CN114404429B - Nanometer silver modified tannic acid-iron network drug-loaded nanometer compound and preparation method and application thereof in reversing tumor drug resistance - Google Patents
Nanometer silver modified tannic acid-iron network drug-loaded nanometer compound and preparation method and application thereof in reversing tumor drug resistance Download PDFInfo
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- CN114404429B CN114404429B CN202111446379.5A CN202111446379A CN114404429B CN 114404429 B CN114404429 B CN 114404429B CN 202111446379 A CN202111446379 A CN 202111446379A CN 114404429 B CN114404429 B CN 114404429B
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Abstract
The invention relates to the technical field of nano-drug presentation systems and contrast agents, in particular to a nano-silver modified drug-loaded nano-composite of a tannic acid-iron network, a preparation method thereof and application thereof in reversing tumor drug resistance. The drug-loaded nano-composite comprises an inner core formed by doxorubicin connected with cell membrane-penetrating peptide, a network structure layer formed by tannic acid and iron ions is wrapped outside the inner core, and nano-silver particles are modified outside the network structure layer. The technical problem of tumor chemotherapy failure caused by tumor drug resistance can be solved, P-gp overexpressed in drug-resistant cells can be down-regulated, accumulation of intracellular chemotherapeutics can be increased, and the antitumor drugs can be effectively delivered to the cell nucleus of the final destination, and the dual-mode (photoacoustic/magnetic resonance) enhanced contrast agent with imaging potential is provided. The scheme can be applied to treatment, visual monitoring and guiding treatment of drug-resistant tumors, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of nano-drug presentation systems and contrast agents, in particular to a nano-silver modified drug-loaded nano-composite of a tannic acid-iron network, a preparation method thereof and application thereof in reversing tumor drug resistance.
Background
Tumor development is a long-term, multi-stage, multi-gene change and accumulation process with the complexity of genetic control and multi-factor regulation. Research at home and abroad shows that: tumor multi-drug resistance (MDR) is the primary cause of failure in tumor chemotherapy. Drug resistance of tumors involves various mechanisms such as reduced intracellular drug concentration, changes in drug target molecules, metabolic detoxification, and imbalance in DNA damage repair functions. Although various nanotechnology-based strategies are adopted by scientists to reverse MDR, such as enhancing drug accumulation through tumor targeting, preventing drug targeting pathway inactivation, and combining photothermal therapy, photodynamic therapy, etc., single drug resistance reversing strategies still cannot fully restore sensitivity of tumor cells to chemotherapeutic drugs, MDR still severely limits the efficacy of chemotherapy. Doxorubicin (DOX) is one of the most representative classical chemotherapeutic drugs. Because the mechanism by which DOX kills tumor cells is to induce cell death by interaction with DNA helices or related enzymes, its efficacy is highly dependent on nuclear pathways. However, nanocarriers undergo endosomal capture and lysosomal degradation after DOX release reaches their target of action. In addition, due to the over-expression of P glycoprotein (P-gp) on MDR cell membrane, DOX may be pumped out of the cell rapidly after reaching the cytoplasm, further reducing the intracellular drug concentration. Thus, there is a need to develop a highly efficient nanocomposite to overcome MDR, to down-regulate P-gp over-expressed in drug resistant cells and increase intracellular DOX accumulation, and to deliver anti-tumor drugs efficiently to their final destination nuclei.
Disclosure of Invention
The invention aims to provide a nano silver modified tannic acid-iron network drug-loaded nano compound to solve the technical problem of tumor chemotherapy failure caused by tumor multi-drug resistance.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a nano silver modified tannic acid-iron network drug-loaded nano composite comprises an inner core formed by doxorubicin connected with cell membrane penetrating peptide, a network structure layer formed by tannic acid and iron ions is wrapped outside the inner core, and nano silver particles are modified outside the network structure layer.
The principle and the advantages of the scheme are as follows: the technical proposal utilizes a network structure layer (TA-Fe) formed by tannic acid and iron ions to wrap an inner core formed by doxorubicin connected with cell membrane penetrating peptide P DOX), and then the nano silver particles are modified outside the network structure layer, so that not only are the loading of various medicinal components realized, but also the synergistic effect between medicines is possible, and the drug resistance of tumors to chemotherapeutic medicines is greatly reduced. The drug-loaded nano-composite is a diagnosis and treatment type nano-composite material, and can simultaneously realize nuclear targeting and endoplasmic reticulum stress to enhance tumor chemotherapy and reverse tumor multi-drug resistance.
