CN102908315B - Chitosan (CS) nanoparticle delivery system of small molecular interfering ribonucleic acid and preparation method thereof - Google Patents
Chitosan (CS) nanoparticle delivery system of small molecular interfering ribonucleic acid and preparation method thereof Download PDFInfo
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- CN102908315B CN102908315B CN201210434863.0A CN201210434863A CN102908315B CN 102908315 B CN102908315 B CN 102908315B CN 201210434863 A CN201210434863 A CN 201210434863A CN 102908315 B CN102908315 B CN 102908315B
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Abstract
The invention discloses a chitosan (CS) nanoparticle delivery system of small interfering ribonucleic acid and a preparation method of the chitosan (CS) nanoparticle delivery system. In the CS nanoparticle delivery system of small interfering ribonucleic acid, CS is taken as a delivery main body, 0.5-2.0 percent of small interfering ribonucleic acid and 10-25 percent of sodium polyphosphate are contained based on the total weight of the delivery system, the particle diameters of nanoparticles are 60-200 nanometers before and after freeze drying, and the Zeta potential is 10-70 mV. Due to the adoption of the CS nanoparticle delivery system, siRNA (small interfering ribonucleic acid) can be delivered into nasopharyngeal darcinoma tissues effectively, high targeting property and small administration dosage are realized, and degradation of siRNA administered by injection before arriving at nasopharynx and uptake by other tissues can be avoided. CS nanoparticles can be used for effectively protecting siRNA from being damaged by a nasal cavity liquid. According to the siRNA delivery system disclosed by the invention, relevant genes can be inhibited effectively in nasopharyngeal darcinoma cells.
Description
Technical field
The present invention relates to field of medicaments, be specially a kind of preparation method of the nose administration small nucleic acids nano-carrier delivery system that is used for the treatment of nasopharyngeal carcinoma.
Background technology
Nasopharyngeal carcinoma (nasopharyngeal carcinoma, NPC) is one of common malignant tumor of China, accounts for tumor of head and neck sickness rate first place.Be apt to occur in Guangdong and Guangxi Provinces, Fujian and Jialing River Basin, sickness rate has the trend raising year by year in recent years.Radiotherapy is the base therapy means of nasopharyngeal carcinoma, can obtain higher Partial controll rate, but due to the rapid and high transitivity of nasopharyngeal carcinoma growth, makes this disease exist higher treatment mortality, and main cause is regional area recurrence and metastasis.Whether gene therapy can be applied to nasopharyngeal carcinoma, be the problem that people extremely pay close attention to.
SiRNA (siRNA) is made up of 21～23 base pairs, can be in Cytoplasm the messenger RNA (mRNA) of specific binding and its base pair complementation, block the expression of its coded protein through nuclease degradation mRNA, disturb (RNAi) to realize gene silencing by RNA.This process both can reticent cell in deleterious gene, again can reticent adventitious viruses gene, therefore, siRNA has important scientific meaning and using value as medicine in the virus infection such as cancer and influenza, hepatitis treatment field.But hydrophilic anion siRNA is easily removed fast from blood circulation, be difficult to cross over the hydrophobicity cell membrane of surperficial negative electricity, easily by nuclease degradation, need carrier delivery system protection safely and efficiently and efficiently transport to enter cells play function.
The non-virus carrier of siRNA is mainly cationic-liposome and cation high molecular at present, as polymine (PEI) and chitosan.Although liposome easily with cell membrane fusion, unstable and have stronger cell and a toxicity in vivo; PEI proton buffer capacity is beneficial to intracellular transport, but also has stronger cell and toxicity in vivo.
Chitosan (Chitosan, CS) be a kind of natural macromolecule amylose extracting from dried small shrimps, Carapax Eriocheir sinensis, chitosan is as natural cationic polysaccharide, the amino protonated rear hydrophobicity cell membrane that easily sticks and cross over surperficial negative electricity on strand, be proved to be there is good biocompatibility, biodegradability and low/avirulence, thereby CS is a kind of gene vector material that has development prospect.
Document: HOWARD KA, RAH BEK UL, L IU X, et al.RNA in terference in vi tro and in vivo using a ch itosan/s iRNA n anopart icle system[J] .MolTher, 2006, 14 (4): 476-484. report, Howard etc. have prepared siRNA chitosan nano, arrive in 1h siRNA chitosan nano by mouse embryo fibroblasts NIH 3T3 cellular uptake by fluorescence microscope in vitro, human lung carcinoma cell H 1299 and Mus peritoneal macrophages testing result show, the caused green fluorescent protein of gene silencing (GFP) being mediated by nanoparticle after 4h is expressed and is reduced respectively 77.9% and 90%, and commercially available transfection agents TransIT2TKO effect 24h just can reach similar effect.Reason may be the interaction that small particle diameter (180 ~ 330nm) and unnecessary positive charge are conducive to nanoparticle and cell membrane.
