CN112870370A - Targeting drug-loading system based on black phosphorus nanosheet and preparation method thereof - Google Patents
Targeting drug-loading system based on black phosphorus nanosheet and preparation method thereof Download PDFInfo
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Abstract
The invention provides a preparation method of a targeted drug-loading system based on black phosphorus nanosheets. According to the invention, the black phosphorus nanosheet is adopted, and due to the excellent optical property of the black phosphorus nanosheet, the nano carrier has a photoacoustic imaging function; secondly, PAMAM is used for modification to improve the biocompatibility of the black phosphorus nanosheet; the Angiopep-2 polypeptide promotes the enrichment of the nano material in tumor cells. The nanometer material improves the treatment effect of the lung cancer brain metastasis, and provides a new idea for the high-efficiency diagnosis and treatment integration of the lung cancer brain metastasis.
Description
Technical Field
The invention belongs to the field of biomedical engineering materials, and particularly relates to a targeted drug loading system based on black phosphorus nanosheets and a preparation method thereof.
Background
At present, the incidence rate of lung cancer is the first of the Chinese malignant tumors, and brain metastasis of the lung cancer is the most leading cause of death of tumor patients. At present, most of the lung cancer brain metastasis treatment methods are traditional operations, radiotherapy, chemotherapy and the like. Surgery and radiotherapy belong to local treatment, are effective only on tumors at the treatment site, and are difficult to exert on migrating tumors. Most chemotherapy drugs have no targeting property, and kill normal tissue cells while killing cancer cells, so that certain normal tissues and organs of an organism can generate obvious toxic reaction. In addition, long-term drug therapy also results in drug resistance and drug molecules are difficult to enter brain tissue due to the presence of the blood-brain barrier.
In recent years, with the research and the deepening of the subjects of tumor immunology, molecular biology and the like, the tumor immunotherapy method which can specifically identify and has small side effect becomes one of the research fields with the fastest development speed and the most prospect in the tumor therapy. Compared with the traditional treatment and the targeted treatment, the immunotherapy has the advantages of wide anticancer range, small toxic and side effect, lasting curative effect and the like. In the last 20 years, immunotherapy of tumors has progressed at a rapid pace. The treatment of Immune Checkpoint Blockade (ICB) refers to blocking the transmission of an organism immune suppression signal by adopting an immune checkpoint inhibitor, preventing the immune escape behavior of tumor cells, and recovering the signal path of activated T lymphocytes to enable a host to play an anti-tumor effect. Programmed cell death protein 1 (PD-1) and Cytotoxic T lymphocyte associated antigen 4(Cytotoxic T-lymphocyte-associated protein 4, CTLA-4) were discovered in 2018 in a physiological or medical reward, indicating that ICB therapy has gained worldwide acceptance in cancer immunotherapy. However, according to clinical data, it is reported that the effective rate of the PD-1 inhibitor is about 10% to 30% when the inhibitor is used alone, and many patients do not work at all or the therapeutic effect lasts for a short time even on the PD-1 inhibitor. To further improve the effectiveness of ICB treatment most researchers tend to choose a combination therapy strategy.
Researchers have found that some drugs have therapeutic effects on lung cancer, such as: paclitaxel, gemcitabine, pemetrexed, etc., wherein pemetrexed in combination with other therapeutic modalities is a recommended regimen. Pemetrexed (PMT) is one of novel cytotoxic drugs with better antitumor activity, is a third-generation multi-target folic acid antagonist, and inhibits three key enzymes, namely thymidylate synthase, dihydrofolate reductase and glycofuroate methyltransferase, related to folic acid metabolism. Pemetrexed has good tolerance, and the main toxic and side effects of the Pemetrexed, such as bone marrow suppression and mucositis, can reduce the occurrence of the Pemetrexed by supplementing vitamins and folic acid. Therefore, the pemetrexed has wide application prospect in treating tumors.