More specifically, doxorubicin is an antitumor antibiotic, can inhibit synthesis of RNA and DNA, has a broad antitumor spectrum, has effects on various tumors, belongs to a period nonspecific drug, and has effects of killing tumor cells in various growth periods. However, doxorubicin itself lacks targeting, and in order for a sufficient amount of doxorubicin to enter the nucleus to exert its inhibitory effect, it is necessary to increase the dose, thereby increasing the possibility of development of drug resistance in tumor cells, and increasing the side effects of the drug. According to the technical scheme, the cell membrane penetrating peptide is connected to the doxorubicin, so that the nuclear aggregation effect of the doxorubicin is increased, and the treatment effect of the doxorubicin is improved. In order to reduce the drug resistance of tumors to the doxorubicin, the technical scheme carries out metal network polyphenol engineering treatment on the surfaces of the nano particles formed by the doxorubicin connected with the cell membrane penetrating peptide, and a network structure layer formed by tannic acid and iron ions enables the nano composite material to have ATP responsive decomposition and ATP consumption characteristics, so that the biocompatibility is improved, meanwhile, the ATP dependent drug pump is reduced, the drug sensitivity of tumor cells is increased, and the therapeutic effect of the doxorubicin is improved. Furthermore, the network structure layer formed by tannic acid and iron ions can also significantly down-regulate the level of P glycoprotein (P-gp) in tumor cells. The P glycoprotein is a transmembrane glycoprotein with a molecular weight of 170KD and has an energy-dependent 'drug pump' function. The P glycoprotein can be combined with the medicine and ATP, and the ATP supplies energy to pump the medicine in the cell out of the cell, so that the concentration of the medicine in the cell is reduced to cause the cell to generate medicine resistance. The network structure layer formed by tannic acid and iron ions is wrapped outside the doxorubicin, so that the drug resistance of tumor cells can be reduced by a double mode of consuming ATP and down-regulating P glycoprotein. The nano silver particles are introduced into the nano system, so that strong endoplasmic reticulum stress in cells can be induced, and apoptosis signals are triggered. In addition, the nano silver particles are attached to a network structure layer formed by tannic acid and iron ions, and further inhibition of expression of P glycoprotein can be realized through synergistic interaction, so that drug-resistant cells are restored to be sensitive to chemotherapy. Therefore, the nano silver particles can also produce double effects, respectively induce apoptosis of tumor cells and increase drug sensitivity of the tumor cells. In addition, the nano-composite has good near infrared absorption and paramagnetic properties, is a bimodal (photoacoustic/magnetic resonance) enhanced contrast agent with imaging potential, and can realize visual monitoring and guiding treatment at one time.
In summary, the drug-loaded nanocomposite of the nano-silver modified tannic acid-iron network of the scheme can overcome MDR through various mechanisms, can also down-regulate P-gp over-expressed in drug-resistant cells and increase accumulation of intracellular chemotherapeutic drugs, and can effectively deliver antitumor drugs to the nuclei of the final destination.
Further, the nano silver modified tannic acid-iron network drug-loaded nano compound comprises doxorubicin, tannic acid and ferric trichloride hydrate connected with cell penetrating peptide; the ratio of the sum of the masses of tannic acid and ferric trichloride hydrate to the mass of doxorubicin in doxorubicin to which cell penetrating peptide is attached was 5:1. in the technical scheme, the mass throwing ratio is controlled at 1:5, so that the ideal encapsulation efficiency and drug loading rate can be obtained. The excessive dosage of the doxorubicin has little help to promote the drug loading, and causes the waste of the drug; too large amounts of tannic acid and ferric trichloride hydrate resulted in too small of doxorubicin loading and increased particle size of the nanoparticles, without administration of the nanoparticles and their high permeability and retention effects through solid tumors into tumor cells, experimental data are detailed in example 1.
Further, the structural formula of doxorubicin connected with cell penetrating peptide is shown as formula (1);
wherein CB5005 represents a cell penetrating peptide; the amino acid sequence of the cell penetrating peptide is shown as SEQ ID NO.1.
According to the technical scheme, a new peptide with a cell membrane penetrating and nuclear positioning sequence is coupled to the doxorubicin, so that phagocytosis and nuclear accumulation of doxorubicin-resistant breast cancer cells are improved, and a nano system with strong anticancer activity is synthesized.