Nasal-cavity administration test shows, compares with blank group with the matched group of staggered arrangement siRNA, and transgenic mice bronchioles epithelial cell EGFP expresses and reduces respectively 37% and 43%.
The chitosan nano transmission system research of siRNA is at present a lot, but major part is all the transmission system based on intravenous administration, is not suitable for the administration of nasopharynx position.
Summary of the invention
The object of the present invention is to provide a kind of small molecule disturbance ribonucleic acid chitosan nano transmission system and preparation method, the defect existing to overcome prior art, meets the needs of clinical practice.
Described small molecule disturbance ribonucleic acid chitosan nano transmission system, take chitosan as transmitting main body, take the gross weight of described transmission system as benchmark, contains 0.5 ~ 2.0% small molecule disturbance ribonucleic acid and 10%～25% sodium polyphosphate;
Preferably, described small molecule disturbance ribonucleic acid chitosan nano transmission system, take chitosan as transmitting main body, contains 1.0～1.5% small molecule disturbance ribonucleic acid and 12%～18% sodium polyphosphate;
Preferably, described small molecule disturbance ribonucleic acid chitosan nano transmission system, also comprises carrier, and described carrier is selected from more than one in cyclodextrin derivative or trehalose; Wherein cyclodextrin derivative has the effect that promotes nanoparticle Nasal Mucosa Absorption, protects nanoparticle effect when trehalose has lyophilizing;
Before and after described nanoparticle lyophilizing, particle diameter is 60 ~ 200nm, Zeta electric potential 10～70mV;
Preferably, before and after lyophilizing, particle diameter is 80 ~ 150nm, Zeta electric potential 20～40mV.
Described carrier with the ratio of chitosan, small molecule disturbance ribonucleic acid and sodium polyphosphate gross weight is
Carrier: gross weight=20～100: 1;
Preferably:
Carrier: gross weight=50～70: 1;
Preferably, described carrier is the mixture of cyclodextrin derivative and trehalose, and weight ratio is:
Cyclodextrin derivative: trehalose=1～3.5: 1;
Described small molecule disturbance ribonucleic acid is the small molecule disturbance ribonucleic acid (being designed and synthesized by Biomics Bioisystech Co., Ltd) of small molecule disturbance ribonucleic acid, targeting Bcl-2 gene, survivin gene or other nasopharyngeal carcinoma related genes without target function gene (feminine gender);
The relevant information of Bcl-2 gene, at p53, p16, bcl-2, progress [J] Chinese journals of practical medicine of cox-2 and Nasopharyngeal Cancer, 2010,26(10): 1849-1851. has detailed report, Bcl-2 gene is positioned on No. 18 chromosomes, containing 3 exons and 2 introns, is anti-apoptotic genes expression, the cancer protein that coding relative molecular weight is 25 × 1000u, its high expressed can hinder the apoptosis of tumor cell, and may and shift closely related with the generation of nasopharyngeal carcinoma, evolution.Bcl-2 can suppress in arbitrary stage of cell cycle the apoptosis of cell, and its biological mechanism is still in conceptual phase.Bcl-2 gene can suppress apoptosis of many kinds, all has expression, as pulmonary carcinoma, ovarian cancer, nasopharyngeal carcinoma, uterus carcinoma etc. in Several Kinds of Malignancy.Some study discovery, and bcl-2 is a kind of anti-apoptotic genes expression of broad sense, have anticancer apoptosis, thereby make the survival of cancer cell multiplication and proliferative cell, make cell balance imbalance cause various tumorigenic effects.
In the Chinese patent that described survivin gene is CN201110079879.X at application number, there is detailed report, Survivin albumen is one of IAP member, there is powerful anti-apoptotic effect, and play an important role maintaining in cell mitogen and vascularization regulation process, be the key factor of oncogenic process.
The viscosity-average molecular weight of chitosan is 5～1,000,000, and deacetylation is more than 80%.
