregulation function, antiinflammatory, anticoagulation, antitumor, antiviral and antibacterial functions etc.Such as, laminarin can be combined with heparitinase competitively with heparan, thus avoid the degraded of heparitinase, protecting group counterdie complete, and then stop the infiltration of tumor cell and migration (IntJCancer, 1999,83:424); Laminarin can also promote the secretion of interleukin, thus promotes hypertrophy, the differentiation of T/B cell, strengthens NK cell activity itself, reaches antiinflammatory object etc.Containing a large amount of active group-OH in the molecular structure of laminarin, therefore can carry out chemical modification by p-OH and realize its different biologic activity, such as to the Sulfation that laminarin carries out in various degree, significantly can suppress the propagation of human pancreatic cancer cell BxPC-3, reduce the expression of Bcl-2 albumen, improve the expression of Bax albumen simultaneously, the procoagulant activity of inhibition tumor cell, thus reach the object (Chongqing Medical, 2004,33:417) of oncotherapy.Therefore, laminarin and derivant thereof have the application prospect of good medicine, clinical and medical aspect.But so far there are no arrives about cationization laminarin and the open report as gene delivery vector thereof.
Summary of the invention
For above-mentioned situation, for solving the defect of prior art, the object of the present invention is just to provide a kind of cationization laminarin and its preparation method and application, effectively can solve the preparation of cationization laminarin and realize preparing the application problem in Therapeutic cancer medicine.
The technical scheme that the present invention solves is, this cationization laminarin forms 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 and activating reagent are reacted, obtains the laminarin of activation, then the laminarin of activation and polymine are reacted, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
Described activating reagent is the one of Potassium metaperiodate., carbonyl dimidazoles, succinic anhydrides 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 prepared, particle size range 50-250nm, be evenly distributed, Stability Analysis of Structures, good biocompatibility, can load nucleic acid antitumor drug high-efficiency transfection to tumor cell, realize the treatment of tumor.
Detailed description of the invention
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 dimethyl sulfoxine, add 400mg maleic anhydride and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide is added, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilization, 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, is joined by 100mg laminarin in 10mL deionized water, 150mg Potassium metaperiodate. is added under stirring condition, lucifuge stirs 48h, then reactant liquor is loaded in bag filter the 2d that dialyses, and obtains being oxidized laminarin; Oxidation laminarin is added in the 5mL phosphate buffer containing 250mg polymine (PEI), dropwise in 1h, then stirring at room temperature 36h, finally add 150mg sodium borohydride, stir 72h, through dialysis, lyophilization, 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; 100mg laminarin is joined in 8mL dimethyl sulfoxide; under nitrogen protection condition; add 100 μ L triethylamines successively; 30mg carbonyl dimidazoles; lucifuge vigorous reaction 4h; then in reactant liquor, drip the dimethyl sulphoxide solution 6mL of 100mg polymine; finally add 50 μ L triethylamines, lucifuge reaction 24h, reactant liquor is through dialysis, lyophilization; 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 dimethyl sulfoxine, add 400mg succinic anhydrides and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide is added, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilization, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
Cationization laminarin prepared by the present invention is through repeatedly repeatedly testing, and its effect is very good, achieves satisfied Advantageous Effects, and related tests data is as follows:
Experiment one: the cationization laminarin of different quality is joined in 20 μ L deionized waters, add 2 μ g plasmid pEGFP-C1, room temperature places 30min, carry out 0.7% agarose gel electrophoresis detection, experimental result shows, when adding the 2 above cationization laminarin of μ g, DNA band disappears completely, this illustrates when cation laminarin is greater than or equal to plasmid DNA, can load DNA completely, and experimental result shows that cation laminarin has good nucleic acid load capacity; Human cervical carcinoma cell Hela is at the DMEM culture medium containing 10% hyclone and 37 DEG C, 5%CO
2cellar culture under condition, before transfection, 16h is according to 1.2 × 10
4individual/hole is inoculated in 96 orifice plates, 8 μ g cation laminarins are joined in 2 μ g ultra-pure waters, add 2 μ g plasmid pEGFP-C1, transfectional cell after room temperature placement 30min, after transfection 48h, the expression of cells were tested by flow cytometry green fluorescent protein, the expression of experimental result display green fluorescent protein is 78.2%, experimental result shows that plasmid pEGFP-C1 transfection can be entered cell by cation laminarin, and high expression goes out green fluorescent protein.