Further, the particle diameter of the nano silver particles is 10nm. The nano silver particles with the particle size can exert ideal effects of stimulating endoplasmic reticulum stress and down regulating P glycoprotein, and can be loaded on a network structure layer formed by tannic acid and iron ions through electrostatic adsorption.
Further, the nano silver modified tannic acid-iron network drug-loaded nano compound has the particle size of 185.9nm and the potential of-33.6 mv. The nano particles with the size can enter tumor cells through high permeability and retention effect of solid tumors, and play an anti-tumor role.
The scheme also provides a preparation method of the nano silver modified tannic acid-iron network drug-loaded nano compound, which comprises the following steps in sequence:
s1: dissolving doxorubicin connected with cell membrane penetrating peptide in dimethyl sulfoxide to obtain DOX/DMSO solution, adding water into DOX/DMSO solution, and performing acoustic shock treatment to obtain kernel suspension;
s2: sequentially adding a tannic acid solution and an iron chloride solution into the nuclear suspension, and adjusting the pH value to 6.4-7.4 after acoustic shock and vortex to obtain a nanoparticle suspension containing TA;
s3: dispersing nano silver solution in TA-containing nanoparticle suspension to obtain Ag-TF@ P DOX。
The scheme couples cell penetrating peptide and doxorubicin by a maleimide method, so that the doxorubicin has the capabilities of cell membrane penetration and nuclear targeting. And then wrapping the tannic acid/iron network around doxorubicin forming nano particles in the aqueous solution by using a solvent replacement method, and modifying the nano silver particles outside the tannic acid/iron network by using a large amount of hydroxyl groups and electrostatic adsorption in the tannic acid/iron network to form a nano composite, so that the nano composite has the capacity of inducing intracellular endoplasmic reticulum stress. Through three strategies of cell membrane penetration, cell nucleus targeting and endoplasmic reticulum stress, the anticancer capability of the chemotherapeutic drug doxorubicin is improved, the sensitivity of the doxorubicin-resistant breast cancer tumor cells to chemotherapy is recovered, and the tumor multi-drug resistance is reversed.
Further, in S1, the dosage ratio of doxorubicin, dimethyl sulfoxide and water to which the cell penetrating peptide was attached was 4.4mg:200 μL:8mL; the time of the acoustic shock treatment is 15s and the power is 60W. The hydrophobic property of the doxorubicin is utilized, and the kernel of the nanoparticle in the technical scheme is formed by a sound shock treatment method.
Further, in S2, the volume ratio of the tannic acid solution and the ferric chloride solution is 1:1, the concentration of solute in tannic acid solution and ferric chloride solution is 40mg/mL and 10mg/mL respectively; in S3, the concentration of the nano silver particles in the nano silver solution is 0.1mg/mL, and the volume ratio of the nano silver solution to the nano particle suspension containing TA is 40 mu L:1mL. The tannic acid/iron network is wrapped around the doxorubicin which forms nano particles in the aqueous solution by using a solvent replacement method, the tannic acid and the ferric chloride with the above dosage can form a network, and the inner core is fully wrapped, so that the generation of the resistance of tumor cells to the doxorubicin is ensured to be reduced. The use amount of the nano silver particles can realize the full load of the nano silver particles on a network structure, and play the roles of promoting the apoptosis of tumor cells and increasing the drug sensitivity of the tumor cells.
The scheme also provides application of the nano silver modified tannic acid-iron network drug-loaded nano compound in preparation of drugs for reversing tumor drug resistance. The nano-composite of the scheme has tumor cell nuclear targeting, can promote apoptosis and reduce drug resistance of tumor cells, and can be used as a drug for reversing tumor drug resistance for clinical application. The experimental data of the drug-loaded nano-composite for reversing drug resistance are shown in experimental example 2, and the in-vivo and in-vitro treatment effect are shown in experimental examples 4 and 5.
The scheme also provides application of the nano-silver modified tannic acid-iron network drug-loaded nano-composite in preparation of contrast agents. The nano-composite of the scheme has good near infrared absorption and paramagnetic properties, is a bimodal (photoacoustic/magnetic resonance) enhanced contrast agent with imaging potential, can realize visual monitoring and guiding treatment at one time, and experimental data are shown in experimental example 3.
Drawings
FIG. 1 is a diagram of the Ag-TF@according to example 1 of the present invention P Schematic of the synthesis process of DOX.
FIG. 2 shows the Ag-TF@of example 1 of the present invention P Scanning electron microscope image of DOX.
