CN104327141A - RNA nanoparticle and application of RNA nanoparticle in preventing and curing stomach cancer - Google Patents
RNA nanoparticle and application of RNA nanoparticle in preventing and curing stomach cancer Download PDFInfo
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Abstract
A RNA nanoparticle is disclosed. According to base pairing rules, a particle is formed from a chain RNA, b chain RNA and c chain RNA, wherein sequence of the a chain RNA is SEQ ID No.1; sequence of the b chain RNA is SEQ ID No.2; and sequence of the c chain RNA is SEQ ID No.3. It shows through experimental verification at the cellular and animal level that the RNA nanoparticle provided by the invention has good biosecurity and excellent gene interference effect and specificity, can effectively inhibit growth of gastric cancer cell lines and transplant subcutaneous sarcoma and can be applied in prevention, cure and diagnosis of stomach cancer.
Description
Technical field
The present invention relates to a kind of biological nano particle, particularly relate to a kind of RNA nano particle, the method with delivered in vitro in siRNA body is carried out using it as carrier, and the application in the living body fluorescent imaging of the RNA nano particle after marking with nir dye in subcutaneous tumors model
Background technology
Cancer of the stomach has high, the easy transfer of sickness rate and case fatality rate high, and according to clinical statistics, the recurrence of root value criterion tumour and the rate of transform are up to 33%.In China, incidence gastric cancer rate is positioned at second, and mortality ratio is positioned at the 3rd.The whole world is annual newly sends out cancer of the stomach more than 100 ten thousand, death about 800,000, and the annual new cancer of the stomach of China accounts for 42% of the whole world, and death accounts for 35%, and its M & M is all that world average level twice is many.
Cancer of the stomach originates from the mucomembranous epithelial cell on the most top layer of coat of the stomach, and can betide each position of stomach, can invade different depths and the range of coat of the stomach, early diagnosis and the treatment of real-time tracing stomach cancer cell to cancer of the stomach of cancer of the stomach are most important.Operation, chemotherapy, radiotherapy and Biological target therapy are the main method for the treatment of malignant tumour.
Chinese invention patent application 201110045024.5 discloses a kind of stomach lymphoglandula and knows method, comprise and first cut hepatogastric ligament, clean the 12nd group of lymph node of hepatodudenal ligament, district's lymphoglandula on the 5th group of pylorus is cleaned again by above pylorus, and cut off, the ligation stomach right side is dynamic, vein, again along diaphram pin, lesser omentum internal film tissue cuts by caudate lobe of liver lower edge, along clockwise direction on the right side of orifice of the stomach district, clean the 1st group of right lymphoglandula of orifice of the stomach and the 3rd group of lymph node of lesser curvature of stomach, capsula pancreatis is cut again along pancreas upper limb place, to pylorus, clean the 6th group of subpyloric lymph nodes, join with district on pylorus, do that surface is cleaned by the 7th group of left gastric artery, by the 8th group of arteria hepatica communis successively, the 9th group of coeliac artery is taken up the dry lymphoglandula of splenic artery, thus completed the removing of lymphoglandula again along arteria hepatica communis.This technology proposes the lymph node dissection method with " surrounding and annihilating formula " first, and takes more reasonably to remove approach, and simplify the operation step greatly, improves operability, reduces scavenging process to the damage of surrounding tissue, significantly reduces the surface of a wound, improve the security of operation.But simple operative treatment is limited for the curative effect of Patients with Gastric Cancer, the essential therapeutic arsenals of end-stage patients or postoperative recurrence or transferrer is chemotherapy and radiation.
Along with deepening continuously of cancer of the stomach molecular biology research, Biological target therapy is that the treatment of cancer of the stomach opens new approach.RNA interference is as current efficient gene silencing technology the most, great application prospect is had in the treatment of tumour, it can the expression of specific blocking-up target gene, lower corresponding protein level and function, regulation and control associated signal paths, thus Tumor suppression grows, invasion and attack, has molecular specificity and selectivity, can narrow spectrum killing off tumor cells, and the healthy tissues of human body is not damaged.But exposed siRNA unprotect; easily degrade by the effect of the nuclease in body and in surrounding environment; stability is low, and cause because siRNA had polyanionic can not free penetrating cytolemma, and dosage when reaching target tissue significantly reduces.Therefore, to deliver to target cell be the challenge that siRNA treats field by specific for siRNA to adopt suitable delivery system.Therefore develop a kind of safe, specific siRNA delivery system the treatment of cancer of the stomach is significant.
