CN108938595A - A kind of cation lipid-mesoporous silicon composite Nano carrier preparation method carrying siRNA and chemotherapeutics altogether - Google Patents
A kind of cation lipid-mesoporous silicon composite Nano carrier preparation method carrying siRNA and chemotherapeutics altogether Download PDFInfo
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- CN108938595A CN108938595A CN201810808835.8A CN201810808835A CN108938595A CN 108938595 A CN108938595 A CN 108938595A CN 201810808835 A CN201810808835 A CN 201810808835A CN 108938595 A CN108938595 A CN 108938595A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a kind of cation lipid-mesoporous silicon composite Nano carrier preparation methods for carrying siRNA and chemotherapeutics altogether, method includes the following steps: synthesizing MDR1-siRNA using template method nanometer grain；Mesoporous silicon and chemotherapeutics are mixed in organic solvent, obtain carrying medicine mesoporous silicon after washing and drying；Medicine mesoporous silicon will be carried to be scattered in the chloroformic solution dissolved with lipid material, decentralized medium is added after solvent evaporated film forming, for ultrasound to being completely dispersed, filtration sterilization squeezes out adjustment particle size repeatedly；It mixes, stood with liposome solutions after siRNA is dissolved to obtain the final product.The complex carrier can enhance the cytotoxicity of drug, induce cell apoptosis, and synergistic antitumor effect is played on the basis of inhibiting MDR.
Description
Technical field
The invention belongs to chemical pharmaceutical technology fields, are related to a kind of cation lipid-Jie for carrying siRNA and chemotherapeutics altogether
The preparation method of hole silicon composite Nano carrier.
Background technique
It is still ineffective in most for the treatment of malignant tumors although chemotherapy of tumors achieves rapid progress in recent years,
One of major reason is the generation of tumor multidrug-resistance (multidrug resistance, MDR).MDR is universal
The main reason for being present in all kinds of tumour cells, being chemotherapy failure.Therefore, inhibition or reversion MDR have weight to oncotherapy
The theory and clinical practice meaning wanted.MDR is generally considered the self-protection of tumour cell confrontation chemotherapeutics toxic damages
Defense mechanism occurs related with many factors.For common resistance mechanism, the method that people devise a variety of reversion MDRs,
Including chemicals, immunological technique, gene technology etc..Wherein, (RNA interference, RNAi) technology is interfered using RNA,
The mRNA for inhibiting MDR1 coding by specificity using MDR1-siRNA, lowers the expression of P-gp, enhances tumour cell
To the sensibility of drug, Reversal effect is high, can be used as the new strategy of oncotherapy.
Nanometer formulation is used as anti-tumor drug transmitting carrier and has in-depth study and exploitation, in recent years some research cards
It is real, drug not only can be enhanced to the lethal effect of tumour there are many nano medicament carrying system, moreover it is possible to reduce the production of drug resistance of tumor
Raw and reversion MDR, while the disposition process of drug is not significantly changed, and can target tumor tissue.Thus, it is carried using nanometer
Body technique overcomes tumour MDR, and more other strategies are more reliable easy, has wide development and application prospect.
Mesoporous silicon oxide (MSNs) is a kind of inorganic nano-particle, and being used as chemotherapeutics transmitting carrier has many advantages,
Including stable in physicochemical property, large specific surface area, aperture and homogeneous grain diameter are controllable, modifiability is strong and biocompatibility is good
Deng, meanwhile, MSNs can also be shared with other means, if joint can lower P-gp and apoptosis-induced siRNA, collective effect in
Mdr cell, enhancing overcome the effect of MDR.Liposome MSNs is prepared, it is novel that core shell composite nano-granule (LMSNs) is made
Transmission system can get more excellent drug carrying ability.Due to the support of MSNs, the physically stable of lipid bilayer is improved
Property, lipid film lysosome destroys after carrier enters cell, MSNs exposure, drug quick release, reduces extracellular let out to reach
Leakage, the effect discharged in concentration intracellular.More importantly, preparation surface has the cationic-liposome of positive charge, is contained with MSNs
Chemotherapeutics, with liposome carry medicine MSNs, then by electrostatic interaction in adsorption MDR1-siRNA, it can be achieved that chemotherapy with
The synergistic effect of gene therapy effectively overcomes the MDR of tumour.