Experiment two: human liver cancer cells Hep G2 is at the DMEM culture medium containing 10% hyclone and 37 DEG C, 5%CO
2cellar culture under condition, according to 1.2 × 10
4individual/hole is inoculated in 96 orifice plates, the cation laminarin of different quality is joined in culture medium, after 24h, tetrazolium-based colorimetric assay (MTT) measures cell proliferation, and experimental result shows, along with the increase of cation laminarin content, cell survival rate slightly declines, but in the scope of 0-100 μ g/mL, cationization laminarin cell growth does not have inhibitory action, and result of the test shows that cation laminarin has good biocompatibility.
Experiment three: human breast cancer cell line Bcap-37 is at the DMEM culture medium containing 10% hyclone and 37 DEG C, 5%CO
2cellar culture under condition, before transfection, 16h is according to 1.2 × 10
4individual/hole is inoculated in 96 orifice plates, be 4/1 to mix the siRNA of cation laminarin and targeting c-fos according to mass ratio, transfectional cell after incubation at room temperature 30min, after transfection 48h, MTT detects cell proliferation, experimental result shows, inhibitory rate of cell growth is 46%, Trizol method is adopted to extract cell total rna, RT-PCR reaction is carried out with specificity c-fos primer and specific beta-actin primer, experimental result shows, expression of target gene suppression ratio is 75%, experimental result shows that cation laminarin/siRNA system can effectively induce RNA interference effect, Tumor suppression grows.
Experiment four: 8 μ g cation laminarins are joined in 2 μ g ultra-pure waters, add 2 μ g plasmid pAIRM-cmv-shT, room temperature places 30min, the solution of cation laminarin and pAIRM-cmv-shT complex is dropped on the copper mesh needed for electron microscopy observation, with 2% phosphotungstic acid dyeing 2min after solution dries, after solution dries again, with projection electron microscopic observation, experimental result shows, cation laminarin/pAIRM-cmv-shT complex is a kind of spherical or dense granule that class is spherical, mean diameter 198nm; By human lung adenocarcinoma epithelial cell A549 at the DMEM culture medium containing 10% hyclone and 37 DEG C, 5%CO
2cellar culture under condition, collects logarithmic (log) phase cell, with normal saline adjustment concentration of cell suspension for 2 × 10
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 the cation of above-mentioned preparation laminarin/pAIRM-cmv-shT complex by tail vein injection in Mice Body, every 5d is administered once, administration 3 times altogether, using injecting normal saline as blank group, mice animation is observed in experimentation, detect Mouse Weight and gross tumor volume, experimental result shows, compared with saline control group, Mouse Weight does not have notable difference, but gross tumor volume change slowly, inhibition rate of tumor growth is 64.7%, and this illustrates that cation laminarin/pAIRM-cmv-shT complex significantly suppress the growth of tumor.
In above-mentioned experiment, used cell strain, plasmid, nucleotide sequence is:
1, cell strain: Hepatocellular carcinoma cell line, breast carcinoma 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 BDBiosciencesClontech company; The RNA interference plasmid pAIRM-cmv-shT of targeted human reverse transcriptase of telomere (hTERT) is built by this laboratory, and XuelingRen is shown in concrete operations, etal.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: forward primer, 5 '-CCGACTCCTTCTCCAGCAT-3 '; Downstream primer 5 '-TCACCGTGGGGATAAAGTTG-3 '.
Specific actin (β-actin) primer: forward primer, 5 '-CTGGGACGACATGGAGAAAA-3 '; Downstream primer 5 '-AAGGAAGGCTGGAAGAGTGC-3 '.