However, most of the chemotherapeutic drugs are hydrophobic and have poor water solubility, and the administration systems of small molecule inhibitors, especially polypeptide molecule inhibitors, have poor stability, are easy to be rapidly cleared in blood after administration, have short half-lives and low bioavailability, so that the application of the chemotherapeutic drugs and the polypeptide inhibitors is limited. In recent years, nanomaterials have attracted much attention in cancer treatment research because of their small size, large specific surface area, easy modification, and unique physical and chemical properties such as optical, electrical, and magnetic properties. The multifunctional nano platform is constructed by taking nano materials as carriers and loading genes, medicines, photo-thermal/photodynamic and other biomolecules with treatment functions on the nano materials. Black Phosphorus Nanosheets (BPNSs) are a novel two-dimensional material following graphene and molybdenum disulfide. The two-dimensional black phosphorus nanosheet is of a waveform layered structure and has a large specific surface area, and the characteristic can be used for efficiently resisting a loaded tumor drug, so that the two-dimensional black phosphorus nanosheet can be used as a novel drug delivery platform and has a potential application prospect in efficient cancer treatment research.
Disclosure of Invention
In order to achieve the aim, the invention provides a targeted drug loading system based on black phosphorus nanosheets and a preparation method thereof, and the system can target tumors and release drugs slowly.
The invention adopts the following technical scheme to realize the purpose of the invention;
in a first aspect, the invention provides a preparation method of a targeted drug-loading system based on black phosphorus nanosheets, which comprises the following steps:
s1 preparation of black phosphorus nanosheets: obtaining BPNSs solution A by a liquid phase stripping method;
s2 PAMAM-modified bps: dispersing the PAMAM in the BPNSs solution A prepared in the step S1, performing ultrasonic centrifugation, collecting precipitates, and resuspending the obtained BPNSs-PAMAM in PBS to obtain a BPNSs-PAMAM solution B;
s3 supporting pemetrexed with PD-1: adding the PAMAM-PMT solution C and the PAMAM-PD-1 solution D into the solution A of S1, stirring for reaction overnight, centrifuging, and removing redundant PMT and PD-1 to obtain a BPNSs-PAMAM-PD-1/PMT system;
s4 synthesizing a targeting nano drug-loading system: dropwise adding the solution F into the solution G, reacting at room temperature to obtain a solution H, and dialyzing the solution H in water to remove impurities to obtain a solution I; adding the solution I into the BPNSs-PAMAM-PD-1/PMT system obtained in the step S3, and mixing and reacting to obtain the targeted BPNSs-PAMAM-PD-1-Ang2/PMT nano drug-loaded system;
wherein the solution F contains EDC, NHS and PEG-DNH2A DMSO solution of (1); the solution G is an aqueous solution of Angiopep-2.
Preferably, the concentration of the black phosphorus in the step S1 is 0.1 mg/mL-5 mg/mL.
Preferably, the concentration of PAMAM in the step S2 is 1 mg/mL.
Preferably, the preparation method of the PAMAM-PMT solution C in the step S3 is: preparing PMT solution, adding EDC and NHS into PMT solution according to the molar ratio of 1:1.5, stirring and reacting for 4 hours at room temperature, finally adding PAMAM solution, and stirring overnight to obtain PAMAM-PMT solution C.
Preferably, the preparation method of the PAMAM-PD-1 solution D in the step S3 is: preparing a PD-1 aqueous solution, adding EDC and NHS into the PD-1 aqueous solution according to the molar ratio of 1:1.5, stirring and reacting at room temperature for 4 hours, finally adding a PAMAM solution, and stirring overnight to obtain a PAMAM-PD-1 solution D.
Preferably, the preparation method of the solution F comprises the following steps: mixing ethylene glycol diamine (PEG-DNH)2) Dissolving in DMSO to obtain solution E; and adding EDC and NHS into the solution E in a molar ratio of 1:1.5, and stirring for reacting for 4 hours to obtain a mixed solution F.