Summary of the invention
It is compound it is an object of the invention to propose a kind of cation lipid-mesoporous silicon for carrying siRNA and chemotherapeutics altogether
The preparation method of nano-carrier, first design synthesis have the high siRNA sequence for inhibiting efficiency to MDR1 gene, construct its expression
Plasmid prepares liposome (cationic liposomes, CLs) with cationic membrane material, carries MDR1- by electrostatic adsorption
siRNA；Chemotherapeutics DOX is contained with MSNs, then medicine MSNs is carried to get siRNA/DOX-CLMSNs with liposome.This is multiple
Closing the remaining positive charge of carrier surface can make it in conjunction with tumour cell, and lipid film destroys after carrier enters cell, and siRNA is de-
Simultaneously silencing MDR1 gene is fallen, so that the outlet of P-gp albumen is acted on decline, while MSNs is exposed and discharges DOX, to enhance drug
Cytotoxicity, induce cell apoptosis, on the basis of inhibiting MDR play synergistic antitumor effect.
Its technical solution is as follows:
A kind of cation lipid-mesoporous silicon composite Nano carrier preparation method carrying siRNA and chemotherapeutics altogether, including
Following steps:
(1) template method nanometer grain is used, MDR1-siRNA is synthesized；
(2) mesoporous silicon and chemotherapeutics are mixed in organic solvent, obtains carrying medicine mesoporous silicon after washing and drying；
(3) medicine mesoporous silicon will be carried to be scattered in the chloroformic solution dissolved with lipid material, and will be added and divides after solvent evaporated film forming
Dispersion media, for ultrasound to being completely dispersed, filtration sterilization squeezes out adjustment particle size repeatedly；
(4) it mixes, stood with liposome solutions after dissolving siRNA to obtain the final product.
In the present invention, in step (1), the partial size of mesoporous silicon is between 40-100nm, and aperture is between 1.2-6.0nm.It is situated between
Hole silicon is synthesized by following steps: using surfactant cetyl trimethylammonium bromide as template, ethyl orthosilicate is silicon
Source is reacted under alkaline condition, then is flowed back in methanol-HCl solution and deionized water, is removed surfactant, is obtained mesoporous
Silicon.
In the present invention, in step (2), chemotherapeutics can be hydrophobic drug or polypeptide, protein, big point of nucleic acid biology
Son.
Preferably, the hydrophobic drug is any in adriamycin (DOX), taxol, Irinotecan or cis-platinum.
In the present invention, siRNA sequence is 5 '-GATTGCATTTGGAGGACAA-3 '.
In the present invention, liposome is prepared by DOTAP, DOPC, cholesterol, DPPG.
In the present invention, the mass ratio of mesoporous silicon and chemotherapeutics is 2: 1-10: 1, and the mass ratio of mesoporous silicon and lipid film is 1
∶1-1∶2。
The invention has the benefit that
1. MSNs large specific surface area, drugloading rate more and unique drug release feature and liposome good biocompatibility can be merged
Advantage, both overcome the shortcomings of；
2. the cladding of lipid film can prevent drug from revealing in advance, realizes and concentrate drug release, and reduce whole body toxic side effect.
3. containing chemotherapeutics with MSNs, loading MDR1-siRNA with cationic-liposome, complex carrier carrying simultaneously is simultaneously
Chemicals and genomic medicine are transmitted,
4. lowering efflux protein expression with siRNA, liposome and MSNs enhancing cellular uptake and drug accumulation is used in combination
Performance inhibits tumour MDR, improves anti-tumor chemotherapeutic effect, and synergistic antitumor effect is played on the basis of inhibiting MDR.
Detailed description of the invention
Fig. 1: transmission electron microscope picture, wherein Figure 1A MSNs, Figure 1B Liposomes, Fig. 1 C are CLMSNs, and Fig. 1 D is
The transmission electron microscope picture of siRNA-CLMSNs.
Fig. 2: the Zeta potential comparison diagram of each nano-carrier.
Fig. 3: the In-vitro release curves figure of medicine (DOX) nanotube sample is respectively carried, wherein Fig. 3 A is pH 7.4, and Fig. 3 B is pH 5.
Fig. 4: external antitumor activity (MTT) result.
Fig. 5: fluorescence imaging result of the different carriers under inverted fluorescence microscope.