Described cyclodextrin derivative is as HP-β-CD or any methyl-β-cyclodextrin etc.;
The preparation method of the nanoparticle transmission system of described small molecule disturbance ribonucleic acid, comprises the steps:
By the DEPC aqueous solution of the DEPC aqueous solution of siRNA and sodium polyphosphate, be added dropwise to the sodium-acetate buffer of pH4 ~ 6 chitosan, speed is 10～25 droplets/minute, then leaves standstill 20～40min, collect the nanoparticle solution of siRNA, mix with carrier again, be concentrated into 10～30% ,-30～25 ℃ of program lyophilizing of original volume, obtain lyophilized products, be the nanoparticle transmission system of described small molecule disturbance ribonucleic acid, 2～8 ℃ of preservations, redissolve into desired concn with front DEPC water; Part by weight 1:1 ~ the 1:10 of lyophilized products and water;
Described DEPC water is the water except nuclease processing through pyrocarbonic acid diethyl ester, vehicle economy PC water;
The concentration of the DEPC aqueous solution of siRNA is 10～40 μ g/100 μ l;
The concentration of the DEPC aqueous solution of sodium polyphosphate is 1～2mg/ml;
In the sodium-acetate buffer of chitosan, the concentration of chitosan is 1～2mg/ml;
Volume ratio is:
The DEPC aqueous solution of siRNA: the EDPC aqueous solution of sodium polyphosphate: sodium-acetate buffer=1 of chitosan: 1～4: 5～20;
The present invention is based on anatomical structure and the physiological characteristics of nasopharynx part uniqueness, developed the chitosan nano transmission system of the siRNA of nasal cavity topical therapeutic nasopharyngeal carcinoma.The present invention can effectively send siRNA to enter tissues of nasopharyngeal carcinoma, and targeting is good, and dosage is little, can avoid after siRNA drug administration by injection the degraded before arriving nasopharynx part and the picked-up of its hetero-organization.CS nanoparticle can effectively protect siRNA not destroyed by nasal cavity liquid.SiRNA transmission system of the present invention can effectively suppress related gene in nasopharyngeal carcinoma cell.
Accompanying drawing explanation
Fig. 1 is the nanoparticle particle diameter potential image of the inventive example 1.
Fig. 2 is agarose gel electrophoresis result.
Fig. 3 is that the nanoparticle of the embodiment of the present invention 3 is to the transfection effect of nasopharyngeal carcinoma cell.
Fig. 4 is that the nanoparticle of the embodiment of the present invention 4 is to the Gene silencing efficacy of nasopharyngeal carcinoma cell (5#).
The specific embodiment
In embodiment, if no special instructions, be all weight percentage.
By negative 40 μ g siRNA 0.1gDEPC water dissolution, obtain siRNA solution;
Get the sodium polyphosphate DEPC aqueous solution that 0.035g siRNA solution, 0.065g DEPC water and 0.1g weight concentration are 0.168%;
Dropwise add the sodium-acetate buffer 0.5g of the chitosan of pH4, wherein: the weight concentration of chitosan is 0.2%, limit edged vortex mixed, rear standing 30min, obtains siRNA-CS nanoparticle suspension, and the viscosity-average molecular weight of chitosan is 1,000,000; Particle diameter Potential distribution is shown in Fig. 1.
Particle diameter (nm) PDI(polydispersity coefficient) Zeta electric potential (mV)
115.8 0.151 27.8
Polydispersity coefficient is defined as follows: polydispersity coefficient (PDI) refers to the grain size dispersity of nanoparticle, is calculated and is provided by instrument, and PDI is the smaller the better between 0 to 1, PDI value.
Zeta electric potential (mV) adopts Ma Erwen laser particle analyzer to record, and has adopted laser Doppler velocimetry (LDV) principle.
1) by 40 μ g siRNA 0.1gEDPC water dissolutioies, get 0.0375g siRNA solution, 0.0875g DEPC water mixes with the DEPC aqueous solution 0.125g of sodium polyphosphate TPP (0.168%), dropwise add the sodium-acetate buffer 0.5g of the chitosan of pH6, wherein, the weight concentration of chitosan is 0.2%, the viscosity-average molecular weight of chitosan is 100,000, obtains siRNA-CS nanoparticle solution; Detecting nanoparticle particle diameter through Ma Erwen laser particle analyzer is 90nm, and Zeta electric potential is 22mV.