SiRNA for MMP-3 gene proceeds in stomach cancer cell line AGS by lipofectamin2000 as transfection reagent by the people such as Salih Gencer, effectively reduces migration and wetting property (the Journal of Gastrointestinal and Liver Diseases.2011Mar of ags cell; 20 (1): 19-26).In addition, the siRNA of Akt1 gene proceeds in gastric cancer cell and BGC-823 by slow virus as carrier by the people such as WeiZhou, shows that the susceptibility of stomach cancer cell to drugs Cisplatin obviously strengthens (Regulatory Peptides.2012Jun10 in body with external research; 176 (1-3): 13-21).The carrier lipofectamin2000 that the siRNA related in above-mentioned two technology sends and slow virus are subject to the restriction of the higher cytotoxicity of lipofectamin2000 and the security of slow virus potential source biomolecule in actual applications, are still difficult to realize being applied in curing gastric cancer.
Summary of the invention
One object of the present invention is to provide a kind of RNA nano particle, and biocompatibility is high, realizes siRNA efficient and specificly to send.
Another object of the present invention is to provide a kind of RNA nano particle, and the silence for BRCAA1 gene effectively can suppress the increment of gastric carcinoma cells and cell death inducing.
Another object of the present invention is to provide a kind of RNA nano particle, and the RNA nano particle marked by nir dye is as the probe of the living body fluorescent imaging of gastric cancer in nude mice subcutaneous transplantation knurl model.
Another object of the present invention is to provide a kind of RNA nano particle, for the control of cancer of the stomach.
A kind of RNA nano particle provided by the invention, presses base pairing rules by a chain RNA, b chain RNA and c chain RNA and forms particle, and its respective sequence is respectively SEQ ID No.1, SEQ ID No.2 and SEQ ID No.3, forms structure as shown in the formula shown in I
Another kind of RNA nano particle provided by the invention, be made up of a chain RNA, b chain RNA and c chain RNA, particle is formed by base pairing rules, its respective sequence is respectively SEQ ID No.1, SEQ ID No.2 and SEQ ID No.3, b chain RNA5 ' end carries breast cancer correlation antigen gene 1 (Breast cancer-associated antigen1, BRCAA1) siRNA, the sense strand of this siRNA is held with b chain RNA5 ' and is connected, sequence is SEQ ID No.4, its antisense strand sequence is SEQ ID No.5, forms structure as shown in the formula shown in II.
SiRNA provided by the invention, for the object of protection stability, also can add protection sequence thereon, as all added the sequence of two u based compositions on the 3 ' end of its antisense strand and sense strand.
RNA nano particle provided by the invention, also at 5 ' the end mark folic acid of a chain RNA.
RNA nano particle provided by the invention, also at 5 ' the end mark tracer agent of c chain RNA, as: but be not limited only to enzyme labelling, fluorescent mark and isotopic labeling etc., make RNA nano particle can be used for the probe of organism (live body) imaging, and make detection reagent (box) composition.
Various RNA nano particle provided by the invention, can realize siRNA efficient and specificly to send and targeted delivery, can be used for the medicine preparing cancer of the stomach control.
The beneficial effect that technical solution of the present invention realizes:
RNA nano particle provided by the invention, press base pairing rules by three kinds of RNA such as a chain RNA, b chain RNA and c chain RNA and form nano particle, biocompatibility is high, can realize siRNA efficient and specificly to send.
The present invention carries siRNA by RNA nano particle and enters stomach cancer cell, realizes killing and wounding stomach cancer cell and suppressing the growth of nude mice by subcutaneous knurl.The stable RNA nano particle of heat power is adopted to carry the RNA interfering of BRCAA1 gene as carrier, and using folic acid as target, realize the specific recognition to the stomach cancer cell line MGC-803 cell of folacin receptor high expression level, and cause the apoptosis of stomach cancer cell, enhance result for the treatment of.
RNA nano particle provided by the invention, after it carries tracer agent, can be used as the living imaging probe of organism subcutaneous transplantation knurl model, is applied to the Diagnosis and Treat of cancer of the stomach.
