CN104327141B - RNA nano particles and its application in stomach cancer preventing and treating - Google Patents
RNA nano particles and its application in stomach cancer preventing and treating Download PDFInfo
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Abstract
A kind of RNA nano particles, form particle, a chains RNA sequence is that SEQ ID No.1, b chains RNA sequence is SEQ ID No.2, and c chains RNA sequence is SEQ ID No.3 by a chain RNA, b chain RNA and c chain RNA by base pairing rules.Experimental verification of the RNA nano particles through cell and animal level that the present invention is provided shows that it has good biological safety, excellent gene interference effect and selectivity, the growth of stomach cancer cell line and subcutaneous transplantation knurl can effectively be suppressed, stomach cancer preventing and treating is can be applied to and diagnose.
Description
Technical field
The present invention relates to a kind of biological nano particle, more particularly to a kind of RNA nano particles, carried out using it as carrier
The method that siRNA is delivered in vivo and in vitro, and RNA nano particles after being marked with nir dye are in subcutaneous tumors model
Application in living body fluorescent imaging
Background technology
Stomach cancer has the features such as incidence of disease is high, easily transfer and case fatality rate are high, according to clinical statisticses, and root value criterion tumour is answered
Hair and the rate of transform are up to 33%.In China, incidence gastric cancer rate is located at second, and the death rate is located at the 3rd.Global annual new hair
Stomach cancer more than 100 ten thousand, death about 800,000, the annual new hair stomach cancer of China accounts for the 42% of the whole world, and death accounts for 35%, its incidence of disease and death
Rate is world average level more than twice.
Stomach cancer originates from the mucomembranous epithelial cell on coat of the stomach most top layer, can betide each position of stomach, can invade coat of the stomach
Different depth and range, the treatment of the early diagnosis and real-time tracing stomach cancer cell of stomach cancer to stomach cancer are most important.Operation, change
Treat, radiotherapy and Biological target therapy are the main methods for treating malignant tumour.
Chinese invention patent application 201110045024.5 discloses a kind of stomach lymph node and understands method, including first cuts
Ligamentum hepatogastricum, cleans the 12nd group of lymph node of hepatodudenal ligament, then cleans area's lymph node on the 5th group of pylorus by pylorus top,
And cut off, ligature the right artery and vein of stomach, then cut lesser omentum internal film tissue along diaphram pin, caudate lobe of liver lower edge, along side clockwise
Cut to around to orifice of the stomach area right side, the 1st group of right lymph node of orifice of the stomach of cleaning and the 3rd group of lymph node of lesser curvature of stomach, then along pancreas upper limb
Capsula pancreatis, to pylorus lower section, cleans area on the 6th group of subpyloric lymph nodes, with pylorus and merges；Again along arteria hepatica communis do surface according to
It is secondary cleaning the 7th group of left gastric artery by, by the 8th group of arteria hepatica communis, the 9th group of arteria coeliaca take up the dry lymph node of arteria linenalis so that complete
Into the removing of lymph node.The technology proposes the lymph node dissection method with " surrounding and annihilating formula " first, and takes and more reasonably remove
Approach, greatly simplifies operating procedure, improves operability, reduces damage of the reset procedure to surrounding tissue, significantly reduces the surface of a wound,
Improve the security of operation.But, simple operative treatment is limited, end-stage patients or postoperative for the curative effect of Patients with Gastric Cancer
The essential therapeutic arsenals of recurrence or transferrer are chemotherapy and radiations.
With deepening continuously for stomach cancer molecular biology research, Biological target therapy opens new way for the treatment of stomach cancer
Footpath.RNA interference has great application prospect as presently the most efficient gene silencing technology in the treatment of tumour, its
The expression of target gene specific can be blocked, corresponding protein level and function is lowered, regulates and controls associated signal paths, so as to press down
Tumour growth processed, invasion and attack, with molecular specificity and selectivity, are capable of the killing tumour cell of selectivity, and to human body just
Often tissue is not damaged.But exposed siRNA unprotect, easily by the nuclease in body and in surrounding environment
Act on and degrade, stability is low, and causes to be unable to free penetrating cell membrane because siRNA had polyanionic, reaches
Dosage during target tissue is significantly reduced.Therefore, using appropriate delivery system by siRNA it is specific be sent to target cell and be
The challenge of siRNA therapy fields.Therefore develop a kind of safe, specific siRNA delivery systems has for the treatment of stomach cancer
Great meaning.
