CN107349432B - Sorafenib/siRNA-loaded mesoporous silica-lactobionic acid targeted nanoparticles - Google Patents
Sorafenib/siRNA-loaded mesoporous silica-lactobionic acid targeted nanoparticles Download PDFInfo
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Abstract
The invention discloses a sorafenib/siRNA loaded mesoporous silica-lactobionic acid targeted nanoparticle and application thereof in preparation of anticancer therapeutic drugs. The targeted nano-particles are formed by carrying out surface amination modification on mesoporous silica nano-particles, loading sorafenib in an inner pore channel of the mesoporous silica nano-particles, covalently coupling lactobionic acid to the outer surface of the mesoporous silica nano-particles, and adsorbing siRNA to the outer surface of the mesoporous silica nano-particles through electrostatic adsorption. The drug loading system provided by the invention can improve the stability of siRNA, and can realize targeted drug delivery of Sorafenib, so that the toxic and side effects of Sorafenib on normal cells are effectively reduced.
Description
Technical Field
The invention belongs to the field of preparation of antitumor drugs, and particularly relates to sorafenib/siRNA-loaded mesoporous silica-lactobionic acid targeted nanoparticles and application thereof.
Background
Over the last several decades, the global environment has worsened leading to an increasing incidence of cancer, with up to 880 million people dying from cancer each year. Chemotherapy remains the mainstay of cancer treatment today. However, most of the chemotherapeutic drugs used for treating cancer have the defects of lack of targeting, multi-drug resistance and low bioavailability, and the defects greatly limit the clinical use of the drugs; thus, new drug delivery systems have been the focus of research in the field of medicine.
Sorafenib is a multi-kinase inhibitor capable of targeting multiple growth factor receptors, and comprises VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-b, c-KIT, FLT-3, RET and the like, and the structural formula of the Sorafenib is as follows:
. Sorafenib was approved by the FDA for the treatment of advanced kidney cancer in 2005 and is by far the only systemic treatment anti-liver cancer drug approved by the FDA. Although sorafenib shows strong curative effect on clinical treatment, its side effect and drug resistance limit further development and application of sorafenib to some extent. Therefore, the development of the sorafenib preparation which can reduce toxic and side effects and drug resistance and improve targeting is particularly important.
RNA interference (RNAi) refers to the processing of double-stranded RNA (dsRNA) into a small molecule RNA (siRNA) of 21-25 nucleotides via specific endonuclease Dicer, which degrades target mRNA by fully pairing with the coding region or UTR region of the target mRNA, causing post-transcriptional silencing of the gene. RNAi technology has the characteristics of simplicity, rapidness and specificity for silencing any gene, so that RNAi technology is widely used for researching target treatment of diseases such as tumors, pulmonary hypertension, congenital genetic diseases and the like, and achieves certain results. However, siRNA is easily degraded in the serum environment, so that it is difficult to exert its RNAi effect in cells. In addition, free siRNA cannot enter cells, and chemical modification or nanoparticle loading is required to be effective in entering cells to exert effects. However, since chemically modified siRNA may lose activity, designing a suitable vector to improve the therapeutic effect of siRNA has received great attention.
The mesoporous silica nano material is a novel inorganic polymer drug carrier. It is mainly characterized in that: (1) the particles have extremely large surface area, pore channel capacity and total specific surface area>900 m2Per g, pore volume>0.9 cm3The/g provides larger storage and reaction space; (2) the particle size is adjustable, the medicine is easy to be phagocytized by tumor cells, has no obvious cytotoxicity and has good in vitro biocompatibility; (3) the aperture is 2 nm-10 nm, the size can be adjusted, and the drug loading capacity can be adjusted by changing the aperture; (4) has an inner surface and an outer surface, and can be functionally modified to prepare the hybrid carrier with excellent performance. These characteristics make mesoporous silica nanoparticles have great potential application value.
Lactobionic Acid (LA) is an active biomolecule produced by the oxidation of lactose and has the structural formula:
. Recent studies have shown that lactobionic acid can specifically bind to ASGPR receptor overexpressed on the surface of cancer cells, and has a highly efficient targeting effect on cancer cells. Therefore, lactobionic acid has received great attention in the study of the drug delivery system of anticancer drugs, and has become a new hot spot for the study of targeting cancer cells.