Specific embodiment
Technical solution of the present invention is described in more detail with reference to the accompanying drawings and detailed description.
The present invention has the mesopore silicon dioxide nano material of regular pore canal structure using template preparation, then with cationic
Liposome is wrapped up, and by electrostatic interaction in adsorption MDR1-siRNA, is constructed to concentrate in tumour cell and be determined
Position release drug and the composite Nano carrier for effectively inhibiting MDR, improving anti-tumor activity.
Embodiment 1
(1) preparation of nanometer particle: magnetite rotor and 1.0g CTAB are added in three-necked bottle, adds 100ml
Deionized water stirs 30min at 95 DEG C.160 μ L DEA liquid are added into bottle, continue to stir 15min.8ml TEOS is taken, slowly
It is added dropwise and (1 hour is added dropwise), after being added dropwise to complete, flow back 3h, and centrifugation discards supernatant liquid.With methanol-HCl solution (4: 1) and go from
Sub- water intersection is washed 3 times, and template agent removing is removed.The dry 12h in 50 DEG C of drying boxes, then it is dried in vacuo 12h.It is about up to average grain diameter
The nanometer grain (MSNs) of 80nm.
(2) take mesoporous silicon particle in 10ml centrifuge tube, adding appropriate PBS to disperse, the adriamycin (DOX) that 5mg/ml is added dropwise is molten
Liquid, constant volume after mixing.For 24 hours, centrifugation carries medicine mesoporous silicon (DOX-MSNs) when being rinsed to flushing liquor with PBS without color for stirring.
(3) 1,2- dioleyl phosphatidyl choline (DOPC) 30mg, cholesterol 30mg, (2,3- dioleoyls-are weighed respectively
Propyl)-trimethylamine (DOTAP) 60mg, 1,2- palmityl phosphatidyl glycerol (DPPG) 30mg and round-bottomed flask, it is dissolved in 8ml chloroform,
10mg MSNs is taken to be scattered in the above chloroformic solution, ultrasound is to being completely dissolved.Flask is installed on Rotary Evaporators, is arranged
Temperature 60 C degree mixes up revolving speed, closes air valve, and air pressure is no more than 0.03MPa, starts to evaporate.After chloroform is evaporated film forming completely,
Air valve to be opened, flask is removed, decentralized medium is added, for ultrasound to being completely dispersed, filtration sterilization squeezes out adjustment particle size repeatedly,
Up to the nanometer grain solution (CLMSNs) of cationic-liposome package.Process made above is repeated using DOX-MSNs,
Medicine cation lipid-mesoporous silicon core shell composite nano-granule (DOX-CLMSNs) must be carried.Another preparation does not contain the cationic lipid of MSNs
Plastid (cationic liposomes, CLs) prepares conventional liposome (Liposomes) with method using common phospholipid material, with
And conventional liposome contains the LMSNs of MSNs.
Partial size, PDI the and zeta current potential that each nano-carrier is measured with Malvern particle instrument, the results are shown in Table 1, show prepared
MSNs partial size is small, good dispersion degree, and zeta current potential is negative value；The partial size of Liposomes and CLs is greater than MSNs, the zeta current potential of CLs
It is very high；Contain slightly become larger when LMSNs and the CLMSNs ratio of MSNs does not contain MSNs, zeta current potential is substantially reduced, it was demonstrated that it is common
Liposome and cationic-liposome are successfully wrapped in the surface MSNs.
Fig. 1 is the transmission electron microscope picture of MSNs (A), Liposomes (B) and CLMSNs (C).It can be seen that MSNs in figure A
With clearly cellular structure, surface characteristics is obvious, can be then clearly observed outside MSNs in figure B, C and wrap up one layer obviously
Liposome membrane.
The partial size and potential measurement result of 1. nano-carrier of table
| Partial size (nm) | Polydispersity coefficient (PDI) | Zeta current potential (mV) | |
| MSNs | 72.4±16 | 0.220 | -33.1±0.5 |
| Liposomes | 143.8±25 | 0.236 | 0.0±0.9 |
| CLs | 174.0±31 | 0.185 | 86.7±2.3 |
| LMSNs | 160.2±27 | 0.277 | -13.1±0.8 |
| CLMSNs | 202.6±35 | 0.314 | 44.8±2.3 |
| siRNA-CLMSNs | 248.6±29 | 0.363 | 23.1±3.8 |
Embodiment 2
(1) two complementary single-stranded dnas corresponding with siRNA 1 are chemically synthesized, both ends have Hind III and Bgl
II restriction enzyme site.It is attached after annealing with by the plasmid pDual of double digestion, product is transformed into E. coli competent
DH5a, picking monoclonal colonies amplification cultivation extract plasmid and identification are sequenced.