Accompanying drawing explanation
Fig. 1 is that RNA nano particle of the present invention carries folic acid, tracer agent and the siRNA structural representation for BRCAA1 gene simultaneously;
Fig. 2 A is the flow cytometer showed figure after RNA nano particle that MGC-803 cell and Alexa Fluor647 and folic acid mark is hatched altogether;
Fig. 2 B is the flow cytometer showed figure after RNA nano particle that GES-1 cell and Alexa Fluor647 and folic acid mark is hatched altogether;
Fig. 3 A adopts fluorescent quantitative PCR experiment checking RNA nano particle to the silencing efficiency figure of BRCAA1 gene;
Fig. 3 B adopts immunoblot experiment checking RNA nano particle to the silencing efficiency figure of BRCAA1 gene;
Fig. 4 is the apoptosis situation map carrying the MGC-803 cell that the RNA nano particle for the siRNA of BRCAA1 gene causes;
Fig. 5 carries RNA nano particle for the siRNA of BRCAA1 gene to the growth-inhibiting situation of nude mice by subcutaneous knurl and comparison diagram that is negative and positive controls;
Fig. 6 A is the living body fluorescent image respectively 30 minutes, 3 hours, 5 hours, 12 hours and 24 hours after intravenous injection RNA nano particle, arrow instruction be tumor locus;
Fig. 6 B is the isolated organ fluorescence imaging figure after intravenous injection RNA nano particle respectively when 5 hours, 24 hours, 48 hours, 96 hours and 7 days; In figure, numeral " 1 " represents tumour, and numeral " 2 " represents heart, and numeral " 3 " represents liver, numeral " 4 " represents spleen, and numeral " 5 " represents lung, and numeral " 6 " represents stomach, numeral " 7 " represents kidney, and numeral " 8 " represents bladder, and numeral " 9 " represents muscle tissue.
Embodiment
Technical scheme of the present invention is described in detail below in conjunction with accompanying drawing.The embodiment of the present invention is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
The present invention relates to molecular biology experiment, if not otherwise specified, can with reference to from " molecular cloning " book (J. Pehanorm Brooker, E.F. be Ritchie, T. Manny A Disi work not, Science Press, 1994).This book and follow-up publication version thereof are those skilled in the art's the most frequently used reference books with directiveness when carrying out the experimental implementation relevant to molecular biology.In addition, according to different experiments object, those skilled in the art complete and test or entrust specialized company to carry out accordingly under the guidance of extensive stock test kit (Kit) incidental operational manual, as: gene sequencing, plasmid check order and determine molecular weight etc.
If the present invention's reagent used does not clearly indicate, then all purchased from Sigma-Aldrich (Sigma-Aldrich).
Following examples of the present invention effectively can suppress propagation and the cell death inducing of people's gastric cancer cell line MGC-803 based on the silence of BRCAA1 gene, its mechanism and its promotion Rb and Bax protein expression, suppress Bcl-2 protein expression relevant.BRCAA1 gene will be a potential gene therapy target spot for cancer of the stomach.
Embodiment 1RNA nano particle carries the realization that siRNA kills and wounds stomach cancer cell
RNA nano particle carries siRNA and enters stomach cancer cell, realizes killing and wounding stomach cancer cell and suppressing the growth of nude mice by subcutaneous knurl, and its experimental technique is as follows:
The first step, the structure of pRNA-3WJ RNA nano particle:
This RNA nano particle is made up of (see Fig. 1) three parts, be respectively 5 ' of three parts such as chain a, chain b and chain c and hold folate molecule (as target part) on difference covalent modification, Alexa Fluor647 (near-infrared fluorescent indicator), and BRCAA1siRNA, make a3WJ, b3WJ and c3WJ tri-part, above-mentioned three parts are produced by TriLink company of the U.S..By a3WJ, b3WJ and c3WJ tri-part with the mixed in molar ratio of 1:1:1 in the ultrapure water of DEPC process or TMS damping fluid (89mM Tris, 5mM MgCl2, pH7.6).In order to the dimer be made up of above-mentioned three partial purifications, tripolymer, with the nano particle of 3WJ structure, then native polyacrylamide gel electrophoresis said mixture being carried out 12% concentration isolates the nano particle of 3WJ structure, is then put in-20 DEG C with dehydrated alcohol overnight precipitation.The precipitation collected is dissolved in pure water after removing ethanol again.