In 2012, Hartonno, s.b. and the like (ACS Nano, volume 6, page 2104, 2012) synthesized silica nanoparticles with large pore diameters (pore diameters larger than 10 nm), and successfully modified electropositive polymer material Poly-L-Lysine PLL (Poly-L-Lysine) on the outer surface and in the pore channels of the particles, and adsorbed siRNA by electrostatic interaction to achieve siRNA interference, but the efficiency of siRNA delivery by the Nano-drug carrier was low, and the particles had high toxicity at low concentration and low biocompatibility. Patent CN 105056239a discloses a mesoporous silica drug-and-siRNA-loaded composite material, its preparation and application in the preparation of anticancer drugs, mesoporous silica with drug-loading effect is used as a core, and the surface is connected with siRNA through disulfide bonds for mesoporous blocking, and simultaneously plays a role in loading drug siRNA. After entering cells, the nano material can cause the breakage of disulfide bonds through the response of highly expressed glutathione in cancer cells and simultaneously release drugs and siRNA, so that the stability of the siRNA is improved, the biocompatibility is good, but the nano material has no good targeting effect before entering the cancer cells and can not improve the uptake of the nano material by the cancer cells. In addition, patent CN 104027821a provides a nanoparticle for delivering siRNA, in which polyethylene glycol and polypeptide molecules are modified on the surface of mesoporous silica, so as to not only improve biocompatibility, but also greatly improve the interference effect of siRNA. However, similar to patent CN 105056239a, due to the lack of targeting molecules, the drug-loaded nanomaterial cannot achieve high enrichment on the surface of tumor cells, and thus cannot achieve optimal therapeutic effect.
Disclosure of Invention
The invention aims to provide sorafenib/siRNA loaded mesoporous silica-lactobionic acid drug-loaded nanoparticles with a targeted anticancer effect, wherein siRNA is adsorbed to the outer surface of mesoporous silica to improve the stability of the siRNA, and the targeted effect of the lactobionic acid on cancer cells is utilized to improve the antitumor activity of the sorafenib.
In order to achieve the purpose, the invention adopts the following technical scheme:
a sorafenib/siRNA loaded mesoporous silica-lactobionic acid targeted nanoparticle comprises the following steps:
1) preparing Mesoporous Silica Nanoparticles (MSN) with the particle size of about 100 nm;
2) dissolving the obtained mesoporous silica nanoparticles in absolute ethyl alcohol, adding 3-aminopropyltriethoxysilane accounting for 0.4 percent of the weight of the nanoparticles, stirring at room temperature for 12 hours, centrifuging, washing with ethanol, and freeze-drying to obtain mesoporous silica nanoparticles (MSN-NH) with amino-modified surfaces2）；
3) The obtained MSN-NH2Dissolving in acetone, stirring at room temperature for 1h, adding Sorafenib, stirring for 30min, centrifuging at 13000rpm for 30min, removing supernatant, washing the obtained precipitate with deionized water, and freeze-drying to obtain Sorafenib-loaded mesoporous silica nanoparticles (SO @ MSN); wherein the weight ratio of the aminated and modified mesoporous silica to sorafenib is 3: 2;
4) adding SO @ MSN, EDC and NHS (the weight ratio of the SO @ MSN to the EDC to the NHS is 3:10: 4) into N, N-dimethylformamide as a solvent, stirring for 4 hours at room temperature, adding a lactobionic acid solution with the mass concentration of 2% according to the volume ratio of 4:1, continuously stirring for 12 hours, centrifuging, washing with deionized water, and freeze-drying to obtain sorafenib-loaded mesoporous silica-lactobionic acid nanoparticles (SO @ MSN-LA);
5) adding SO @ MSN-LA into acetone, ultrasonically dispersing for 10min, then adding siRNA into the solution according to the mass-volume ratio of 1:3 g/L, and stirring for 20min to obtain the targeted nanoparticle (SO/siRNA @ MSN-LA).