Salih Gencer et al. are by lipofectamin2000 as transfection reagent by for MMP-3 genes
SiRNA is transferred in stomach cancer cell line AGS, effectively reduces migration and wellability (the Journal of of ags cell
Gastrointestinal and Liver Diseases.2011Mar；20(1):19-26).In addition, WeiZhou et al. passes through
The siRNA of Akt1 genes is transferred in gastric cancer cell and BGC-823 by slow virus as carrier, internal and external
Research shows that stomach cancer cell is remarkably reinforced (Regulatory Peptides.2012Jun10 to the sensitiveness of drugs Cisplatin；176
(1-3):13-21).The carrier lipofectamin2000 for the siRNA deliverings being related in above-mentioned two technologies and slow virus are in reality
Limited in the application of border by cytotoxicity higher lipofectamin2000 and slow virus potential source biomolecule security, Shang Nan
To realize being applied in curing gastric cancer.
The content of the invention
It is an object of the present invention to provide a kind of RNA nano particles, biocompatibility is high, realize siRNA efficiently and
Specific delivering.
It is another object of the present invention to provide a kind of RNA nano particles, the silence for BRCAA1 genes can be effective
Suppress increment and the inducing cell apoptosis of gastric carcinoma cells.
It is yet a further object of the present invention to provide a kind of RNA nano particles, the RNA nanometers that nir dye is marked
The probe that grain is imaged as the living body fluorescent of gastric cancer in nude mice subcutaneous transplantation knurl model.
A further object of the present invention is to provide a kind of RNA nano particles, the preventing and treating for stomach cancer.
A kind of RNA nano particles that the present invention is provided, are formed by a chain RNA, b chain RNA and c chains RNA by base pairing rules
Particle, its respective sequence is respectively SEQ ID No.1, SEQ ID No.2 and SEQ ID No.3, forms the structure such as institute of following formula I
Show
Another RNA nano particles that the present invention is provided, are made up of a chain RNA, b chain RNA and c chains RNA, by base pairing
Rule forms particle, and its respective sequence is respectively SEQ ID No.1, SEQ ID No.2 and SEQ ID No.3, b chains RNA5 '
End carries the siRNA of breast cancer correlation antigen gene 1 (Breast cancer-associated antigen1, BRCAA1), should
SiRNA sense strand is connected with b chains RNA5 ' ends, and sequence is SEQ ID No.4, and its antisense strand sequence is SEQ ID No.5, shape
Into structure as shown in following formula II.
The siRNA that the present invention is provided, for the purpose of protection stability, can also add protection sequence thereon, such as at it
Sequence on 3 ' ends of antisense strand and sense strand plus two u base compositions.
The RNA nano particles that the present invention is provided, also 5 ' the end mark folic acid in a chains RNA.
The RNA nano particles that the present invention is provided, also 5 ' the end mark tracers in c chains RNA, such as：But it is not limited only to enzyme mark
Note, fluorescence labeling and isotope marks etc. so that RNA nano particles can be used for the probe that organism (live body) is imaged, and be made
Detection reagent (box) composition.
The various RNA nano particles that the present invention is provided, can realize siRNA efficient and specific delivering and targeted delivery,
Available for the medicine for preparing stomach cancer preventing and treating.
The beneficial effect that technical solution of the present invention is realized：
The RNA nano particles that the present invention is provided, are advised by three kinds of RNA such as a chain RNA, b chain RNA and c chains RNA by base pairing
Then form nano particle, biocompatibility is high, can realize that siRNA is efficient and specific delivering.
The present invention carries siRNA by RNA nano particles and enters stomach cancer cell, realizes killing stomach cancer cell and suppresses naked
Mouse subcutaneous tumors grow.The RNA interfering of BRCAA1 genes is carried as carrier using the stable RNA nano particles of heat power, and will
Folic acid realizes the specific recognition of the stomach cancer cell line MGC-803 cells to folacin receptor height expression as target, and causes stomach
The apoptosis of cancer cell, enhances therapeutic effect.