FIG. 3 is a graph showing the Ag-TF@according to example 1 of the present invention P Particle size distribution profile of DOX.
FIG. 4 shows the Ag-TF@of example 1 and example 2 according to this invention P DOX and TF @ P Potential profile of DOX.
FIG. 5 shows the Ag-TF@of example 1 and example 2 according to this invention P DOX、TF@ P DOX、AgNPs、TA-Fe 3+ 、 P Ultraviolet-visible spectrum of DOX.
FIG. 6 shows the Ag-TF@of example 1 according to this invention P Results of the 14-day stability test of DOX.
FIG. 7 shows the Ag-TF@of example 1 according to this invention P DOX release profile in ATP environment.
FIG. 8 is a confocal fluorescence microscope photograph of the case of phagocytic drugs of experimental example 1 of the present invention.
FIG. 9 shows the results of the drug core localization study of Experimental example 1 of the present invention.
FIG. 10 shows the results of flow cytometry detection of the case of phagocytosis of drugs by cells according to Experimental example 1 of the present invention.
FIG. 11 shows the expression of endoplasmic reticulum stress-related proteins after various drug treatments according to Experimental example 2 of the present invention.
FIG. 12 shows the Ag-TF@of experimental example 2 of the present invention P Biological transmission electron micrographs after DOX treatment.
FIG. 13 shows the P-gp protein expression (flow cytometer assay and WB assay) after treatment with different drugs according to Experimental example 2 of the present invention.
FIG. 14 shows the Ag-TF@C of experimental example 3 of the invention P In vitro photoacoustic imaging results of DOX.
FIG. 15 shows the Ag-TF@of experimental example 3 of the present invention P In vivo photoacoustic imaging results of DOX.
FIG. 16 shows the Ag-TF@of experimental example 3 of the present invention P In vitro magnetic resonance imaging results of DOX.
FIG. 17 shows the Ag-TF@of experimental example 3 of the present invention P In vivo magnetic resonance imaging results of DOX.
FIG. 18 shows the Ag-TF@C of experimental example 4 of the invention P DOX CCK8 assay results (doxorubicin concentration 50. Mu.g/ml).
FIG. 19 shows the Ag-TF@C of experimental example 4 of the present invention P DOX apoptosis was measured by flow cytometry (doxorubicin concentration 50. Mu.g/ml).
FIG. 20 shows the Ag-TF@C of experimental example 4 of the present invention P DOX cell death staining results (doxorubicin concentration 50. Mu.g/ml).
FIG. 21 shows the Ag-TF@of experimental example 4 of the present invention P CCK8 experimental results of DOX (concentration of nano silver of 0, 0.25, 05 and 1.0. Mu.g/ml).
FIG. 22 is a photograph of tumor-bearing mice under different treatments of experimental example 5 of the present invention.
FIG. 23 is a graph showing the relative tumor volume change of tumor-bearing mice under different treatments according to experimental example 5 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. Unless otherwise indicated, the technical means used in the following examples and experimental examples are conventional means well known to those skilled in the art, and the materials, reagents and the like used are all commercially available.
Example 1: preparation of drug-loaded nano-composite
DOX after coupling 4.4mg with cell penetrating peptide P DOX) was dissolved in 200. Mu.L of DMSO solution. 200. Mu.L of the fully dissolved DOX/DMSO solution was then poured into 8mL of deionized water and sonicated for 15s (60 w) continuously. 80. Mu.L of tannic acid (40 mg/mL) and 80. Mu.L of ferric trichloride hydrate (10 mg/mL) aqueous solution were sequentially added to the above solutions, and continuous shaking (60 w) was performed during the addition, followed by vortexing for 25 seconds, and further neutralization of the pH of the solution with 1. Mu.M sodium hydroxide solution, the pH of the resulting suspension was required to be controlled to be 6.4-7.4, and in this example, to be specifically controlled to be 7.0. Next, 40. Mu.L of a nano silver solution (0.1 mg/mL, particle size 10 nm) was added to 1mL of the above solution and stirred overnight (about 8 h), and after centrifugation for 25 minutes (13000 rpm), re-suspended with deionized water to finally obtain a nanocomposite (Ag-TF @) P DOX). The preparation process of the drug-loaded nano-composite in the scheme is shown in fig. 1.
