CN114404429A - Nano-silver modified tannin-iron network drug-loaded nano-composite, preparation method thereof and application thereof in reversing tumor drug resistance - Google Patents
Nano-silver modified tannin-iron network drug-loaded nano-composite, preparation method thereof and application thereof in reversing tumor drug resistance Download PDFInfo
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- CN114404429A CN114404429A CN202111446379.5A CN202111446379A CN114404429A CN 114404429 A CN114404429 A CN 114404429A CN 202111446379 A CN202111446379 A CN 202111446379A CN 114404429 A CN114404429 A CN 114404429A
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Classifications
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/38—Silver; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the technical field of nano-drug presentation systems and contrast agents, in particular to a nano-silver modified tannin-iron network drug-loaded nano-composite, a preparation method thereof and application thereof in reversing tumor drug resistance. The drug-loaded nano-composite comprises an inner core formed by adriamycin connected with cell-penetrating peptide, wherein a network structure layer formed by tannic acid and iron ions wraps the outer side of the inner core, and nano-silver particles are modified outside the network structure layer. The scheme can solve the technical problem of tumor chemotherapy failure caused by tumor drug resistance, can down-regulate over-expressed P-gp in drug-resistant cells and increase the accumulation of chemotherapy drugs in the cells, can effectively deliver the anti-tumor drugs to the cell nucleus of the final destination, and is a bimodal (photoacoustic/magnetic resonance) enhanced contrast agent with imaging potential. The scheme can be applied to treatment, visual monitoring and guided 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 tannin-iron network drug-loaded nano-composite, a preparation method thereof and application thereof in reversing tumor drug resistance.
Background
Tumorigenesis is a long-term, multi-staged, multi-gene change and accumulation process with the complexity of gene control and multifactorial regulation. The domestic and foreign research shows that: tumor multidrug resistance (MDR) is a major cause of tumor chemotherapy failure. The drug resistance of the tumor relates to various mechanisms such as the reduction of the concentration of intracellular drugs, the change of drug target molecules, metabolic detoxification, the imbalance of DNA damage repair functions and the like. Although scientists have adopted various nanotechnology-based strategies to reverse MDR, such as enhancing drug accumulation by tumor targeting, preventing inactivation of drug-targeting pathways, and combining photothermal therapy, photodynamic therapy, etc., a single strategy to reverse drug resistance has not been able to fully restore the sensitivity of tumor cells to chemotherapeutic drugs, and 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 by inducing cell death through interaction with DNA helices or related enzymes, its efficacy is highly dependent on the nuclear pathway. However, nanocarriers are subject to endosomal trapping and lysosomal degradation after releasing DOX to its target of action. In addition, due to overexpression of P glycoprotein (P-gp) on MDR membrane, DOX may be rapidly pumped out of the cell after reaching cytoplasm, further reducing intracellular drug concentration. Therefore, there is a need to develop a highly efficient nanocomposite to overcome MDR, to down-regulate P-gp that is overexpressed in drug-resistant cells and increase accumulation of intracellular DOX, and to efficiently deliver anti-tumor drugs to the nucleus of their final destination.
Disclosure of Invention
The invention aims to provide a nano-silver modified tannin-iron network drug-loaded nano-composite to solve the technical problem of tumor chemotherapy failure caused by tumor multidrug resistance.
In order to achieve the purpose, the invention adopts the following technical scheme:
a drug-loaded nano-composite of a tannin-iron network modified by nano-silver comprises an inner core formed by adriamycin connected with cell-penetrating peptide, a network structure layer formed by tannin and iron ions wraps 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 adriamycin connected with cell-penetrating peptide to formCore of (a)PDOX) and then modifying the nano-silver particles outside the network structure layer, not only realizing the loading of various drug effect components, but also making the synergistic effect between the drugs possible and greatly reducing the drug resistance of the tumor to chemotherapeutic drugs. The drug-loaded nano-composite is a diagnosis and treatment type nano-composite, and can simultaneously realize nuclear targeting and endoplasmic reticulum stress to enhance tumor chemotherapy and reverse tumor multi-drug resistance.