(2) load of siRNA 1: the siRNA of dry powder-shaped is centrifuged 10 minutes, is dissolved with the DEOC water of 375 μ l, by gained
Solution is mixed with above-mentioned CLMSNs, is stood to obtain the final product, is denoted as siRNA-CLMSNS.SiRNA-CLMSNS is measured with Malvern particle instrument
Partial size, PDI and zeta current potential, the results are shown in Table 1, compared with CLMSNS, the partial size of siRNA-CLMSNS is significantly increased, zeta electricity
Position is substantially reduced, this is because electronegative siRNA has neutralized the part positive charge on its surface.Fig. 1 (D) is siRNA-CLMSNS
Transmission electron microscope picture, it can be seen that its partial size becomes larger after load siRNA, and shape more rounding.
Fig. 2 is shown in the Zeta potential comparison of each nano-carrier.
Application Example 1
It (is contained using each carrier LMSNs, CLMSNs, siRNA-CLMSNS for being provided in the embodiment of the present invention 1,2
DOX), drugloading rate and encapsulation rate are measured.
1. the drafting of standard curve: weighing 2.0mg DOX, be dissolved in the PBS of pH7.4, it is molten to be made into 0.04mg/ml standard
Liquid.Carry out gradient dilution, the final DOX standard solution for obtaining 0.04,0.02,0.01,0.005 and 0.0025mg/ml.?
Light absorption value is measured under 490nm wavelength and draws standard curve.
2. taking above each carrier, it is centrifuged 10min under 12000r/min revolving speed, measures the volume of supernatant, measures supernatant
Liquid UV absorption substitutes into the DOX that standard curve finds out adriamycin in supernatant.Bring formula calculating: drugloading rate=medication amount into
(containing)/carrier amount encapsulation rate=medication amount (containing)/total dose.
Table 2 is drugloading rate and entrapment efficiency determination as a result, each carrier can effectively contain DOX, wherein the drugloading rate of CLMSNs
With encapsulation rate highest, the drugloading rate and encapsulation rate of siRNA-CLMSNS is relatively low, this is because load siRNA carries medicine energy to it
Power has a certain impact.
2. drugloading rate of table, entrapment efficiency determination result
| LMSNs | CLMSNs | siRNA-CLMSNs | |
| Drugloading rate (μ g/mg) | 4.40 | 5.87 | 3.44 |
| Encapsulation rate (%) | 83.55 | 96.81 | 58.53 |
Application Example 2
It (is wrapped using each carrier MSNs, LMSNs, CLMSNs, siRNA-CLMSNS for being provided in the embodiment of the present invention 1,2
Carry DOX), measure vitro release.
Above each carrier is placed in bag filter, both ends system mouthful is placed on (pH in the beaker for filling 100ml dissolution medium
Respectively 7.4,5), with preservative film sealed beaker.Be placed in shaking table, respectively 10,30min and 1,2,4,6,8,12, the moment takes for 24 hours
Sample surveys absorbance with ultraviolet specrophotometer.The dissolution medium with pH in equal volume is added after taking liquid every time.The absorbance that will be measured
Value substitutes into standard curve and calculates, and obtains a series of DOX concentration.Release percentage is calculated according to the following formula；
Qn=CnVo+ ∑ CiVi (i=0~n-1) discharges percentage (%)=Q/W 100%
Using the time as abscissa, drug release rate is ordinate mapping.
Fig. 3 is releasing curve diagram of each carrier under the conditions of two kinds of pH.The result shows that pH can find out drug release when being 7.4
Spend MSNs > LMSNs > CLMSNs > siRNA-CLMSNs.Because the encapsulation rate of MSNs is smaller, dosage is identical, causes to dialyse
The amount of the adriamycin to dissociate in bag is more, so its release is maximum；Negatively charged LMSNs is more than positively charged CLMSNs
It is easy release drug；The presence of siRNA affects the release of DOX.MSNs release is maximum in a short time when pH is 5, with
Its release of the increase of time is minimum；Because in addition several carriers release more DOX as time increases.At this time
The influence of siRNA is less than the influence of pH, so LMSNs > siRNA-CLMSNs > CLMSNs, simulation tumour is weak when pH is 5
Acidic micro-environment is more advantageous to the release of drug.