In the technical scheme, the sequence of the cell penetrating peptide is as follows: NH (NH) 2 KLKLALALALAVQRKRQKLMP-COOH (SEQ ID NO. 1) and then adding a cysteine (C) to its carboxyl end to form NH 2 KLKLALALALAVQRKRQKLMPC-COOH (SEQ ID NO. 2). The thiol group of cysteine is used to allow the transmembrane peptide to form a covalent linkage with DOX by conventional maleimide methods of the prior art. DOX after cell membrane-penetrating peptide coupling P DOX) entrusted with the synthesis of biotechnology company, protein in medicine or carrier is realized by the maleimido methodThe connection is a conventional means in the prior art. P DOX has a molecular formula shown in formula (1), wherein the amino acid sequence of CB5005 is SEQ ID NO.1.CB5005 is engineered to form a sequence as shown in SEQ ID NO.2, and cysteine (C) provides a thiol group attached to a maleimide group, and a protein of sequence as shown in SEQ ID NO.2 is attached to the amino group of doxorubicin via the maleimide group.
The prepared nano-composite is spherical, and a scanning electron microscope shows that the surface is rough after the nano-silver particles are adsorbed (figure 2). The particle size of the nanocomposite was measured by a Markov particle size potentiometer to be about 185.9nm (FIG. 3) and the potential was about-33.6 mv (FIG. 4). After loading doxorubicin, the characteristic peak belonging to doxorubicin at 480nm in the nanocomposite red shifted to 495 nm. The encapsulation efficiency of doxorubicin in the nanocomposite was about 79.2% and the drug loading was about 35.2% as measured by ultraviolet-visible light spectroscopy and high performance liquid chromatography (fig. 5). The encapsulation efficiency was calculated as shown in the following formula (% w/w) = (doxorubicin/doxorubicin addition to the nanocomposite) ×100%. The method comprises the steps of carrying out a first treatment on the surface of the The drug loading calculation formula is shown as follows, the drug loading (% w/w) = (doxorubicin/total nanocomposite mass in nanocomposite) x 100% in 14 days, the particle size of the nanocomposite is not significantly changed (figure 6), which shows that the nanocomposite has good stability. Drug release experiments showed that about 80.4% of doxorubicin could be released after 48 hours of the nanocomposite was placed in a 5mM ATP containing solution (FIG. 7).
In this technical scheme, the operation of neutralizing the pH value with sodium hydroxide solution is very important, and the inventors tried to adjust the pH of the suspension to 6.4 and 7.4. Under the two pH values, nano silver is added in the following steps according to the method described above, and the suspension of the nano composite with good dispersity can be obtained by stirring and mixing. The inventors have also tried other pH effects on experimental results, in particular pH values of 9.4 and 5.5 for suspensions adjusted with sodium hydroxide. The subsequent addition of nanosilver as described above was found to produce a large amount of flocculent precipitate during subsequent agitation, the nanocomposite was very prone to aggregation and poor dispersion in the liquid phase, resulting in failure of nanocomposite fabrication. Therefore, in the process, the pH value is maintained to be 6.4-7.4, and the successful preparation of the nano silver modified tannic acid-iron network drug-loaded nano compound is very critical.
For a pair of P The proportional relationship between DOX and tannic acid body was studied, and the results are shown in Table 1. In table 1, the mass addition ratio refers to the effective ingredient DOX (i.e.: P the mass of DOX minus the mass of cell penetrating peptide and MAL groups) to tannic acid + ferric trichloride hydrate. "2" in table 1 is the best mode described hereinabove, P the mass of DOX was 4.4mg, and the mass of tannic acid+ferric trichloride hydrate was 4mg in terms of DOX, so that the mass-to-mass ratio was 1:5 (800. Mu.g: 4 mg). As can be seen from the data in table 1, a preferable encapsulation efficiency and drug loading can be obtained by controlling the mass-to-charge ratio to 1:5.
Table 1: P proportional relation pair between DOX and tannic acid body P Effect of DOX drug loading, encapsulation efficiency and particle size
Example 2
The drug-loaded nano-composite without nano-silver particles is prepared by the specific preparation method:
DOX after coupling 4.4mg with cell penetrating peptide P DOX) was dissolved in 200. Mu.l DMSO solution. 200 μl of the fully dissolved DOX/DMSO solution was then poured into 8ml deionized water and sonicated for 15 seconds (60 w) continuously. 80. Mu.l of tannic acid (40 mg/ml) and 80. Mu.l of an aqueous solution of ferric trichloride hydrate (10 mg/ml) were sequentially added to the above solution and subjected to continuous sonic shock and vortexing, and then the pH of the solution was neutralized with 1. Mu.M sodium hydroxide solution, followed by centrifugation for 25 minutes (13000 r)pm) re-suspension with deionized water to finally obtain the nanocomposite (TF @) P DOX). The potential diagram is shown in fig. 4, and the ultraviolet-visible spectrum is shown in fig. 5.