More particularly, adriamycin is an antitumor antibiotic, can inhibit the synthesis of RNA and DNA, has a wide antitumor spectrum, has effects on various tumors, belongs to a periodic nonspecific medicine, and has killing effects on tumor cells in various growth periods. However, doxorubicin itself lacks targeting properties, and in order to allow sufficient amounts of doxorubicin to enter the nucleus to exert its inhibitory effect, it is necessary to increase the dosage, thereby increasing the possibility of drug resistance in tumor cells, as well as increasing the side effects of the drug. According to the technical scheme, the cell-penetrating peptide is connected to the adriamycin, so that the nuclear aggregation effect of the adriamycin is improved, and the treatment effect of the adriamycin is improved. In order to reduce the drug resistance of tumors to adriamycin, the technical scheme is that the surface of nanoparticles formed by the adriamycin connected with cell-penetrating peptides is subjected to metal network polyphenol engineering treatment, and a network structure layer formed by tannic acid and iron ions enables the nanocomposite to have ATP responsive decomposition and ATP consumption characteristics, so that the biocompatibility is improved, ATP-dependent drug external pumps are reduced, the drug sensitivity of tumor cells is increased, and the treatment effect of the adriamycin 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. 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 drug and ATP, and the ATP can supply energy to pump the drug in the cell out of the cell, so that the drug concentration in the cell is reduced to ensure that the cell generates drug resistance. The network structure layer formed by tannic acid and iron ions is wrapped outside adriamycin, and the drug resistance of tumor cells can be reduced through a dual mode of consuming ATP and reducing P glycoprotein. According to the scheme, the nano silver particles are introduced into a 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 can further inhibit the expression of P glycoprotein through synergistic interaction, so that drug-resistant cells recover sensitivity to chemotherapy. Therefore, the nano silver particles can also generate double effects, respectively induce the apoptosis of tumor cells and increase the 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 guide treatment at one time.
In conclusion, the drug-loaded nano-composite of the nano-silver modified tannin-iron network can overcome MDR through various mechanisms, can also down-regulate over-expressed P-gp in drug-resistant cells, increase the accumulation of chemotherapy drugs in cells, and can effectively deliver anti-tumor drugs to the cell nucleus of the final destination.
Further, a nano-silver modified tannin-iron network drug-loaded nano-composite, which comprises the raw materials of adriamycin connected with cell-penetrating peptide, tannic acid and ferric trichloride hydrate; the ratio of the sum of the mass of the tannic acid and the ferric chloride hydrate to the mass of the adriamycin in the adriamycin connected with the cell-penetrating peptide is 5: 1. in the technical scheme, the ideal encapsulation efficiency and drug loading rate can be obtained by controlling the mass adding ratio to be 1: 5. The high dosage of the adriamycin does not help greatly to improve the drug loading capacity, so that the drug waste is caused; the excessive use amounts of tannic acid and ferric chloride hydrate can cause the doxorubicin drug-loading rate to be too small, the particle size of the nanoparticles can be increased, the nanoparticle administration is not utilized, and the nanoparticles can enter tumor cells through the high permeability and retention effect of solid tumors, and experimental data are detailed in example 1.
Further, the structural formula of the adriamycin 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 in SEQ ID NO. 1.
The technical scheme couples a new peptide with a cell membrane penetration and nuclear localization sequence to the adriamycin, improves the phagocytosis and the nuclear accumulation of adriamycin-resistant breast cancer cells, and synthesizes a nano system with strong anticancer activity.
Further, the particle size of the nano silver particles is 10 nm. The nano silver particles with the particle sizes can exert ideal effects of stimulating endoplasmic reticulum stress and reducing 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 tannin-iron network drug-loaded nano-composite has the particle size of 185.9nm and the potential of-33.6 mv. The nanoparticles with the size can enter tumor cells through the high permeability and retention effect of solid tumors to play the role of anti-tumor.