2) in the product of step 1), add 37.5mg HP-β-CD and 37.5mg trehalose, ultrafiltration and concentration;
3) product-30～25 that 2 steps obtained ℃ program lyophilizing, obtains negative small molecule disturbance ribonucleic acid nanoparticle transmission system, and 2～8 ℃ of preservations, with front DEPC water redissolution;
Adopt DEPC water redissolution nanoparticle, carry out nasal cavity liquid stability test:
Rat pentobarbital sodium anesthesia posterula is with normal saline 10ml perfusion half an hour, get perfusate 0.5ml, add respectively and redissolve 20 μ g/ml siRNA nanoparticles after 0.5ml 20 μ g/ml siRNA and embodiment 2 lyophilizing, hatch for 37 ℃, 0,30,2h, 5h sample 0.2ml, deposit for-20 ℃.
80 ℃, above-mentioned sample heating 5min end enzymatic activitys, and 5ul heparin adds vortex centrifugal after 50ul sample, supernatant 4% agarose gel electrophoresis, and gel imaging system is observed.
Fig. 2 is electrophoresis result, in Fig. 2, is followed successively by from top to bottom 4 kinds of siRNA nanoparticles and naked siRNA nasal cavity liquid and hatches the sample of 0min, 2h.Wherein No. 4, No. 9 sample is nanoparticle prepared by embodiment 2.No. 5, No. 10 is naked siRNA.
Show: siRNA nanoparticle extends with nasal cavity perfusate incubation time, and siRNA band shoals.Naked siRNA band is shallow compared with siRNA nanoparticle.
Above result shows that siRNA nanoparticle can improve the stability of siRNA in nasal cavity liquid.
By 40 μ g Cy3-siRNA 0.1gEDPC water dissolutioies, get 0.035gCy3-siRNA solution, 0.065gEDPC water mixes with the DEPC aqueous solution 0.1g of sodium polyphosphate TPP (0.168%), dropwise add the sodium-acetate buffer 0.5g of the chitosan of pH5, wherein, the weight concentration of chitosan is 0.2%, the viscosity-average molecular weight of chitosan is 100,000, obtains Cy3-siRNA-CS nanoparticle solution; Detecting nanoparticle particle diameter through Ma Erwen laser particle analyzer is 110nm, and Zeta electric potential is 28mV.
Cell culture and transfection:
The negative siRNA of the Cy3 labelling that described Cy3-siRNA refers to.Wherein, Cy3 is a kind of red fluorescence probe in recent years newly developed, and it is brighter than other red fluorescence probe of the overwhelming majority, be more not easy cancellation, and background is lower.
Fluorescently-labeled siRNA detects transfection efficiency, a kind of the most frequently used method of optimization transfection method.After fluorescently-labeled siRNA transfectional cell, can directly use with fluorescence microscope, confocal laser scanning microscope, also can detect by flow cytometer, determine whether the height of effective transfection and transfection efficiency.Fluorescently-labeled siRNA also can be used as following the trail of the location of siRNA in born of the same parents and the situation of distribution.
CNE cell adds in 24 orifice plates to be cultivated, and culture medium 1640+10%FBS adds respectively Cy3-siRNA nanoparticle solution to make final concentration be followed successively by 10nM, 20nM, 50nM and 100nM;
CNE cell refers to KB cell, and CNE cell is in " Shandong medicine " 51 phases in 2011, the anti-pharyngeal cancer cell strain of PABA/NO CNE cell proliferation and migration on this is had a detailed report;
The Cy3-siRNA(siRNA concentration that positive control adopts Lipofecatamine 2000 to mediate is 100nM);
Negative control adopts naked Cy3-siRNA aqueous solution directly to hatch (siRNA concentration is 100nM).
3 multiple holes of each experiment.After adding various Cy3-siRNA preparations, hatch 12 ~ 24 hours, PBS washed cell 5 times, paraformaldehyde is fixed, the Hoechst 10min that dyes, PBS washed cell, fluorescence microscope is taken pictures.Transfection results is shown in Fig. 3, and Cy3-siRNA nanoparticle cell transfecting effect is better than same concentration positive control.
1) by 40 μ g BCl2-siRNA 0.1gEDPC water dissolutioies, get 0.0375g BCl2-siRNA solution, 0.087gDEPC water mixes with the DEPC aqueous solution 0.125g of sodium polyphosphate TPP (0.168%), dropwise add the sodium-acetate buffer 0.5g of the chitosan of pH5, the viscosity-average molecular weight of chitosan is 50,000, the weight concentration of chitosan is 0.2%, obtains siRNA-CS nanoparticle solution; Detecting nanoparticle particle diameter through Ma Erwen laser particle analyzer is 135nm, and Zeta electric potential is 35mV.