DOX after coupling 4.4mg with cell penetrating peptide P DOX) was dissolved in 200. Mu.l DMSO solution. 200 μl of the DOX/DMSO solution was then poured into 8ml of deionized water and subjected to continuous shaking for 15 seconds (60 w) to obtain P DOX nanoparticles, the UV-visible spectrum of which is shown in FIG. 5. Dissolving tannic acid and ferric trichloride hexahydrate powder in deionized water, and stirring to obtain TA-Fe3 + The ultraviolet-visible spectrum is shown in fig. 5.
Experimental example 1: cell membrane penetration and targeting capabilities of drug-loaded nanocomposites
The common Doxorubicin (DOX) is coupled with the doxorubicin after passing through the cell membrane penetrating peptide P DOX) and nanocomposite (TF@coated with example 2) P DOX) were incubated with doxorubicin-resistant breast cancer cells (MCF-7/ADR) for 0.5, 1, 3, 6 hours. Wherein the doxorubicin concentration was 20. Mu.g/ml, and the cell density was 1.5X10 4 Individual cells/per confocal dish. The confocal fluorescence microscope detects that the doxorubicin and the nanocomposite of example 2 after cell-penetrating peptide coupling can be phagocytized into cytoplasm and nucleus in large quantity, while the unconjugated doxorubicin stays in cytoplasm and cannot enter nucleus. At the same time, the flow cytometer also proves the conclusion by quantitatively detecting the fluorescence intensity in cells. This demonstrates that doxorubicin, functionalized with cell-penetrating peptides, has the ability to penetrate cell membranes and target the nucleus. Confocal fluorescence microscopy pictures of the condition of phagocytosis of the drug by the cells are shown in FIG. 8 (blue fluorescence represents nucleus, red fluorescence represents doxorubicin or doxorubicin after cell-penetrating peptide coupling), and the results of drug nucleus localization study are shown in FIG. 9 (DOX group in sequence from left to right), P DOX group and TF @ P DOX group, blue fluorescence indicates nuclei, red fluorescence indicates doxorubicin or doxorubicin after cell-penetrating peptide coupling), and flow cytometry detection results of the case of phagocytosis of drug by cells are shown in fig. 10.
Experimental example 2: research on drug-loaded nano-composite reversal drug resistance
In this experimental example, after addition of nano silver particles to the nanosystem (Ag-TF@prepared in example 1) P DOX), the ability of the nanocomposite to induce tumor cell endoplasmic reticulum stress. The experimental scheme is as follows: PBS, TF @ P DOX and Ag-TF @ P DOX (DOX content 50. Mu.g/ml) was added to a cell density of 1X 10, respectively 6 For 6h, and then the related protein expression was detected using a western bolt. As compared with the nano-composite without nano-silver particles and the control group, the protein expression related to endoplasmic reticulum stress in the cells is obviously improved after the nano-silver particles are added through western bolt detection, and particularly, the expression amounts of GRP78, ATF4 and Caspase-12 are greatly up-regulated as compared with the protein expression related to endoplasmic reticulum stress (figure 11). Biological transmission electron microscopy also showed that the polymer was prepared via nanocomposite (Ag-TF @, a P DOX) after co-incubation, the endoplasmic reticulum within the cell swells significantly (fig. 12, the lower panel is an enlarged view of the upper panel, the arrows indicate where significant swelling of the endoplasmic reticulum occurs), indicating that the nanocomposite initiates signaling of intracellular endoplasmic reticulum stress. We examined their effect on intracellular P-gp expression using different reagents. The nano-composite containing nano-silver particles can be used for maximally down-regulating P-gp as proved by flow cytometry and western bolt detection, which is beneficial to restoring the sensitivity of cells to chemotherapeutic drugs (FIG. 13, left flow cytometry detection result, right WB detection result). In FIG. 13, quantitative measurement is performed using streaming software P The fluorescence value of DOX group flow fluorescence value is slightly higher than that of control group and DOX group, and is consistent with WB result. Under the action of the iron tannic acid, p the up-regulation of P-gp by DOX is greatly inhibited, and the inhibition of P-gp expression is further enhanced if nano-silver particles are further added to the nanoparticles. Among them, P-gp (P glycoprotein) is a transmembrane glycoprotein with a molecular weight of 170KD, which has an energy-dependent "drug pump" function. P-gp can be combined with the drug and ATP, and ATP supplies energy to pump the intracellular drug out of the cell, so that the concentration of the intracellular drug is reduced to enable the cell to generate drug resistance.