Preferably, the preparation method of the solution G is as follows: angiopep-2 was dissolved in water to obtain solution G.
In a second aspect, the invention provides a nano drug-loaded system prepared by the preparation method.
In a third aspect, the invention provides an application of the nano drug-loaded system in preparing a drug for treating tumors.
The invention has the beneficial effects that: firstly, a liquid phase stripping method is adopted to synthesize black phosphorus nanosheets, and due to the excellent optical properties of the black phosphorus nanosheets, the nanocarriers have the photoacoustic imaging function; secondly, PAMAM is used for modification to improve the biocompatibility of the black phosphorus nanosheet; the Angiopep-2 polypeptide promotes the enrichment of the nano material in tumor cells. The nanometer material improves the treatment effect of the lung cancer brain metastasis, and provides a new idea for the high-efficiency diagnosis and treatment integration of the lung cancer brain metastasis.
Drawings
FIG. 1 is a transmission electron micrograph of BPNS (Panel A) and BPNSs-PAMAM (Panel B)
FIG. 2 is the NMR spectrum of PMT and PAMAM-PMT
FIG. 3 is a graph of PMT standard curve (panel A) and PMT drug release curve (panel B)
FIG. 4 is a graph showing the cytotoxicity of BPNSs-PAMAM against A549 at various concentrations
FIG. 5 is a graph showing the PA amplitude of BPNSs-PAMAM at different concentrations
Detailed Description
In order to show technical solutions, purposes and advantages of the present invention more concisely and clearly, the technical solutions of the present invention are described in detail below with reference to specific embodiments. Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Example 1 preparation of a targeted Nanocarrier System of the invention
The method comprises the following steps: preparation of Black phosphorus Nanosheet (BP NSs)
Preparation of BPNSs by liquid phase exfoliation: dispersing 25mg of Black Phosphorus (BP) in 50ml of pure water, introducing argon for a few minutes to eliminate oxygen molecules dissolved in the water and reduce oxidation in the stripping process, and then carrying out ultrasonic treatment on the dispersion liquid for 12 hours under the ice bath condition (the strength: 250W, the on/off cycle: 45s/15 s); centrifuging the resulting brown dispersion at 1000rpm for 10min to remove large chunks of BP and collecting the supernatant containing BPNSs; then, putting the collected supernatant containing BPNSs into a centrifuge tube, centrifuging for 30min at 4000rpm under the condition of 4 ℃, and collecting the precipitate; the pure BPNSs obtained were resuspended in PBS buffer to obtain BPNSs solution A, which was stored at 4 ℃ until use.
Step two: dendrimer Polyamidoamine (PAMAM) modified BPNSs
Dispersing 10mg of PAMAM in 10mL of BPNSs solution A (BP concentration is 200 mu g/mL), carrying out ultrasonic treatment for 30min, stirring for reaction for 4h, placing the obtained mixed solution in a centrifuge tube, centrifuging for 30min at 4000rpm at 4 ℃ to remove excessive PAMAM, collecting precipitates, washing twice, resuspending the obtained BPNSs-PAMAM sample in PBS to obtain BPNSs-PAMAM solution B, and storing at 4 ℃ for later use.
Respectively dispersing the synthesized BPNS and BPNSs-PAMAM in pure water, and characterizing the BPNS and the BPNSs-PAMAM by using a transmission electron microscope, wherein as shown in figure 1, the BP nano-sheet is a dispersed sheet-shaped structure, the transverse dimension is about 200 nanometers, and the appearance of the PAMAM is not changed after modification.
Step three: load Pemetrexed (PMT) or/and PD-1
1. Load pemetrexed Plug (PMT)
Weighing 5mg of PMT to dissolve in 5mL of dimethyl sulfoxide to obtain a PMT solution, weighing 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-N-hydroxysuccinimide (NHS) to add into the PMT solution, wherein the molar ratio of EDC to NHS is 1:1.5, stirring at room temperature for reaction for 4 hours, finally adding 5mL of solution B, and stirring overnight to obtain BPNSs-PAMAM-PMT solution C.