The scheme also provides a preparation method of the nano-silver modified tannin-iron network drug-loaded nano-composite, which comprises the following steps in sequence:
s1: dissolving adriamycin connected with cell-penetrating peptide in dimethyl sulfoxide to obtain a DOX/DMSO solution, then adding water into the DOX/DMSO solution and performing acoustic shock treatment to obtain an inner core suspension;
s2: sequentially adding a tannic acid solution and an iron chloride solution into the core suspension, and adjusting the pH value to 6.4-7.4 after acoustic shock and vortex to obtain a TA-containing nanoparticle suspension;
s3: dispersing the nano silver solution into the nano particle suspension containing TA to obtain Ag-TF @PDOX。
The scheme couples the cell penetrating peptide and the adriamycin by a maleimide method, so that the adriamycin has the capabilities of cell membrane penetration and nuclear targeting. Then, a tannin/iron network is wrapped around adriamycin which forms nano particles in aqueous solution by a solvent replacement method, and then nano silver particles are modified outside the tannin-iron network by utilizing the hydroxyl and electrostatic adsorption action which are greatly existed in the tannin/iron network to form a nano compound, so that the nano compound has the capacity of inducing endoplasmic reticulum stress in cells. Through three strategies of cell membrane penetration, cell nucleus targeting and endoplasmic reticulum stress, the anticancer capability of the chemotherapeutic drug adriamycin is improved, the sensitivity of adriamycin-resistant breast cancer tumor cells to chemotherapy is restored, and the multidrug resistance of tumors is reversed.
Further, in S1, the amount ratio of doxorubicin to cell-penetrating peptide-attached, dimethyl sulfoxide, and water was 4.4 mg: 200 μ L: 8 mL; the duration of the acoustic shock treatment was 15s and the power was 60W. The inner core of the nanoparticle of the technical scheme is formed by utilizing the hydrophobicity of the adriamycin and a method of acoustic shock treatment.
Further, in S2, the ratio by volume of the tannic acid solution to the ferric chloride solution is 1: 1, the concentrations of solutes in the tannic acid solution and the ferric chloride solution are respectively 40mg/mL and 10 mg/mL; 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 TA-containing nanoparticle suspension is 40 μ L: 1 mL. The tannin/iron network is wrapped around the adriamycin which forms nano particles in aqueous solution by using a solvent replacement method, the tannin and the ferric chloride can form the network by using the above dosage, and the inner core is fully wrapped, so that the generation of the adriamycin resistance of tumor cells is reduced. The dosage of the nano silver particles can realize the full load of the nano silver particles on a network structure, and the effects of promoting the apoptosis of tumor cells and increasing the drug sensitivity of the tumor cells are exerted.
The scheme also provides application of the nano-silver modified tannin-iron network drug-loaded nano-composite in preparation of drugs for reversing tumor drug resistance. The nano-composite has tumor cell nucleus targeting property, can promote apoptosis and reduce drug resistance of tumor cells, and can be clinically applied as a drug for reversing tumor drug resistance. The data of the research experiment of the drug-loaded nano-composite for reversing drug resistance are detailed in experimental example 2, and the research of in vivo and in vitro treatment effects are detailed in experimental examples 4 and 5.
The scheme also provides application of the nano-silver modified tannin-iron network drug-loaded nano-composite in preparation of the contrast agent. The nano composite 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 guided treatment at one time, and experimental data are detailed in experimental example 3.
Drawings
FIG. 1 shows Ag-TF @ in example 1 of the present inventionPSchematic diagram of the synthesis process of DOX.
FIG. 2 shows Ag-TF @ in example 1 of the present inventionPScanning electron microscopy images of DOX.
FIG. 3 is Ag-TF @, which is an example 1 of the present inventionPParticle size distribution profile of DOX.
FIG. 4 shows Ag-TF @ in examples 1 and 2 of the present inventionPDOX and TF @PPotential profile of DOX.
FIG. 5 shows Ag-TF @ in examples 1 and 2 of the present inventionPDOX、TF@PDOX、AgNPs、TA-Fe3+、PUv-vis spectrum of DOX.