But cell strain used, carrier DNA and nucleic acid are not used to limit the scope of the invention, but for Advantageous Effects of the present invention being described as embodiment.
In an experiment, described cationization laminarin, as the application of gene delivery vector in oncotherapy, also comprises and being mixed with cationization laminarin by Antioncogene medicine, then carries out the biological assessment of antitumor cell and anti-tumor in vivo.
Described Antioncogene medicine is: one or more in the plasmid DNA being mounted with therapeutic gene, the viral vector DNA being mounted with therapeutic gene, antisense oligonucleotide, siRNA.
Described tumor cell behaviour organ surface or the inner various solid tumor cells occurred, comprise the one in breast cancer cell, lung carcinoma cell, hepatoma carcinoma cell, nasopharyngeal carcinoma cell, esophageal cancer cell, ovarian cancer cell, prostate gland cancer cell, kidney cancer cell, stomach cancer cell, carcinoma of penis cell, testicular cancer cell, skin cancer cell, leukaemia, pancreatic cancer cell, Human Tongue Carcinoma Lines, malignant melanoma cell.
Described tumor behaviour organ surface or the inner various solid tumors occurred, comprise the one in breast carcinoma, pulmonary carcinoma, hepatocarcinoma, nasopharyngeal carcinoma, the esophageal carcinoma, ovarian cancer, carcinoma of prostate, renal carcinoma, gastric cancer, carcinoma of penis, carcinoma of testis, skin carcinoma, leukemia, cancer of pancreas, carcinoma of tongue, malignant melanoma.
Shown by above-mentioned, subject cationic laminarin is through repeated tests, all achieve satisfied useful technique effect, sufficient proof, the present invention is by being connected to laminarin by polymine, overcome the shortcoming that laminarin is known, cation laminarin good water solubility in the present invention, physics and stable chemical nature, preparation condition easily meets, material source enriches, preparation cost is low, good biocompatibility, nucleic acid load capacity is strong, cationization laminarin is as a kind of good Antioncogene treatment carrier, and use it for field of gene, effectively achieve cationization laminarin as the application of gene delivery vector in anti-tumor medicine, preparation method is simple, open 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 forms 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 according to claim 1, is characterized in that, laminarin and activating reagent is reacted, the laminarin that must activate, again the laminarin of activation and polymine are reacted, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin; Described activating reagent is the one of Potassium metaperiodate., carbonyl dimidazoles, succinic anhydrides 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 dimethyl sulfoxine, add 400mg maleic anhydride and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide is added, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilization, 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, 150mg Potassium metaperiodate. is added under stirring condition, lucifuge stirs 48h, then reactant liquor is loaded in bag filter the 2d that dialyses, obtain being oxidized laminarin; Oxidation laminarin is added in the 5mL phosphate buffer containing 250mg polymine, dropwise in 1h, then stirring at room temperature 36h, finally add 150mg sodium borohydride, stir 72h, through dialysis, lyophilization, 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; under nitrogen protection condition; add 100 μ L triethylamines successively; 30mg carbonyl dimidazoles; lucifuge vigorous reaction 4h; then in reactant liquor, drip the dimethyl sulphoxide solution 6mL of 100mg polymine; finally add 50 μ L triethylamines, lucifuge reaction 24h, reactant liquor is through dialysis, lyophilization; 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 dimethyl sulfoxine, add 400mg succinic anhydrides and 10mg4-dimethylamino pyridine, 50 DEG C are stirred 24h, then 10mg1-ethyl (3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 5mgN-N-Hydroxysuccinimide is added, stir 4h, finally add 300mg polymine, stirring at room temperature 48h, through dialysis, lyophilization, obtain the laminarin of polyethylene imine beautify, i.e. cationization laminarin.