Experimental example 3: study of imaging Effect
Because the nano-composite contains a metal polyphenol network (tannic acid-iron), the nano-particle has the characteristics of near infrared absorption and paramagnetism, so the nano-composite has the potential of becoming a contrast agent for photoacoustic imaging and magnetic resonance imaging. In vitro experiments demonstrated that the relaxation rates of photoacoustic signals (fig. 14) and magnetic resonance (fig. 16) have a good linear relationship with the concentration of the nanocomposite. Meanwhile, in vivo experiments also prove that the nano system can realize photoacoustic imaging (figure 15) and magnetic resonance imaging (figure 17) of a living organism.
Experimental example 4: in vitro cytotoxicity studies
The cytotoxicity of the nanocomposite on MCF-7/ADR cells was examined in vitro and in vivo, and the cell density of the MCF-7/ADR cells was 5X 10 3 The number of cells/holes, adding the drugs to be tested, are respectively: empty control, doxorubicin (DOX) without membrane-penetrating peptide and doxorubicin with membrane-penetrating peptide p DOX), nanoparticle TF @ P DOX, nanoparticle Ag-TF@ P DOX, co-cultured for 6h, 12h and 24h, and then subjected to CCK-8 cell activity detection. Wherein, except for the blank control, the concentration of doxorubicin was kept at 50 μg/ml in all the other experimental groups. Through CCK8 detection (figure 18), apoptotic cell detection (figure 19) and cell live and dead double-staining detection (figure 20, green fluorescence indicates live cells and red fluorescence indicates dead cells), we found that the nanocomposite containing cell-penetrating peptide coupled doxorubicin and nano silver particles had the strongest cytotoxicity. This means that the nanocomposite with the ability to penetrate cell membranes, target nuclei and induce endoplasmic reticulum stress can most effectively restore the sensitivity of drug-resistant cells to chemotherapeutic drugs, and can reverse cell resistance.
In addition, MCF-7/ADR was subjected to various forms of nano-silver cytotoxicity experiments, the experimental groups including nano-silver alone, nano-silver in combination with nano-silver inhibitor (TUDCA), ag-TF @, and combinations thereof P DOX、Ag-TF@ P DOX is combined with TUDCA. The drug treatment time was 24 hours, and the concentration of silver particles was controlled to 0, 0.25, 0.5 and 1.0. Mu.g/ml, respectively. As a result of the experiment, referring to FIG. 21, it was found that TUDCA was able to almost completely remove the inhibition of cells by nano silver from 66.7% to 91.7% at a nano silver concentration of 1.0. Mu.g/mlThe variation was 25.0%. However, nano silver is loaded on the nano composite to form Ag-TF@ P After DOX, the cell inhibition rate increased from 21.0% to 50.3% with TUDCA relative to without TUDCA, with a change of 29.3%. TUDCA is a high-efficiency and specific nano-silver inhibitor, and the variation shows the independent toxic effect of nano-silver on cells to be tested. The cytotoxicity of the nano-silver is further enhanced after loading the nano-silver onto the nano-composite, which suggests that in this solution the nano-composite has a synergistic effect on the toxic effects of the nano-silver.
Experimental example 5: in vivo cytotoxicity studies
An MCF-7/ADR tumor-bearing mouse model is established, and the inhibition capability of various drug-carrying nano-composite tumors is studied. The specific cases of dosing and experimental grouping are: a control group, a DOX group, P DOX group, TF @ P DOX group and Ag-TF @ P DOX groups, the administration concentration of each administration concentration is uniformly converted into the administration concentration of doxorubicin, and the specific concentration is 1.5mg/kg DOX for each mouse body weight injection. The photographs of tumor-bearing mice under different drug treatments are shown in detail in FIG. 22, and the tumor growth curves of the tumor-bearing mice are shown in FIG. 23. In vivo experiments also prove that the nanocomposite of the scheme has the most obvious tumor growth inhibition on tumor-bearing mice.