The lactobionic acid solution in step 4) was prepared by stirring 40 mg lactobionic acid, 100 mg dichloroethane and 0.1mol MES (pH = 6) for 24h at room temperature.
In view of the defects of the prior art, sorafenib is loaded into the inner pore channel of the mesoporous silica, lactobionic acid is coupled to the outer surface of the mesoporous silica through a covalent bond, and siRNA is adsorbed to the outer surface of the mesoporous silica through the electrostatic charge effect. On the one hand, the stability of the siRNA and the biocompatibility of a drug-carrying system are improved, so that the siRNA can enter cells to fully play a role; on the other hand, the high-efficiency targeted anticancer effect of the lactobionic acid can also improve the antitumor effect of sorafenib. Therefore, the targeted nano-particles obtained by the invention can be used for preparing targeted drugs for tumor treatment.
The invention has the advantages that:
1. the mesoporous silicon dioxide is used as the carrier of the siRNA, so that the stability of the siRNA can be obviously enhanced, and the efficiency of silencing genes of the siRNA is improved;
2. according to the invention, the lactobionic acid is adopted as a targeting molecule, so that sorafenib can be enriched around cancer cells, and the uptake rate of the cells to drugs can be obviously improved, so that the toxic and side effects of sorafenib on normal tissues are reduced while the anti-tumor effect of sorafenib is improved;
3. the nano drug delivery system constructed by the invention is also suitable for other anticancer drugs with large toxic and side effects or indissolvable properties except sorafenib;
4. the drug-loaded system designed by the invention has simple preparation method and easily obtained materials, and is beneficial to further expanding the preparation yield.
Drawings
Fig. 1 is a TEM image of Mesoporous Silica Nanoparticles (MSNs) prepared in example 1.
FIG. 2 is a graph showing the distribution of particle size of Sorafenib-loaded mesoporous silica-lactobionic acid (SO @ MSN-LA) prepared in example 4.
FIG. 3 shows Mesoporous Silica (MSN) and mesoporous silica (MSN-NH) with aminated surface2) Activated lactoseAn infrared absorption spectrum chart of the aldehydic acid (LA) and sorafenib-loaded mesoporous silica-lactobionic acid (SO @ MSN-LA).
FIG. 4 shows Mesoporous Silica (MSN) and mesoporous silica (MSN-NH) with aminated surface2) And a Zeta potential diagram of sorafenib-loaded mesoporous silica-lactobionic acid (SO @ MSN-LA).
Figure 5 is a graph of cumulative release rate of sorafenib over time in different drug-loaded systems.
FIG. 6 shows the results of the MTT test in example 7.
FIG. 7 shows the results of the apoptosis assay in example 8.
FIG. 8 shows the results of the cell uptake assay in example 9.
FIG. 9 shows the results of the cell transfection experiment in example 10, in which A is a graph showing the effect under a fluorescent field and B is the cell transfection efficiency.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Example 1 Synthesis of mesoporous silica nanoparticles
Adding 2 g of hexadecyl triethyl ammonium bromide, 0.1 g of triethanolamine and 20 mL of deionized water into a reaction bottle, and reacting for 1h at 95 ℃; then adding 1.5 mL of tetraethyl orthosilicate drop by drop within 20-30 min, and continuing to react for 1h at 95 ℃ after the addition is finished; after the reaction is finished, centrifuging at 12000 rpm for 15 min at room temperature to obtain a crude mesoporous silica nano material, respectively washing with deionized water and absolute ethyl alcohol twice, suspending the obtained solid in acidic ethyl alcohol (concentrated hydrochloric acid: absolute ethyl alcohol =5:1, V: V), refluxing for 24h to remove unreacted hexadecyl triethyl ammonium bromide, centrifuging, washing with deionized water, and freeze-drying at-50 ℃ to obtain a pure mesoporous silica nano particle.
Fig. 1 is a TEM image of the prepared mesoporous silica nanoparticle. As can be seen, the particle size is about 100 nm.