The synthesized PAMAM-PMT was subjected to nuclear magnetic characterization, and as shown in fig. 2, peaks at 7.281ppm and 7.728ppm were assigned to the proton hydrogen on PMT, the proton peak at 6.437ppm was assigned to PMT, and for PAMAM-PMT, the peak at 2.5 to 3.5ppm was assigned to PAMAM, and the PMT peak described above was also present on the hydrogen spectrum thereof. These results indicate that BPNSs-PAMAM-PMT has been successfully synthesized.
2. Load PD-1
Weighing 10mg of PD-1, dissolving in 2mL of water to obtain a PD-1 solution, weighing 20mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 22mg of N-N-hydroxysuccinimide (NHS) into the PD-1 solution, stirring and reacting for 4h at room temperature, finally adding 5mL of solution B, and stirring overnight to obtain BPNSs-PAMAM-PD-1 solution D.
3. BPNSs-PAMAM nano system simultaneously loading PMT and PD-1
And the PMT solution and the PD-1 solution were added dropwise to 10mL of the BPNSs-PAMAM solution B of step two, and the reaction was stirred at room temperature overnight. After the reaction is finished, the mixture is centrifuged at 4000rpm for 30min at 4 ℃ to remove excessive PMT and PD-1, and the mixture is washed twice with water to obtain BPNSs-PAMAM-PD-1/PMT.
Step four: synthesis of targeting nano drug-carrying system
1. Preparation of PEG-Angiopep-2
a. 20mg of polyethylene glycol diamine (PEG-DNH) was taken2) Dissolving in 10mL DMSO to obtain a solution E;
b. adding EDC and NHS into the solution E in a molar ratio of 1:1.5, stirring for reacting for 4h to obtain a mixed solution F,
c. dissolving 12.28mg of Angiopep-2 in 10mL of water to obtain a solution G;
d. solution F was added dropwise to solution G and reacted at room temperature for 12H to give solution H, which was then dialyzed against water for 3 days to remove impurities (MW 500Da) to give PEG-Angiopep-2 solution I.
2. Preparation of targeting nano drug-carrying system
And adding the solution I into a 10mL nano system obtained in the third step, and mixing and reacting for 12h under continuous stirring to obtain the targeted BPNSs-PAMAM-PD-1-Ang2/PMT nano drug-loaded system.
Test example 1 drug Release
In order to test the drug sustained release effect of the targeted BPNSs-PAMAM-PD-1-Ang2/PMT nano drug-loaded system, the following experiment is designed in the experimental example:
BPNSs-PAMAM-PD-1-Ang2/PMT samples were placed in PBS systems at different pH values (pH 7.4 or pH 5.7). First, 1mL of BPNSs-PAMAM-PD-1-Ang2/PMT solution is centrifuged, and then the solution is respectively dispersed into 1mL of PBS systems with different pH values and placed in a constant temperature shaking table at 37 ℃ for incubation. After incubation for various time intervals (0.5, 2, 5, 7, 20, 30, 48 and 72h), the supernatants were centrifuged and collected, and the incubation with shaking was continued by adding fresh PBS of various pH values. The absorbance of the supernatant at 257nm was measured using ultraviolet spectroscopy, and the amount of released pemetrexed was calculated from the standard curve of pemetrexed, and then the cumulative amount released was calculated. FIG. 3A is a standard curve of PMT, from which it can be seen that the concentration of PMT has a good linear relationship with its absorbance, and the linear equation is Y-0.0348X-0.0193, R20.9969. The drug loading rate is 6.8% by calculation. Fig. 3B is the drug release curve of PMT under different pH conditions. The release rate at pH 5.7 increased by a factor of 1.5 compared to pH 7.4 due to the accelerated degradation of the nanomaterial at pH 5.7, breaking the covalent bond between PAMAM and PMT. Due to the existence of an acidic tumor microenvironment, the pH-dependent release of BPNSs-PAMAM-PMT is beneficial to the release of the drug in the tumor. The nano-drug-loaded system of the present invention is demonstrated to have pH responsiveness at pH 5.5.