The RNA nano particles that the present invention is provided, after it carries tracer, can be used as organism subcutaneous transplantation knurl model
Living imaging probe, diagnosis and treatment applied to stomach cancer.
Brief description of the drawings
Fig. 1 is that RNA nano particles of the present invention carry folic acid, tracer and the siRNA structures for BRCAA1 genes simultaneously
Schematic diagram；
Fig. 2A is the stream after the RNA nano particles that MGC-803 cells are marked with Alexa Fluor647 and folic acid are incubated altogether
Formula analysis chart；
Fig. 2 B are the streaming after the RNA nano particles that GES-1 cells are marked with Alexa Fluor647 and folic acid are incubated altogether
Analysis chart；
Fig. 3 A are to verify silencing efficiency figure of the RNA nano particles to BRCAA1 genes using fluorescent quantitative PCR experiment；
Fig. 3 B are to verify silencing efficiency figure of the RNA nano particles to BRCAA1 genes using immunoblot experiment；
Fig. 4 is apoptosis feelings of the carrying for MGC-803 cells caused by the siRNA of BRCAA1 genes RNA nano particles
Condition figure；
Fig. 5 is directed to the siRNA of BRCAA1 genes growth inhibition situation of the RNA nano particles to nude mice by subcutaneous knurl for carrying
With the comparison figure of negative and positive controls；
Fig. 6 A are to be injected intravenously after RNA nano particles respectively at 30 minutes, 3 hours, 5 hours, 12 hours and 24 hours
Living body fluorescent image, arrow indicate for tumor locus；
Fig. 6 B are to be injected intravenously after RNA nano particles respectively at 5 hours, 24 hours, 48 hours, 96 hours and 7 days
Isolated organ fluorescence imaging figure；In figure, digital " 1 " represents tumour, and digital " 2 " represent heart, and digital " 3 " represent liver, numeral
" 4 " represent spleen, and digital " 5 " represent lung, and digital " 6 " represent stomach, and digital " 7 " represent kidney, and digital " 8 " represent bladder, numeral
" 9 " represent musculature.
Embodiment
Technical scheme is described in detail below in conjunction with accompanying drawing.Skill of the embodiment of the present invention only to illustrate the present invention
Art scheme and it is unrestricted, although the present invention is described in detail with reference to preferred embodiment, one of ordinary skill in the art
It should be appreciated that can be modified to the technical scheme of invention or equivalent substitution, without departing from the essence of technical solution of the present invention
God and scope, it all should cover in scope of the presently claimed invention.
The present invention relates to molecular biology experiment, if not otherwise specified, refer to certainly《Molecular cloning》One book (J. Pehanorms
Not Ritchie, T. Mannies A Disi write by Brooker, E.F., Science Press, 1994).The book and its follow-up version of publishing are abilities
The field technique personnel reference book with directiveness the most frequently used in the experimental implementation that progress is related to molecular biology.This
Outside, according to different experiments purpose, finger of the those skilled in the art in extensive stock kit (Kit) incidental operation manual
Leading lower completion tests or entrusts accordingly specialized company to carry out, such as：Gene sequencing, plasmid order-checking and determination molecular weight etc..
Indicate, be purchased from Sigma-Aldrich (Sigma- if the reagent used in the present invention is not known
Aldrich)。
Silence of the following examples of the present invention based on BRCAA1 genes can effectively suppress the propagation of human gastric cancer MGC-803 cells
And inducing cell apoptosis, its mechanism promotes Rb and Bax protein expressions with it, suppresses Bcl-2 protein expressions relevant.BRCAA1 genes
It will be a potential gene therapy target spot for being directed to stomach cancer.
Embodiment 1RNA nano particles carry the realization that siRNA kills stomach cancer cell
RNA nano particles carry siRNA and enter stomach cancer cell, realize killing stomach cancer cell and suppress the life of nude mice by subcutaneous knurl
Long, its experimental method is as follows：
The first step, the structure of pRNA-3WJ RNA nano particles：
The RNA nano particles are made up of (referring to Fig. 1) three parts, 5 ' ends point of three parts such as respectively chain a, chain b and chain c
Folate molecule (being used as targeting ligand) on other covalent modification, Alexa Fluor647 (near-infrared fluorescent indicator), and
BRCAA1siRNA, is made the part of a3WJ, b3WJ and c3WJ tri-, and above-mentioned three part is produced by TriLink companies of the U.S..Will
The part of a3WJ, b3WJ and c3WJ tri- is with 1:1:1 mixed in molar ratio in DEPC treat ultra-pure water in either TMS buffer solutions
(89mM Tris,5mM MgCl2,pH7.6).For the dimer being made up of above-mentioned three partial purification, tripolymer, and 3WJ structures
Nano particle, by said mixture carry out 12% concentration native polyacrylamide gel electrophoresis be then demultiplex out 3WJ knot
The nano particle of structure, is then put in -20 DEG C with absolute ethyl alcohol overnight precipitation.The precipitation being collected into is removed to be redissolved in after ethanol
In pure water.