Example 2 surface amino groupsChemically modified mesoporous silica nanoparticles (MSN-NH)2) Preparation of
Dissolving 100 mg of the mesoporous silica nanoparticles prepared in example 1 in 20 mL of absolute ethanol, adding 400 μ g of 3-aminopropyltriethoxysilane, stirring at room temperature for 12h, centrifuging, washing with ethanol for multiple times to remove unreacted 3-aminopropyltriethoxysilane, and freeze-drying to obtain surface amino-modified mesoporous silica nanoparticles (MSN-NH)2）。
Example 3 preparation of Sorafenib-loaded mesoporous silica nanoparticles (SO @ MSN)
30 mg of MSN-NH prepared in example 2 were taken2Dissolving in 30 mL of acetone, stirring at room temperature for 1h, adding 20 mg of sorafenib, stirring for 30min, centrifuging at 13000rpm for 30min, removing supernatant, washing the obtained precipitate with deionized water, and freeze-drying to obtain the sorafenib-loaded mesoporous silica nanoparticle (SO @ MSN).
Example 4 preparation of Sorafenib-loaded mesoporous silica-Lactobronic acid nanoparticles (SO @ MSN-LA)
Firstly, activating LA, namely adding 40 mg of lactobionic acid, 100 mg of dichloroethane and 0.1mol of morpholine ethanesulfonic acid monohydrate (MES, pH = 6) into a reaction flask, and stirring at room temperature for 24 hours to obtain the activated LA.
And (3) taking 30 mg of SO @ MSN prepared in example 3, 20 mL of N, N-dimethylformamide, 100 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 40 mg of N-hydroxysuccinimide (NHS) in a round-bottom flask, stirring for 4h at room temperature, then adding 5 mL of 2% LA solution into the mixed solution, stirring for 12h, centrifuging, washing with deionized water, and freeze-drying to obtain the Sorafenib-loaded mesoporous silica-lactobionic acid nanoparticles (SO @ MSN-LA).
FIG. 2 is a graph showing the particle size distribution of the SO @ MSN-LA obtained. As can be seen from FIG. 2, the average particle size was about 150 nm.
FIG. 3 shows Mesoporous Silica (MSN) and mesoporous silica (MSN-NH) with aminated surface2) Activated Lactobionic Acid (LA) and sorafenib-loaded mesoporous dioxideIR absorption spectrum of silico-lactobionic acid (SO @ MSN-LA).
FIG. 4 shows Mesoporous Silica (MSN) and mesoporous silica (MSN-NH) with aminated surface2) And a Zeta potential diagram of sorafenib-loaded mesoporous silica-lactobionic acid (SO @ MSN-LA). As can be seen from FIG. 4, the mean Zeta potential of MSN is about-19 mV, MSN-NH2The average Zeta potential of about +27 mV, i.e., the potential changes from negative to positive after MSN amination, indicating that MSN-NH has been successfully prepared2(ii) a And the Zeta potential of SO @ MSN-LA is +17 mv.
Example 5 preparation of Sorafenib/siRNA-loaded mesoporous silica-Lactobionic acid nanoparticles (SO/siRNA @ MSN-LA)
Weighing 20 mg of SO @ MSN-LA prepared in example 4, dissolving in 20 mL of acetone, ultrasonically dispersing for 10min, then taking 6 mu L of the solution and 2 mu g of siRNA, and stirring for 20min to obtain the sorafenib and siRNA loaded mesoporous silica-lactobionic acid nanoparticles (SO/siRNA @ MSN-LA).
Example 6 determination of Sorafenib in vitro Release
Sorafenib, SO @ MSN prepared in example 3 and SO @ MSN-LA prepared in example 4 were each suspended in 2 mL of PBS buffer (pH = 7.4) at 2mg and shaken at 37 ℃ for in vitro release experiments. 500 mu L of sample liquid is taken at different time, after centrifugation is carried out for 10min at 13000rpm, the Sorafenib concentration in the supernatant is detected by adopting an ultraviolet spectrophotometer at 210 nm, and a graph of the cumulative release percentage and the time is drawn, and the result is shown in figure 5.
As can be seen from FIG. 5, there is no significant difference in the Sorafenib release rates of SO @ MSN and SO @ MSN-LA, indicating that the use of lactobionic acid as the targeting molecule does not hinder the release of Sorafenib.