FIG. 6 shows Ag-TF @ in example 1 of the present inventionPExperimental results were tested for 14-day stability of DOX.
FIG. 7 shows Ag-TF @ in example 1 of the present inventionPDOX release profile in ATP environment.
FIG. 8 is a confocal fluorescence microscope photograph showing the phagocytosis of the drug by the cells in Experimental example 1.
FIG. 9 shows the results of the nuclear localization study of the drug of Experimental example 1 of the present invention.
FIG. 10 shows the flow cytometry results of the phagocytosis of drugs by the cells in Experimental example 1 of the present invention.
FIG. 11 shows the expression of proteins involved in endoplasmic reticulum stress after different drug treatments in Experimental example 2 of the present invention.
FIG. 12 shows Ag-TF @ of Experimental example 2 of the present inventionPTransmission electron microscopy of organisms after DOX treatment.
FIG. 13 shows P-gp protein expression (flow cytometry and WB) after different drug treatments in Experimental example 2 of the present invention.
FIG. 14 shows Ag-TF @ of Experimental example 3 of the present inventionPIn vitro photoacoustic imaging results of DOX.
FIG. 15 shows Ag-TF @ of Experimental example 3 of the present inventionPDOX in vivo lightAnd (5) acoustic imaging results.
FIG. 16 shows Ag-TF @ of Experimental example 3 of the present inventionPAnd (4) in-vitro magnetic resonance imaging results of DOX.
FIG. 17 shows Ag-TF @ of Experimental example 3 of the present inventionPIn vivo magnetic resonance imaging results of DOX.
FIG. 18 shows Ag-TF @ of Experimental example 4 of the present inventionPCCK8 test results for DOX (doxorubicin at a concentration of 50. mu.g/ml).
FIG. 19 shows Ag-TF @ of Experimental example 4 of the present inventionPFlow cytometry detection of apoptosis of DOX (doxorubicin concentration 50. mu.g/ml).
FIG. 20 shows Ag-TF @ of Experimental example 4 of the present inventionPCell live-dead staining results for DOX (doxorubicin concentration 50. mu.g/ml).
FIG. 21 is Ag-TF @, which is an example of experiment 4 of the present inventionPCCK8 test results for DOX (concentrations of nanosilver of 0, 0.25, 0.5 and 1.0. mu.g/ml).
FIG. 22 is a photograph of tumor-bearing mice treated differently in Experimental example 5 of the present invention.
FIG. 23 is a graph showing the relative tumor volume changes of tumor-bearing mice under different treatments in Experimental example 5 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, 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 therein are commercially available.
Example 1: preparation of drug-loaded nanocomposites
DOX (D) after coupling 4.4mg with cell-penetrating peptidePDOX) was dissolved in 200. mu.L DMSO solution. Then 200. mu.L of the DOX/DMSO solution dissolved completely was poured into 8mL of deionized water and sonicated continuously for 15s (60 w). Adding 80 μ L tannic acid (40mg/mL) and 80 μ L ferric chloride hydrate (10mg/mL) aqueous solution into the above solution, continuously shaking (60w) during the adding process, vortexing for 25s, and neutralizing the pH value of the solution with 1 μ M sodium hydroxide solution to obtain suspension with pH controlled at 64-7.4, specifically controlled to 7.0 in this example. Next, 40. mu.L of a nanosilver solution (0.1mg/mL, particle size 10nm) was added to 1mL of the above solution and stirred overnight (about 8h), centrifuged for 25 minutes and then resuspended (13000rpm) with deionized water to finally obtain a nanocomposite (Ag-TF @PDOX). The preparation process of the drug-loaded nano-composite of the scheme is shown in figure 1.