Second step, flow cytometry analysis gastric cancer cell line MGC-803 and gastric epithelial cell GES-1 are to the different ingestion efficiencies of the RNA nano particle that step one builds
First be inoculated in six orifice plates by MGC-803 cell and GES-1 cell, grow overnight, the RNA nano particle then marked by AlexaFluor647 and MGC-803 cell and GES-1 cell incubation, RNA concentrations of nanoparticles is 200nM, and incubation time is 3 hours.After hatching end, with PBS wash buffer three times, then collect 1 × 10 respectively
5individual MGC-803 cell and GES-1 cell carry out flow cytometry.The FL-4 passage (participate in Fig. 2 A and Fig. 2 B) of what collecting cell fluorescent signal adopted is BD FACSCalibur.
3rd step, 3WJ RNA nano particle is to the silencing efficiency of the BRCAA1 gene in MGC-803 cell
The RNA nano particle of two types is used for studying silencing efficiency, and a kind of is the siRNA combining BRCAA1 in the c3WJ part of RNA nano particle, and another kind of RNA nano particle combines random siRNA in contrast in c3WJ part.Two kinds of particles are collectively referred to as 3WJ RNA nano particle in the present embodiment.
In addition, with the siRNA of Lipofectamine2000 transfection BRCAA1 as positive control.Using 3WJ RNA nano particle and the Lipofectamine2000 process MGC-803 cell 12 hours as transfection reagent, the concentration of the siRNA of 3WJ RNA nano particle and corresponding BRCAA1 is 200nM.Continue after hatching to cultivate, amount to 48 hours.Then collect the total serum IgE of the MGC-803 cell of different treatment with Trizol reagent, then reverse transcription becomes cDNA, and carries out fluorescent quantitation RCR to measure the silencing efficiency (see Fig. 3 A) of mRNA level in-site.
The BRCAA1 primer used is as follows:
Upstream: 5'-ACCAAATCTCCCGCAAGG-3';
Downstream: 5'-CATATTTTCCAGGTCCGACA-3'
The GAPDH primer used is as follows:
Upstream: 5'-GAAGGTGAAGGTCGGAGTC-3';
Downstream: 5'-GAAGATGGTGATGGGATTTC--3'.
MGC-803 cell is carried out above-mentioned similar process, and collecting cell lysate does the silencing efficiency (see Fig. 3 B) that immune protein Blot experiment measures protein level.
4th step, the mensuration of MGC-803 Level of Apoptosis
By carrying out above-mentioned steps three kinds process with 3WJ RNA particle to MGC-803 cell, then adopt the two dye method of Annexin V-FITC/PI also by the apoptosis situation (see Fig. 4) of flow cytomery MGC-803 cell.As seen from Figure 4, compared to the control group of MGC-803 cell not doing any process, the RNA nano particle carrying random siRNA only causes the apoptosis of minute quantity, the cell that the RNA nano particle carrying BRCAA 1 siRNA then causes 2.51% there occurs early apoptosis, and the cell of 15.0% there occurs late apoptic.
5th step: 3WJ RNA nano particle is to the restraining effect of nude mice by subcutaneous knurl
First the subcutaneous tumors model of nude mice is built: will 2 × 10 of logarithmic phase be in
6individual MGC-803 cell suspension, in the PBS damping fluid of 200 μ l, is then injected in Female nude mice subcutaneous (18g-22g), after raising 2 weeks-3 weeks, treats that the volume of tumour reaches 100mm
3-150mm
3left and right, can be used to do subcutaneous tumors inhibition test.Subcutaneous tumors model nude mice stochastic averagina identical for 18 growth conditions is divided into three groups at random, often organizes 6.
Control group every other day injects 100 μ lPBS damping fluids, in two other laboratory group, one group of nude mice every other day intratumor injection 100 μ l concentration is the 3WJ RNA nano particle that 200nM carries BRCAA 1 siRNA, and it is that 200nM carries random siRNA (scrambled control) that the nude mice of other a group every other day injects 100 μ l concentration.Within 14 days, post-tensioning cervical vertebra puts to death mouse, gets tumor tissues observation and takes pictures (see Fig. 5).As seen from Figure 5, the gross tumor volume of the control group of injection PBS damping fluid is maximum, its gross tumor volume of experimental group that the RNA nano particle of random siRNA is carried in injection has the trend diminished relative to control group, and the experimental group of the RNA nano particle of BRCAA 1 siRNA is carried in injection, its gross tumor volume is minimum.