Example 7 MTT assay
First, when Huh7 cells and HepG2 cells were cultured separately and kept in the logarithmic growth phase and in a good condition, they were digested with trypsin, and then counted on a hemocytometer to adjust the cell density to 1 × 105Preparing cell suspension per mL; inoculating to 96-well plate at 100 μ L per well, sealing with PBS, and placing at 37 deg.C and 5% CO2Culturing in an incubator overnight; when the cell activity reaches 80%, adding MSN-LA, SO @ MSN-LA, SO/siRNA @ MSN-LA and SO of different concentration gradients incubated by a culture solution, and culturing for 24 hours; removing culture solution, adding 100 μ L MTT solution diluted with serum-free and phenol-free medium, and culturing at 37 deg.C for 4 hr; the 96-well plate was taken out, 100. mu.L of DMSO was added after the MTT solution was aspirated, the mixture was slowly shaken on a shaker for 10min, the OD value was measured at 570 nm with a multifunction microplate reader after shaking, and the cell proliferation inhibition rate was calculated using GraphPad Prism 5, and the results are shown in FIG. 6.
As can be seen from FIG. 6, MSN-LA has almost no inhibitory effect on Huh7 cells and HepG2 cells, while SO, SO @ MSN-LA and SO/siRNA @ MSN-LA have sequentially improved inhibitory rates on Huh7 cells and HepG2 cells, and the inhibitory effect is more obvious with the increase of dosage. The cell inhibition effect of SO @ MSN-LA on Huh7 cells and HepG2 cells (the cell activities after treatment are respectively 12% and 18%) is obviously superior to that of SO @ MSN (the cell activities after treatment are respectively 28% and 30%), which shows that the anti-tumor effect of sorafenib can be improved by coupling the lactobionic acid molecules on the SO @ MSN-LA; in addition, the inhibition effect (cell activity after treatment is 4% and 7%) of SO/siRNA @ MSN-LA is more remarkable than that of SO @ MSN-LA, which shows that compared with the single administration of SO, the SO and siRNA are loaded on the nanoparticle together to achieve the synergistic treatment effect.
Example 8 apoptosis assay
Apoptosis assays were determined by flow cytometry. HepG2 cell inoculations were applied separately to the cells to which the MSN-NH prepared in example 2 was added2(control), Sorafenib, SO @ MSN prepared in example 3, SO @ MSN-LA prepared in example 4, SO/siRNA @ MSN-LA prepared in example 5, in 6-well plate medium, cell density was adjusted to 1X 105Each well plate was incubated at 37 ℃ for 24 hours, then centrifuged at 1500 rpm for 5 minutes to obtain cells, washed three times with PBS, the cells were suspended in 500. mu.L of 1 Xbinding buffer, stained with 10. mu.L of a mixture of Annexin-V FITC and PI in a volume ratio of 1:1 in the dark for 10min, and the resulting samples were examined by flow cytometry, the results of which are shown in FIG. 7.
The results of FIG. 7 show that the promotion effect of SO/siRNA @ MSN-LA is much stronger than that of SO @ MSN-LA, SO @ MSN and sorafenib applied alone no matter early apoptosis or late apoptosis, which indicates that SO/siRNA @ MSN-LA can significantly improve the anticancer effect of sorafenib and siRNA, i.e. has synergistic antitumor curative effect.
Example 9 cellular uptake assay
Adding 2mg of FITC and 20 mu L of APTMS into 2 mL of ethanol, and stirring at room temperature in the dark for 12h to ensure that FITC and APTES are covalently coupled; respectively dissolving 200 mg of MSN and MSN-LA in 50 mL of ethanol, performing ultrasonic treatment for 30min, mixing with 3mL of ethanol solution of LFITC/APTES, stirring for 24h in the dark, centrifuging the mixture, washing and purifying with pure ethanol to obtain the FITC @ MSN and FITC @ MSN-LA nanoparticles. HepG2 cells were seeded in a 24-well plate containing 400. mu.L of DMEM medium to adjust the cell density to 5X 105Each well was incubated at 37 ℃ for 24 hours. After the cells grow adherent, the culture solution is discarded, the culture dish is washed three times by PBS, then 100 mu g/mL of FITC @ MSN, FITC @ MSN-LA and FITC @ MSN-LA + LA are respectively added into the cells, and the cells are cultured for 2h at 37 ℃. The cells in the well plate were washed three times with PBS and then stained for nuclei with Hoechst 33342, and finally the samples were observed with a confocal microscope, and the results are shown in FIG. 8.