In this technical scheme, the sequence of the cell-penetrating peptide is: NH (NH)2-KLKLALALALAVQRKRQKLMP-COOH (SEQ ID NO.1) to which a cysteine (C) has been added at its carboxy terminus to form NH2-KLKLALALALAVQRKRQKLMPC-COOH (SEQ ID NO. 2). The thiol group of cysteine was used to allow the cell-penetrating peptide to form a covalent linkage with DOX by the conventional maleimide method of the prior art. DOX after coupling of cell-penetrating peptides (A)PDOX) was synthesized by biotechnology companies, and it was a conventional means in the prior art to link proteins to drugs or carriers by the maleimide method.PThe molecular formula of DOX is shown in a formula (1), wherein the amino acid sequence of CB5005 is SEQ ID NO. 1. CB5005 is modified to form a sequence shown as SEQ ID NO.2, cysteine (C) provides a sulfydryl connected with a maleimide group, and a protein with the sequence shown as SEQ ID NO.2 is connected with the amino of adriamycin through 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 determined by Malvern particle size potentiometer to be about 185.9nm (FIG. 3) and the potential was about-33.6 mv (FIG. 4). After loading adriamycin, the characteristic peak of the nano-composite at 480nm of the adriamycin is red-shifted to 495 nm. The encapsulation efficiency of the adriamycin in the nano-composite is about 79.2 percent and the drug loading rate is about 35.2 percent, which are measured by ultraviolet-visible light spectrum and high performance liquid chromatography (figure 5). The encapsulation efficiency is calculated by the following formula, encapsulation efficiency (% w/w) × (doxorubicin/doxorubicin addition amount in the nanocomposite) × 100%. (ii) a The drug loading rate is calculated according to the following formula, wherein the drug loading rate (% w/w) × 100% (total mass of adriamycin/nano compound in the nano compound) is 14 days, the particle size of the nano compound is not obviously changed (figure 6), and the stability of the nano compound is better. Drug release experiments showed that approximately 80.4% of doxorubicin was released 48 hours after placing the nanocomplexes in a solution containing 5mM ATP (figure 7).
In the present solution, the operation of neutralizing the pH value using a 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 according to the method described above, and the nano composite suspension with good dispersity can be obtained through stirring and mixing. The inventors also tried other pH effects on the experimental results, specifically using pH 9.4 and 5.5 of the suspension adjusted with sodium hydroxide. The subsequent addition of nano silver according to the method described above, found that a great amount of flocculent precipitate is generated during the subsequent stirring process, the nano composite is very easy to aggregate, and the dispersion degree in the liquid phase is poor, resulting in the failure of the preparation of the nano composite. Therefore, in the process, the pH value is maintained to be 6.4-7.4, which is very critical for the successful preparation of the nano-silver modified tannin-iron network drug-loaded nano-composite.
To pairPThe relationship between the ratio of DOX and the tannin bodies was investigated and the results are shown in table 1. In table 1, the mass administration ratio refers to the amount of DOX (i.e.:Pmass of DOX minus mass of cell penetrating peptide and MAL groups) to tannic acid + ferric chloride hydrate. "2" in table 1 is the best mode described in the foregoing,Pthe mass of DOX was 4.4mg, converted to 800. mu.g, and the mass of tannic acid + ferric trichloride hydrate was 4mg, so that the mass addition ratio was 1:5 (800. mu.g: 4 mg). As can be seen from the data in table 1, the encapsulation efficiency and the drug loading rate can be more preferably obtained by controlling the mass addition ratio to 1: 5.
Table 1:Pproportional relationship between DOX and tannin bodyPEffect of DOX drug Loading, encapsulation efficiency and particle size
Example 2
The drug-loaded nano-composite without nano-silver particles is prepared by the embodiment, and the specific preparation method comprises the following steps:
DOX (D) after coupling 4.4mg with cell-penetrating peptidePDOX) was dissolved in 200 μ Ι dmso solution. Then 200. mu.l of the DOX/DMSO solution dissolved completely was poured into 8ml of deionized water and sonicated continuously for 15 seconds (60 w). Sequentially adding 80 μ l tannic acid (40mg/ml) and 80 μ l ferric trichloride hydrate (10mg/ml) aqueous solution into the above solution, continuously performing acoustic shock and vortex, neutralizing the pH value of the solution with 1 μ M sodium hydroxide solution, centrifuging for 25 min (13000rpm), and re-suspending with deionized water to obtain nanometer composite (TF @)PDOX). The potential diagram is shown in figure 4, and the ultraviolet-visible spectrum is shown in figure 5.