Application Example 3
Different nano-carriers (LMSNs, CLMSNs, siRNA-CLMSNs contain DOX), which are detected, with mtt assay carries medicine entrance
Cytotoxicity after cell examines extracorporeal anti-tumor effect.
Cell density is reached to MCF-7 cell pancreatin/EDTA digestion of 80%-90% fusion, dispelling disperses cell
Uniformly.It is inoculated in 96 orifice plates with 1 × 105/hole, DMEM culture solution is added, is put into 37 DEG C of CO2 incubator and cultivates 48h
Afterwards, the pharmaceutical carrier of series of concentrations (DOX concentration is respectively 1,5,10,20,50 μ g/ml) is added in 96 orifice plates, continues to train
Support 48h.After being incubated for culture, the MTT solution that 20 μ l are added in every hole continues to be incubated for 4h.Liquid in hole is discarded, every hole is added 100
μ l dmso solution generates blue (or bluish violet) formazan not soluble in water, and 96 orifice plates are shaken in gas bath oscillator
30min measures absorbance with microplate reader at 570nm wavelength.
Fig. 4 is MTT measurement result, and each nano-carrier can inhibit growth of tumour cell after carrying medicine as can be seen from the results, and
There is apparent concentration dependent, load concentration is higher, and tumor killing effect is better, and each carrier makees the inhibition of MCF-7 cell after carrying medicine
With being apparently higher than free DOX (solution).The ability of CLMSNs kill cell is most strong in the case where same DOX concentration, because its
It is positively charged, it is easier to enter cell.LMSNs is negatively charged, and the ability into cell is weaker, therefore its Execution is lower than it
Its carrier.SiRNA-CLMSN kills the ability of tumour cell lower than LMSNs, with DOX concentration under low DOX concentration levels
It is opposite to increase situation.Speculate part the reason is that because siRNA has neutralized the charge of cationic-liposome, charge value between
Between LMSNs and CLMSNs, therefore enter born of the same parents' ability lower than CLMSNs, the siRNA that surface of liposome loads under low DOX concentration is dry
The release of DOX has been disturbed,
With the increase of DOX concentration, siRNA largely sheds into cell from the surface CLMSNs, effectively inhibits tumour thin
The MDR of born of the same parents is acted on, and is conducive to DOX molecule and is stranded in into the cell, therefore shows stronger antitumor activity.
Application Example 4
It investigates and measures different nano-carriers (MSNs, LMSNs, CLMSNs, siRNA-CLMSNs) and carry DOX and taken the photograph by cell
The amount taken, the cell traffic ability of checking carrier.
By MCF-7 cell with the inoculation of 1 × 105/hole, every hole is added the DMEM culture solution of 2ml 10%, is put into 37 DEG C
After cultivating for 24 hours in CO2 incubator, culture medium is discarded, PBS is added and washs 2-3 times, is proportionally added into respectively containing above each carrier
Culture solution (containing DOX), while blank control is made with DOX solution, continues to cultivate 12h poststaining.Discard culture medium, PBS
Nuclear staining agent (Hoechst 33342) is added after flushing, collected by trypsinisation cell continues to cultivate 30min.Be centrifuged after taking-up,
It washs and is suspended with PBS, measure cell fluorescence positive rate and average fluorescent strength using flow cytometer (FCM), use simultaneously
Fluorescence microscope is observed.
Fig. 5 is the fluorescence imaging result of different carriers under the microscope with transhipment DOX, and to enter the intracellular fluorescence of MCF-7 strong
Degree comparison, wherein red fluorescence indicates DOX, i.e. DOX and the intake situation of each carrier in the cell, and blue-fluorescence indicates nucleus
Positioning scenarios.The result shows that each carrier can effectively be transported into cell, LMSNs and the cell of CLMSNs transmitting efficiency are opposite more
Height, fluorescence intensity are followed successively by CLMSNs, LMSNs, siRNA-CLMSNs, MSNs from high to low.This result and MTT measurement result base
This is consistent, it was demonstrated that the CLMSNs that cationic-liposome contains MSNs has due to electrostatic adsorption with tumour cell very strong affine
Power and lethal effect, the siRNA-CLMSNs for loading siRNA still remain stronger cellular uptake ability, while dense in high DOX
Under degree, the inhibition MDR effect of siRNA is conducive to DOX molecule and is stranded in into the cell, its antitumor activity is made to be better than conventional liposome packet
Carry the LMSNs of MSNs.