Embodiment 2RNA nano particle is as the probe of imaging
The present embodiment is for the RNA nano particle realizing tracer agent (Infrared dyes) nearly and mark is as organism (as: gastric cancer in nude mice subcutaneous transplantation knurl model) living body fluorescent image probe, and its experimental technique is as follows:
The first step, the foundation of nude mice by subcutaneous knurl model
Adopt the MGC-803 cell strain subcutaneous tumors model of the method establishment nude mice of the 5th step in embodiment 1, be used for doing living body fluorescent experimentation on animals when the volume of tumour reaches about 200mm3.
By the RNA nano particle intravenous injection that is marked with folic acid and nir dye Alexa Fluor647 in nude mouse (by 32mg/kg body weight concentration, add about 200 μ l and be dissolved in 20nmol RNA nano particle in PBS damping fluid), 30 minutes after intravenous injection, 3 hours, 5 hours, 12 hours and 24 hours equi-time points carry out the living body fluorescent imaging of whole body respectively to nude mice, the excitation wavelength adopted is 620 nanometer-640 nanometers, emission wavelength is 685 nanometer-715 nanometers, time shutter is that 15 seconds (see Fig. 6 A) is from Fig. 6 A, about 30 minutes after intravenous injection, the fluorescence background of whole body is very strong, the fluorescent signal of tumor locus is difficult to distinguish.As time goes on, the signal of tumor locus constantly strengthens, and the background at other positions of health then constantly weakens, therefore the showing more and more clearly of tumor locus.
Second step, the fluorescence imaging of isolated organ.Major organs is got in the execution of the nude mice of isodose for intravenous injection previous step RNA nano particle and carries out fluorescence imaging observation.The time point killing mouse is that after intravenous injection 3 hours, 24 hours, 48 hours and 96 hours and 7 days equi-time points carry out the living body fluorescent imaging of whole body to nude mice, the excitation wavelength adopted is 620 nanometer-640 nanometers, emission wavelength is 685 nanometer-715 nanometers, time shutter is that 15 seconds (see Fig. 6 B) is from Fig. 6 B, in isolated organ, the signal of tumour is stronger, and still keep higher strength of signal behind after intravenous injection 48 hours, illustrate that this RNA nano particle has stronger stomach cancer target effect.
Claims (11)
1. a RNA nano particle, presses base pairing rules by a chain RNA, b chain RNA and c chain RNA and forms particle, forms structure as shown in the formula shown in I
Described a chain RNA sequence is SEQ ID No.1;
Described b chain RNA sequence is SEQ ID No.2;
Described c chain RNA sequence is SEQ ID No.3.
2. RNA nano particle according to claim 1, is characterized in that 5 ' the end mark folic acid of described a chain RNA.
3. RNA nano particle according to claim 1, is characterized in that 5 ' the end mark tracer agent of described c chain RNA.
4. RNA nano particle according to claim 1, is characterized in that described b chain RNA5 ' end carries siRNA.
5. RNA nano particle according to claim 1, is characterized in that described b chain RNA5 ' holds the siRNA carried for BRCAA1 gene.
6. RNA nano particle according to claim 1, it is characterized in that described b chain RNA5 ' holds the siRNA carried for BRCAA1 gene, described siRNA comprises sense strand and antisense strand, and described sense strand is held with described b chain RNA5 ' and is connected.
7. RNA nano particle according to claim 1, it is characterized in that described b chain RNA5 ' holds the siRNA carried for BRCAA1 gene, described siRNA comprises sense strand and antisense strand, described sense strand is held with described b chain RNA5 ' and is connected, sequence is SEQ ID No.4, and the sequence of described antisense strand is SEQ ID No.5.
8. RNA nano particle according to claim 1, is characterized in that the structure of described RNA nano particle is as shown in the formula shown in II
9. RNA nano particle according to claim 1, is characterized in that described RNA nano particle can be used for the probe of organism imaging.
10. the application of RNA nano particle according to claim 1 in preparation treatment and prevention gastric cancer medicament.
11. 1 kinds, for the composition diagnosed or detect, is characterized in that comprising the described RNA nano particle of one of claim 1-8.
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