DOX (D) after coupling 4.4mg with cell-penetrating peptidePDOX) was dissolved in 200 μ Ι dmso solution. Then, 200. mu.l of the completely dissolved DOX/DMSO solution was poured into 8ml of deionized water and continuously sonicated for 15 seconds (60w) to obtainPThe ultraviolet-visible light spectrum of DOX nano-particles is shown in figure 5. Dissolving the powder of tannic acid and ferric trichloride hexahydrate in deionized water, and stirring to obtain TA-Fe3+The ultraviolet-visible spectrum thereof is shown in FIG. 5.
Experimental example 1: cell membrane penetration and targeting capabilities of drug-loaded nanocomposites
Coupling ordinary adriamycin (DOX) with cell-penetrating peptide (DOX)PDOX) and nanocomposite (TF @) encapsulating example 2PDOX) were incubated with adriamycin-resistant breast cancer cells (MCF-7/ADR) for 0.5, 1, 3, 6 hours. Wherein the adriamycin concentration is 20 μ g/ml, and the cell density is 1.5 × 104Per confocal dish. Through the detection of a confocal fluorescence microscope, the adriamycin coupled with the cell-penetrating peptide and the nano-composite of the example 2 can be phagocytized into cytoplasm and cells in large quantityMost of the unconjugated doxorubicin stays in the cytoplasm and cannot enter the nucleus. Meanwhile, the flow cytometer also proves the conclusion by quantitatively detecting the fluorescence intensity in the cells. This shows that the adriamycin functionalized by cell-penetrating peptide has the capability of cell membrane penetration and cell nucleus targeting. The confocal fluorescence microscope picture of the drug phagocytosis of the cells is shown in FIG. 8 (blue fluorescence indicates cell nucleus, red fluorescence indicates adriamycin or adriamycin coupled by cell-penetrating peptide), and the study result of the drug nuclear localization is shown in FIG. 9 (from left to right, DOX group, and DOX group, B,PDOX group and TF @PIn DOX group, blue fluorescence indicates cell nucleus, red fluorescence indicates doxorubicin or doxorubicin conjugated with cell-penetrating peptide), and the flow cytometry detection result of the drug phagocytosis of cells is shown in fig. 10.
Experimental example 2: research for drug-loaded nano-composite to reverse drug resistance
In this experimental example, the nano silver particles added to the nano system (Ag-TF @, prepared in example 1) were analyzedPDOX), the ability of the nanocomposite to induce endoplasmic reticulum stress in tumor cells. The experimental scheme is as follows: mixing PBS, TF @PDOX and Ag-TF @PDOX (DOX content 50. mu.g/ml) was added to the cells at a cell density of 1X 106The culture flask of (3) was incubated for 6h, and then the expression of the relevant protein was detected using a western bolt. Through western bolt detection, compared with the nano-composite without the added nano-silver particles and a control group, after the nano-silver particles are added, the protein expression related to endoplasmic reticulum stress in cells is obviously improved, and particularly, the expression quantity of the proteins related to endoplasmic reticulum stress is greatly up-regulated, wherein GRP78, ATF4 and Caspase-12 are equal to that of the proteins related to endoplasmic reticulum stress (figure 11). Biotransmission electron microscopy also showed that the protein was complexed via the nanocomposite (Ag-TF @)PDOX) the endoplasmic reticulum in the cells was significantly swollen after co-incubation (fig. 12, lower panel is an enlarged view of the upper panel, arrows indicate locations where significant swelling of the endoplasmic reticulum occurred), indicating that the nanocomplex initiates signaling pathway transmission of intracellular endoplasmic reticulum stress. We used different reagents to examine their effect on intracellular P-gp expression. The flow cytometry and the western bolt detection prove that the nano-composite containing the nano-silver particles can reach the maximum rangeThe level of P-gp was down-regulated, which would be beneficial to restore the sensitivity of the cells to chemotherapeutic drugs (FIG. 13, left flow cytometry test, right WB test). In FIG. 13, quantitative measurements were made using streaming softwarePThe flow fluorescence values of the DOX groups are slightly higher than those of the control group and the DOX group, and are consistent with WB results. Under the action of the iron tannate,pthe up-regulation effect of DOX on P-gp is greatly inhibited, and if nano silver particles are further added into the nanoparticles, the inhibition effect on the expression of P-gp is further enhanced. Wherein, P-gp (P glycoprotein) is a transmembrane glycoprotein with the molecular weight of 170KD and has the function of an energy-dependent drug pump. P-gp can be combined with the medicine and ATP, and ATP supplies energy to pump the medicine in the cell out of the cell, so that the medicine concentration in the cell is reduced, and the cell generates the medicine resistance.