To sum up, preparation method of the present invention is simple, and cation lipid obtained-mesoporous silicon composite Nano carrier can wrap simultaneously
It carries chemotherapeutics DOX and loads siRNA, drugloading rate, encapsulation rate are higher, and tablets in vitro behavior is good, can be ingested into thin
Born of the same parents are right with stronger cell traffic ability and tumor inhibition effect compared to the LMSNs that conventional liposome contains MSNs
There is great potential using value especially with the oncotherapy of MDR feature in malignant tumour.
The foregoing is only a preferred embodiment of the present invention, the scope of protection of the present invention is not limited to this, it is any ripe
Know those skilled in the art within the technical scope of the present disclosure, the letter for the technical solution that can be become apparent to
Altered or equivalence replacement are fallen within the protection scope of the present invention.
Claims (7)
1. a kind of cation lipid-mesoporous silicon composite Nano carrier preparation method for carrying siRNA and chemotherapeutics altogether, feature
It is, comprising the following steps:
(1) template method nanometer grain is used, MDR1-siRNA is synthesized；
(2) mesoporous silicon and chemotherapeutics are mixed in organic solvent, obtains carrying medicine mesoporous silicon after washing and drying；
(3) medicine mesoporous silicon will be carried to be scattered in the chloroformic solution dissolved with lipid material, dispersion is added after solvent evaporated film forming and is situated between
Matter, for ultrasound to being completely dispersed, filtration sterilization squeezes out adjustment particle size repeatedly；
(4) it mixes, stood with liposome solutions after dissolving siRNA to obtain the final product.
2. cation lipid-mesoporous silicon composite Nano the carrier according to claim 1 for carrying siRNA and chemotherapeutics altogether
Preparation method, which is characterized in that in step (1), the partial size of mesoporous silicon is between 40-100nm, and aperture is between 1.2-6.0nm；
Mesoporous silicon is synthesized by following steps: using surfactant cetyl trimethylammonium bromide as template, ethyl orthosilicate is
Silicon source is reacted under alkaline condition, then is flowed back in methanol-HCl solution and deionized water, is removed surfactant, is situated between
Hole silicon.
3. cation lipid-mesoporous silicon composite Nano the carrier according to claim 1 for carrying siRNA and chemotherapeutics altogether
Preparation method, which is characterized in that in step (2), chemotherapeutics is that hydrophobic drug or polypeptide, protein, nucleic acid biology are big
Molecule.
4. cation lipid-mesoporous silicon composite Nano the carrier according to claim 3 for carrying siRNA and chemotherapeutics altogether
Preparation method, which is characterized in that the hydrophobic drug is any in adriamycin, taxol, Irinotecan or cis-platinum.
5. cation lipid-mesoporous silicon composite Nano the carrier according to claim 1 for carrying siRNA and chemotherapeutics altogether
Preparation method, which is characterized in that siRNA sequence is 5 '-GATTGCATITGGAGGACAA-3 '.
6. cation lipid-mesoporous silicon composite Nano the carrier according to claim 1 for carrying siRNA and chemotherapeutics altogether
Preparation method, which is characterized in that liposome is prepared by DOTAP, DOPC, cholesterol, DPPG.
7. cation lipid-mesoporous silicon composite Nano the carrier according to claim 1 for carrying siRNA and chemotherapeutics altogether
Preparation method, which is characterized in that the mass ratio of mesoporous silicon and chemotherapeutics is 2: 1-10: 1, the mass ratio of mesoporous silicon and lipid film
It is 1: 1-1: 2.
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| CN114306639A (en) * | 2022-01-06 | 2022-04-12 | 上海交通大学 | Hydrophobic drug nanocrystal/siRNA (small interfering ribonucleic acid) co-loaded ordered structure lipid nano preparation as well as preparation method and application thereof |
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