2), in the product of step 1), add any methyl-β-cyclodextrin of 60mg and 18.75mg trehalose, ultrafiltration and concentration;
3) mixture-30～25 that 2 steps obtained ℃ program lyophilizing, 2 ℃ of preservations, with front DEPC water redissolution; Cell culture and transfection:
CNE cell adds in 24 orifice plates to be cultivated, culture medium 1640+10%FBS, and before transfection, cell degree of converging is 30%～50%.By rear above-mentioned nano-granule freeze-dried powder redissolution and other 5 kinds of nanometer formulation transfectional cells, BCl2-siRNA final concentration is 50nM;
Positive control is that Lipofecatamine 2000 transfection BCl2-siRNA(BCl2-siRNA concentration are 50nM);
Negative control is that naked BCl2-siRNA water preparation is directly hatched.After 72 hours, collecting cell, RISO extracts cell total rna.QRT-PCR quantitative analysis.
– detects BCl2 and GAPDH gene
– primer
Hs-BCL2-F':GGTCATGTGTGTGGAGAGC
Hs-BCL2-R':GATCCAGGTGTGCAGGTG
Hs-GD-F’:GAAGGTGAAGGTCGGAGTC
Hs-GD-R’:GAAGATGGTGATGGGATTTC
– does homogenization with GAPDH, adopts 2-Δ Δ Ct method to calculate relative expression and leads.
Transfection results is shown in 5# preparation in Fig. 4, and BCl2 Gene silencing efficacy is better than positive control (PC).
Claims (3)
1. the chitosan nano transmission system of small molecule disturbance ribonucleic acid, it is characterized in that, take chitosan as transmitting main body, take the gross weight of described transmission system as benchmark, contain 0.5～2.0% small molecule disturbance ribonucleic acid and 10%～25% sodium polyphosphate and carrier, described carrier with the ratio of chitosan, small molecule disturbance ribonucleic acid and sodium polyphosphate gross weight is:
Carrier: gross weight=20～100: 1;
Before and after described nanoparticle lyophilizing, particle diameter is 60～200nm, Zeta electric potential 10～70mV;
Described carrier is the mixture of cyclodextrin derivative and trehalose, and weight ratio is: cyclodextrin derivative: trehalose=1～3.5: 1, and the viscosity-average molecular weight of chitosan is 5～1,000,000, deacetylation is more than 80%;
Described cyclodextrin derivative is HP-β-CD or any methyl-β-cyclodextrin;
The preparation method of the nanoparticle transmission system of described small molecule disturbance ribonucleic acid, comprises the steps:
By the DEPC aqueous solution of the DEPC aqueous solution of siRNA and sodium polyphosphate, be added dropwise to the sodium-acetate buffer of pH4～6 chitosan, speed is 10～25 droplets/minute, then leaves standstill 20～40min, collect the nanoparticle solution of siRNA, mix with carrier again, be concentrated into 10～30% ,-30～25 ℃ of program lyophilizing of original volume, obtain lyophilized products, be the nanoparticle transmission system of described small molecule disturbance ribonucleic acid, 2～8 ℃ of preservations, redissolve into desired concn with front DEPC water; Part by weight 1:1～the 1:10 of lyophilized products and water;
Described DEPC water is the water except nuclease processing through pyrocarbonic acid diethyl ester, vehicle economy PC water;
The concentration of the DEPC aqueous solution of siRNA is 10～40 μ g/100 μ l;
The concentration of the DEPC aqueous solution of sodium polyphosphate is 1～2mg/ml;
In the sodium-acetate buffer of chitosan, the concentration of chitosan is 1～2mg/ml;
Volume ratio is:
The DEPC aqueous solution of siRNA: the EDPC aqueous solution of sodium polyphosphate: sodium-acetate buffer=1 of chitosan: 1～4: 5～20.
2. the chitosan nano transmission system of small molecule disturbance ribonucleic acid according to claim 1, it is characterized in that, described carrier is the mixture of cyclodextrin derivative and trehalose, weight ratio is: cyclodextrin derivative: trehalose=1～3.5: 1, the viscosity-average molecular weight of chitosan is 5～1,000,000, and deacetylation is more than 80%.
3. according to the chitosan nano transmission system of the small molecule disturbance ribonucleic acid described in claim 1～2 any one, it is characterized in that, described small molecule disturbance ribonucleic acid is the small molecule disturbance ribonucleic acid without the small molecule disturbance ribonucleic acid of target function gene, targeting Bcl-2 gene, survivin gene or other nasopharyngeal carcinoma related genes.
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| "壳聚糖-siRNA纳米粒的制备及其特征分析;姚鹏飞 等;《中华神经医学杂质》;20071231;第6卷(第12期);第1225-1226页 * |
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