7. the application of cationization laminarin according to claim 1 in anti-tumor medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410095542.1A CN103834035B (en) | 2014-03-17 | 2014-03-17 | A kind of cationization laminarin and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410095542.1A CN103834035B (en) | 2014-03-17 | 2014-03-17 | A kind of cationization laminarin and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103834035A CN103834035A (en) | 2014-06-04 |
| CN103834035B true CN103834035B (en) | 2016-01-20 |
Family
ID=50797955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410095542.1A Expired - Fee Related CN103834035B (en) | 2014-03-17 | 2014-03-17 | A kind of cationization laminarin and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103834035B (en) |
Families Citing this family (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 |
| CN111358955B (en) * | 2020-04-01 | 2023-05-02 | 重庆理工大学 | Inflammation targeted bindarit nanoparticle for treating lipid metabolism diseases, 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 |
Citations (1)
| 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 |
-
2014
- 2014-03-17 CN CN201410095542.1A patent/CN103834035B/en not_active Expired - Fee Related
Patent Citations (1)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103834035A (en) | 2014-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liu et al. | Tumor associated macrophage-targeted microRNA delivery with dual-responsive polypeptide nanovectors for anti-cancer therapy | |
| CN102888404B (en) | Sirna conjugate and preparation method thereof | |
| CN105705638B (en) | What is improved has dynamical nanoparticle form oligonucleotide structure and preparation method thereof | |
| CN104258416B (en) | Deliver the nano-carrier and preparation method of drug and gene altogether based on oligonucleotide | |
| Kim et al. | Synergistic anti-tumor effects of bevacizumab and tumor targeted polymerized VEGF siRNA nanoparticles | |
| CN109381705A (en) | Reversible crosslink Biodegradable polymer vesicles and preparation method thereof with asymmetric membrane structure | |
| Shang et al. | Dual antisense oligonucleotide targeting miR-21/miR-155 synergize photodynamic therapy to treat triple-negative breast cancer and inhibit metastasis | |
| CN103834035B (en) | A kind of cationization laminarin and its preparation method and application | |
| CN103768080A (en) | Targeting preparation for resisting drug-resistant tumor, as well as preparation method and application thereof | |
| CN107998082A (en) | A kind of application for reducing responsive polymer vesica Nano medication in treatment of brain tumor medicine is prepared | |
| Zhang et al. | Orally delivered targeted nanotherapeutics for the treatment of colorectal cancer | |
| CN109464397A (en) | A kind of graphene oxide multiple medicine based on biomineralization is total to loading system and its preparation method and application | |
| CN101361712A (en) | Blood vessel target liposome carrier mediated by fiber forming growth factor receptor and preparation method and use thereof | |
| CN105765069A (en) | Liver cancer related genes-specific siRNA, double-stranded oligo RNA molecules comprising the siRNA, and composition for preventing or treating cancer comprising the same | |
| Yang et al. | “Star” miR-34a and CXCR4 antagonist based nanoplex for binary cooperative migration treatment against metastatic breast cancer | |
| Song et al. | Self-assembly of multifunctional DNA nanohydrogels with tumor microenvironment-responsive cascade reactions for cooperative cancer therapy | |
| CN105779458B (en) | Ribonucleic acid aptamer with inhibitory effect on non-small cell lung cancer and pharmaceutical composition containing ribonucleic acid aptamer | |
| CN106727323B (en) | Hyaluronic acid nano vesicle and preparation method and application thereof | |
| CN113501889A (en) | Preparation method and application of pseudo-ginseng polysaccharide cationic derivative | |
| CN111888482A (en) | Liver cancer cell targeted graphene oxide drug-loaded compound and preparation method thereof | |
| CN104072766B (en) | A kind of for carrying medicament with the carrier of gene, medicine-gene vector system and preparation method thereof | |
| CN105534956A (en) | Anticancer miRNA (microRNA)-based medicinal composition for treating esophageal cancer | |
| CN105412943A (en) | Nano particle composition and anti-tumor application thereof | |
| EP3372233B1 (en) | Pharmaceutical composition for treating and/or preventing cancer | |
| CN101804209A (en) | PEDF (Pigment Epithelial Derived Factor) gene PLGA nano compound as well as preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160120 Termination date: 20170317 |