Second step, flow cytometry analysis gastric cancer cell line MGC-803 and gastric epithelial cell GES-1 are built to step one
RNA nano particles different ingestion efficiencies
MGC-803 cells and GES-1 cells are inoculated in six orifice plates first, growth is stayed overnight, then will
RNA nano particles and MGC-803 cells and the GES-1 cell incubations of AlexaFluor647 marks, RNA concentrations of nanoparticles is
200nM, incubation time is 3 hours.After incubation terminates, flushed three times with PBS, 1 × 10 is then collected respectively5Individual MGC-
803 cells and GES-1 cells carry out flow cytometry.Collect cell fluorescence signal and use BD FACSCalibur's
FL-4 passages (participate in Fig. 2A and Fig. 2 B).
3rd step, silencing efficiency of the 3WJ RNA nano particles to the BRCAA1 genes in MGC-803 cells
Two kinds of RNA nano particles are used for studying silencing efficiency, and a kind of tied in the c3WJ parts of RNA nano particles
BRCAA1 siRNA is closed, another RNA nano particles are to combine random siRNA as control in c3WJ parts.Two kinds
Particle is collectively referred to as 3WJ RNA nano particles in the present embodiment.
In addition, being used as positive control with the Lipofectamine2000 siRNA for transfecting BRCAA1.By 3WJ RNA nanometers
Grain and Lipofectamine2000 as transfection reagent processing MGC-803 cells 12 hours, 3WJ RNA nano particles with
And corresponding BRCAA1 siRNA concentration is 200nM.Incubation continues to cultivate after finishing, and amounts to 48 hours.Then Trizol is used
Reagent collects the total serum IgE of the MGC-803 cells of different disposal, and then reverse transcription is into cDNA, and carries out fluorescent quantitation RCR to determine
The silencing efficiency of mRNA level in-site (referring to Fig. 3 A).
The BRCAA1 primers used are as follows：
Upstream:5'-ACCAAATCTCCCGCAAGG-3'；
Downstream:5'-CATATTTTCCAGGTCCGACA-3'
The GAPDH primers used are as follows：
Upstream:5'-GAAGGTGAAGGTCGGAGTC-3'；
Downstream:5'-GAAGATGGTGATGGGATTTC--3'.
MGC-803 cells are subjected to above-mentioned similar processing, and collect cell pyrolysis liquid doing the survey of immune protein Blot experiment
Determine the silencing efficiency of protein level (referring to Fig. 3 B).
4th step, the measure of MGC-803 Level of Apoptosis
Three kinds of processing of above-mentioned steps are carried out to MGC-803 cells by using 3WJ RNA particles, then using Annexin V-
Double dye methods of FITC/PI and with the apoptosis situation of flow cytomery MGC-803 cells (referring to Fig. 4).From fig. 4, it can be seen that comparing
In the control group for the MGC-803 cells for not doing any processing, the RNA nano particles for carrying random siRNA are only caused seldom
The Apoptosis of amount, and the cell that the RNA nano particles for carrying the siRNA of BRCAA 1 then cause 2.51% there occurs that early stage withers
Die, 15.0% cell there occurs late apoptic.
5th step：Inhibitory action of the 3WJ RNA nano particles to nude mice by subcutaneous knurl
The subcutaneous tumors model of nude mice is built first：By 2 × 10 in logarithmic phase6Individual MGC-803 cells are suspended in 200 μ l
PBS in, it is subcutaneous (18g-22g) to be then injected in Female nude mice, raises after 2 weeks -3 weeks, treats that the volume of tumour reaches
100mm3-150mm3Left and right, can be used to do subcutaneous tumors suppression experiment.By 18 growth conditions identical subcutaneous tumors model nude mices with
Machine mean random is divided into three groups, every group 6.