The foregoing is merely exemplary of the present invention, and specific technical solutions and/or features that are well known in the art have not been described in detail herein. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present invention, and these should also be regarded as the protection scope of the present invention, which does not affect the effect of the implementation of the present invention and the practical applicability of the patent. The protection scope of the present application shall be subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.
SEQUENCE LISTING
<110> Chongqing medical university affiliated second Hospital
<120> drug-loaded nanocomposite of nano-silver modified tannic acid-iron network, preparation method thereof and anti-swelling agent
Tumor drug resistance application
<130> 11.30
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 21
<212> PRT
<213> artificial sequence
<400> 1
Lys Leu Lys Leu Ala Leu Ala Leu Ala Leu Ala Val Gln Arg Lys Arg
1 5 10 15
Gln Lys Leu Met Pro
20
<210> 2
<211> 22
<212> PRT
<213> artificial sequence
<400> 2
Lys Leu Lys Leu Ala Leu Ala Leu Ala Leu Ala Val Gln Arg Lys Arg
1 5 10 15
Gln Lys Leu Met Pro Cys
20
Claims (9)
1. A nano-silver modified tannic acid-iron network drug-loaded nano-composite, which is characterized in that: the cell membrane-penetrating peptide-containing doxorubicin comprises an inner core formed by doxorubicin connected with the cell membrane-penetrating peptide, wherein a network structure layer formed by tannic acid and iron ions is wrapped outside the inner core, and nano silver particles are modified outside the network structure layer;
the structural formula of the doxorubicin connected with the cell penetrating peptide is shown as a formula (1);
wherein CB5005 represents a cell penetrating peptide; the amino acid sequence of the cell penetrating peptide is shown as SEQ ID NO.1.
2. The nano-silver modified tannic acid-iron network drug-loaded nanocomposite of claim 1, wherein: the raw materials comprise doxorubicin, tannic acid and ferric trichloride hydrate which are connected with cell penetrating peptide; the ratio of the sum of the masses of tannic acid and ferric trichloride hydrate to the mass of doxorubicin in doxorubicin to which cell penetrating peptide is attached was 5:1.
3. the nano-silver modified tannic acid-iron network drug-loaded nanocomposite of claim 2, wherein: the particle size of the nano silver particles is 10nm.
4. A nano-silver modified tannic acid-iron network drug loaded nanocomposite according to claim 3, wherein: the particle size was 185.9nm and the potential was-33.6 mv.
5. The method for preparing the nano-silver modified tannic acid-iron network drug-loaded nano-composite according to claim 4, wherein the method comprises the following steps: the method comprises the following steps of:
s1: dissolving doxorubicin connected with cell membrane penetrating peptide in dimethyl sulfoxide to obtain DOX/DMSO solution, adding water into DOX/DMSO solution, and performing sonication treatment to obtain kernel suspension;
s2: sequentially adding a tannic acid solution and an iron chloride solution into the nuclear suspension, and adjusting the pH value to 6.4-7.4 after sound vibration and vortex to obtain a nanoparticle suspension containing tannic acid TA;
s3: dispersing nano silver solution in TA-containing nanoIn the rice grain suspension, the drug-loaded nano-composite Ag-TF@of the tannic acid-iron network modified by nano-silver is obtained P DOX。
6. The method for preparing the nano-silver modified tannic acid-iron network drug-loaded nano-composite according to claim 5, wherein the method comprises the following steps: in S1, the dosage ratio of doxorubicin, dimethyl sulfoxide and water to which cell penetrating peptide was attached was 4.4mg:200 μL:8mL; the time of the sonication is 15s and the power is 60W.
7. The method for preparing the nano-silver modified tannic acid-iron network drug-loaded nano-composite according to claim 5, wherein the method comprises the following steps: in S2, the volume ratio of tannic acid solution to ferric chloride solution is 1:1, the concentration of solute in tannic acid solution and ferric chloride solution is 40mg/mL and 10mg/mL respectively; in S3, the concentration of the nano silver particles in the nano silver solution is 0.1mg/mL, and the volume ratio of the nano silver solution to the nano particle suspension containing TA is 40 mu L:1mL.
8. Use of a nano-silver modified tannic acid-iron network drug-loaded nanocomposite according to any one of claims 1-4 in the preparation of a medicament for reversing tumor resistance.
9. Use of a nano-silver modified tannic acid-iron network drug-loaded nanocomposite according to any of claims 1-4 for the preparation of contrast agents.
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