As can be seen in FIG. 8, FITC @ MSN-LA showed the highest fluorescence intensity, indicating the highest uptake rate by the cells. The fluorescence intensity of FITC @ MSN-LA + LA is slightly lower than that of FITC @ MSN-LA, so that LA can compete with FITC @ MSN-LA for receptors on cancer cells, and the targeted anticancer effect of LA is further proved.
Example 10 in vitro transfection assay
Adding 2 mu g of siRNA into 6 mu L of MSN and 6 mu L of MSN-LA respectively, and slowly stirring for 20min at room temperature to obtain siRNA @ MSN and siRNA @ MSN-LA. HepG2 cells were seeded in 24-well plates with cell density adjusted to 5X 105And culturing the cells/pore plate for 24h, adding siRNA and the prepared siRNA @ MSN and siRNA @ MSN-LA into the culture solution respectively, and transfecting for 48 h. After transfection, the cells were observed with an Olympus IX71 fluorescence microscope and the transfection efficiency was calculated as shown in FIG. 9.
As can be seen in FIG. 9, the transfection efficiency of free siRNA is only 4.5%, which is lower than that of siRNA @ MSN (23%), indicating that the nanoparticles are used as carriers to improve the stability of siRNA and enhance the transfection efficiency; and the transfection rate of siRNA @ MSN-LA is as high as 45%, which indicates that the coupled LA can play a targeted anticancer role.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (2)
1. A sorafenib/siRNA loaded mesoporous silica-lactobionic acid targeted nanoparticle is characterized in that: the preparation method comprises the following steps:
1) carrying out amination modification on the surface of the mesoporous silica nanoparticle: (ii) a
2) Loading sorafenib on an inner pore channel of the mesoporous silica subjected to amination modification;
3) coupling lactobionic acid to the outer surface of the mesoporous silica loaded with sorafenib through a covalent bond;
4) adsorbing siRNA to the outer surface of the mesoporous silica-lactobionic acid coupling product obtained in the step 3) through electrostatic adsorption;
the specific operation of the step 1) is as follows: dissolving mesoporous silica nanoparticles in absolute ethyl alcohol, adding 3-aminopropyltriethoxysilane accounting for 0.4 percent of the weight of the nanoparticles, stirring at room temperature for 12 hours, centrifuging, washing with ethyl alcohol, and freeze-drying; the particle size of the mesoporous silica nano-particles is 100 nm;
the specific operation of the step 2) is as follows: dissolving the mesoporous silica subjected to amination modification in acetone, stirring for 1h at room temperature, adding sorafenib, stirring for 30min, centrifuging for 30min at 13000rpm, washing the obtained precipitate with deionized water, and freeze-drying; wherein the weight ratio of the aminated and modified mesoporous silica to sorafenib is 3: 2;
the specific operation of the step 3) is as follows: adding mesoporous silica loaded with sorafenib, EDC and NHS into N, N-dimethylformamide as a solvent, stirring for 4h at room temperature, adding a lactobionic acid solution with the mass concentration of 2% according to the volume ratio of 4:1, continuously stirring for 12h, centrifuging, washing with deionized water, and freeze-drying; wherein the weight ratio of the sorafenib-loaded mesoporous silica to EDC to NHS is 3:10: 4; the lactobionic acid solution is prepared by stirring 40 mg of lactobionic acid, 100 mg of dichloroethane and 0.1mol of MES at room temperature for 24 hours;
the specific operation of the step 4) is as follows: adding the mesoporous silica-lactobionic acid coupling product into acetone, ultrasonically dispersing for 10min, then adding siRNA into the solution according to the mass-volume ratio of 1:3 g/L, and stirring for 20 min.
2. Use of the targeted nanoparticle of claim 1 for the preparation of an anticancer drug.
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