Experimental example 3: study of imaging Effect
Because the nano-composite contains a metal polyphenol network (tannin-iron), the nano-particles have the characteristics of near infrared region absorption and paramagnetism, and therefore the nano-composite has the potential of becoming a contrast agent for photoacoustic imaging and magnetic resonance imaging. In vitro experiments demonstrated that the photoacoustic signal (figure 14) has a good linear relationship with the magnetic resonance (figure 16) relaxation rate 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 nano-composite on MCF-7/ADR cells is detected in vitro and in vivo, and the cell density of the MCF-7/ADR cells is 5 multiplied by 103Adding the drugs to be detected into each cell/hole, wherein the drugs to be detected are respectively as follows: empty control, Doxorubicin not conjugated to cell-penetrating peptide (DOX), Doxorubicin conjugated to cell-penetrating peptide: (pDOX), nanoparticle TF @PDOX, Nano-particle Ag-TF @PAnd (4) DOX, co-culturing for 6h, 12h and 24h, and then carrying out CCK-8 cell activity detection. Except for the blank control, doxorubicin concentration of 50. mu.g/ml was maintained in all experimental groups. CCK8 (FIG. 18), apoptotic cell (FIG. 19) and double staining of cells (FIG. 20) with green fluorescence indicating viable cells and redFluorescence indicates dead cells) we found that the nanocomplexes containing cell-penetrating peptide-conjugated doxorubicin and nanosilver particles had the strongest cytotoxicity. This means that the nanocomplex, which has the ability to penetrate cell membranes, target nuclei and induce endoplasmic reticulum stress, can most effectively restore the sensitivity of resistant cells to chemotherapeutic drugs, and can reverse the drug resistance of cells.
In addition, MCF-7/ADR is subjected to cytotoxicity experiments of nano-silver in different forms, and the experimental groups comprise the single use of nano-silver, the nano-silver combined nano-silver inhibitor (TUDCA), Ag-TF @PDOX、Ag-TF@PDOX in combination with TUDCA. The drug treatment time was 24 hours each, and the concentration of silver particles was controlled to 0, 0.25, 0.5 and 1.0. mu.g/ml, respectively. Referring to fig. 21, it can be seen that TUDCA can almost completely release the inhibitory effect of nano-silver on cells at a nano-silver concentration of 1.0 μ g/ml, increasing from 66.7% to 91.7%, with a variation of 25.0%. However, loading of nanosilver onto the nanocomposite forms Ag-TF @PAfter DOX, the cytostatic rate increased from 21.0% to 50.3% with TUDCA compared to TUDCA not used, with a 29.3% variation. TUDCA is a high-efficiency and specific nano-silver inhibitor, and the variation shows that nano-silver has independent toxic effect on cells to be detected. The cytotoxicity of the nano-silver is further enhanced when the nano-silver is loaded on the nano-composite, which shows that the nano-composite has a synergistic effect on the toxic effect of the nano-silver in the scheme.