Control group is every other day injected in 100 μ lPBS buffer solutions, two other laboratory group, and one group of nude mice is every other day
The μ l concentration of intratumor injection 100 is the 3WJ RNA nano particles that 200nM carries the siRNA of BRCAA 1, and the nude mice of another set is every
100 μ l concentration are injected every two days carries random siRNA (scrambled control) for 200nM.Post-tensioning cervical vertebra is put to death within 14 days
Mouse, takes tumor tissues observation to take pictures (referring to Fig. 5).As seen from Figure 5, the gross tumor volume of control group of PBS is injected most
Greatly, its gross tumor volume of the random siRNA of the injection carrying experimental group of RNA nano particles has the trend diminished relative to control group,
And the experimental group for the RNA nano particles for carrying the siRNA of BRCAA 1 is injected, its gross tumor volume is minimum.
Embodiment 2RNA nano particles as imaging probe
The present embodiment for realize nearly tracer (IR dyes) mark RNA nano particles as organism (such as：Nude mice
Stomach cancer subcutaneous transplantation knurl model) living body fluorescent image probe, its experimental method is as follows：
The first step, the foundation of nude mice by subcutaneous knurl model
The MGC-803 cell line subcutaneous tumors models of nude mice are set up using the method for the 5th step in embodiment 1, the body of tumour is treated
Product reaches to be used for doing living body fluorescent zoopery during 200mm3 or so.
The RNA nano particles for being marked with folic acid and nir dye Alexa Fluor647 are injected intravenously into nude mouse
(pressing 32mg/kg body weight concentration, add the 20nmol RNA nano particles that about 200 μ l are dissolved in PBS), in intravenous injection
Afterwards 30 minutes, 3 hours, 5 hours, 12 hours and 24 hours equi-time points nude mice is carried out respectively the living body fluorescent of whole body into
Picture, the excitation wavelength of use is 620 nanometers -640 nanometers, and launch wavelength is 685 nanometers -715 nanometers, and the time for exposure is 15 seconds
(referring to Fig. 6 A), from Fig. 6 A, 30 minutes or so after intravenous injection, the fluorescence background of whole body was very strong, tumor locus it is glimmering
Optical signal is difficult to distinguish.Over time, the signal of tumor locus constantly strengthens, and the background at other positions of body
Then constantly weaken, therefore tumor locus increasingly clearly indicates out.
Second step, the fluorescence imaging of isolated organ.The nude mice of the isodose RNA nano particles of previous step will be injected intravenously
Execution takes major organs to carry out fluorescence imaging observation.Kill mouse time point for intravenous injection after 3 hours, 24 hours, 48
Hour and 96 hours and 7 days equi-time points the living body fluorescent of whole body is carried out to nude mice and is imaged, the excitation wavelength of use is 620 to receive
- 640 nanometers of rice, launch wavelength is 685 nanometers -715 nanometers, and the time for exposure is 15 seconds (referring to Fig. 6 B) from Fig. 6 B, in vitro
The signal of tumour is stronger in organ, and higher signal intensity is remained in that behind 48 after intravenous injection hour, illustrates this
RNA nano particles have stronger stomach cancer target effect.
Claims (3)
1. a kind of RNA nano particles, are made up of a chain RNA, b chain RNA and c chains RNA, by base pairing rules formation particle,
The a chains RNA sequence is SEQ ID No.1；
The c chains RNA sequence is SEQ ID No.3；
The b chains RNA sequence is SEQ ID No.2, and its 5 ' end carries the siRNA, the siRNA of breast cancer correlation antigen gene 1
Sense strand and b chains RNA5 ' end be connected, sequence is SEQ ID No.4, and its antisense strand sequence is SEQ ID No.5, formation structure
As shown in following formula II；
5 ' the ends of a chains RNA also mark folic acid；
Shown c chains RNA 5 ' end marks also remember tracer.
2. the RNA nano particles described in a kind of claim 1 are preparing the application in treating and preventing gastric cancer medicament.
3. a kind of composition for diagnosing or detecting, it is characterised in that including the RNA nano particles described in claim 1.
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