Experimental example 5: in vivo cytotoxicity Studies
An MCF-7/ADR tumor-bearing mouse model is established, and the inhibition capability of various drug-loaded nano-composite tumors is researched. The details of the administration and experimental groups were: the control group, the DOX group,PDOX group, TF @PDOX group and Ag-TF @PIn the DOX group, the concentration of each administration is uniformly converted into the administration concentration of the adriamycin, and the specific concentration is 1.5mg/kg of DOX injected into each mouse body weight. The details of the photographs of tumor-bearing mice under different drug treatments are shown 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 nano-composite of the scheme is used for carrying tumorTumor growth inhibition was most pronounced in mice.
The foregoing is merely an example of the present invention and common general knowledge in the art of designing and/or characterizing particular aspects and/or features is not described in any greater detail herein. It should be noted that, for those skilled in the art, without departing from the technical solution of the present invention, several variations and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
SEQUENCE LISTING
<110> Chongqing medical university affiliated second hospital
<120> nano-silver modified tannin-iron network drug-loaded nano-composite, preparation method thereof and tumor reversal 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 (10)
1. A drug-loaded nano-composite of a nano-silver modified tannin-iron network is characterized in that: the cell-penetrating peptide-containing adriamycin nanoparticle comprises an inner core formed by adriamycin connected with cell-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.
2. The drug-loaded nano-composite of the nano-silver modified tannin-iron network of claim 1, which is characterized in that: the raw materials comprise adriamycin connected with cell-penetrating peptide, tannic acid and ferric chloride hydrate; the ratio of the sum of the mass of the tannic acid and the ferric chloride hydrate to the mass of the adriamycin in the adriamycin connected with the cell-penetrating peptide is 5: 1.
3. the drug-loaded nano-composite of the nano-silver modified tannin-iron network of claim 2, which is characterized in that: the structural formula of the adriamycin 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 in SEQ ID NO. 1.
4. The drug-loaded nano-composite of the nano-silver modified tannin-iron network of claim 3, which is characterized in that: the particle size of the nano silver particles is 10 nm.
5. The drug-loaded nano-composite of the nano-silver modified tannin-iron network of claim 4, which is characterized in that: the grain diameter is 185.9nm, and the potential is-33.6 mv.
6. The preparation method of the nano-silver modified tannin-iron network drug-loaded nano-composite according to claim 5, which is characterized by comprising the following steps: comprises the following steps in sequence:
s1: dissolving adriamycin connected with cell-penetrating peptide in dimethyl sulfoxide to obtain a DOX/DMSO solution, then adding water into the DOX/DMSO solution and performing acoustic shock treatment to obtain an inner core suspension;
s2: sequentially adding a tannic acid solution and an iron chloride solution into the core suspension, and adjusting the pH value to 6.4-7.4 after acoustic shock and vortex to obtain a TA-containing nanoparticle suspension;
s3: dispersing the nano silver solution into the nano particle suspension containing TA to obtain Ag-TF @PDOX。
7. The preparation method of the nano-silver modified tannin-iron network drug-loaded nano-composite according to claim 6, which is characterized by comprising the following steps: in S1, the amount ratio of doxorubicin to cell-penetrating peptide-linked, dimethylsulfoxide, and water was 4.4 mg: 200 μ L: 8 mL; the duration of the acoustic shock treatment was 15s and the power was 60W.
8. The preparation method of the nano-silver modified tannin-iron network drug-loaded nano-composite according to claim 6, which is characterized by comprising the following steps: in S2, the volume ratio of the tannic acid solution to the ferric chloride solution is 1: 1, the concentrations of solutes in the tannic acid solution and the ferric chloride solution are respectively 40mg/mL and 10 mg/mL; 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 TA-containing nanoparticle suspension is 40 μ L: 1 mL.
9. The use of the nanosilver-modified tannin-iron network drug-loaded nanocomposite as claimed in any one of claims 1 to 5 in the preparation of a drug for reversing tumor drug resistance.
10. Use of a nanosilver-modified tannin-iron network drug-loaded nanocomposite according to any one of claims 1-5 in the preparation of a contrast agent.
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