Test example 2
In order to test the influence of the targeted BPNSs-PAMAM-PD-1-Ang2/PMT nano drug-loaded system on cells, the following experiment is designed in the experimental example:
the cytotoxicity of BPNSs-PAMAM on A549 cells is evaluated by using a method for detecting the cell activity by CCK-8. The specific operation steps are as follows: a549 cells were first seeded at a density of 5000 cells/well in 96-well plates and then placed in a carbon dioxide incubator overnight for adherence. Subsequently, the original medium was aspirated and replaced with fresh complete medium containing different concentrations of BPNSs-PAMAM, selected in the range of 10-500. mu.g/mL, 5 replicates per concentration. The cells were then incubated in an incubator for 24h, after which the cells were washed once with PBS and 100. mu.L of fresh medium (containing 10% CCK-8) was added to each well. Placing the mixture in an incubator for incubation for a period of time, finally detecting and recording the absorbance at the wavelength of 450nm by using a microplate reader, and calculating the cell survival rate by the following formula: cell survival (%) × (experimental absorbance-blank absorbance)/(negative control absorbance-blank absorbance) × 100%. As shown in FIG. 4, the cell survival rates of A549 cells were 102.16% when the concentration of BPNSs-PAMAM nanoparticles was 10. mu.g/mL, respectively, and it can be seen that the low concentration of black phosphorus nanoparticles did not affect cell proliferation. In addition, the survival rate of A549 cells is slightly reduced but still high with the gradual increase of the concentration of the black phosphorus nanoparticles, and the cytotoxicity is shown when the concentration is as high as 320 mu g/mL. The black phosphorus nano-sheet has good biocompatibility and is a safe nano-drug carrier.
Test example 3
In order to detect the in vitro photoacoustic imaging performance of the BPNSs-PAMAM photoacoustic imaging device, the following experiments are designed in the experimental example:
firstly, diluting BPNSs-PAMAM into a series of solutions with different concentrations, wherein the concentrations of black scale nano-sheets are respectively 20, 40, 80, 160 and 320 mu g/mL, then respectively taking 20 mu L of each concentration to be arranged in an imaging tube, collecting in-vitro images by using a PA imaging instrument (Vevo LAZR2100, VisualSonics), recording PA images and measuring the PA signal intensity by using built-in software. As a result, as shown in FIG. 5, the PA image signal was gradually increased with the increase of the BP concentration, and was strongest at a BP concentration of 320. mu.g/mL. The BP concentration and the PA imaging capacity are in a direct proportion relationship by drawing a BP concentration-PA signal intensity curve. The PA amplitudes value reached 2.78 when the Au concentration was 0.32 mg/mL. The result shows that the BPNSs-PAMAM has potential PA imaging application prospect.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A preparation method of a targeted drug loading system based on black phosphorus nanosheets is characterized by comprising the following steps:
s1 preparation of black phosphorus nanosheets: obtaining BPNSs solution A by a liquid phase stripping method;
s2 PAMAM-modified bps: dispersing the PAMAM in the BPNSs solution A prepared in the step S1, performing ultrasonic centrifugation, collecting precipitates, and resuspending the obtained BPNSs-PAMAM in PBS to obtain a BPNSs-PAMAM solution B;
s3 supporting pemetrexed with PD-1: adding the PAMAM-PMT solution C and the PAMAM-PD-1 solution D into the solution A of S1, stirring for reaction overnight, centrifuging, and removing redundant PMT and PD-1 to obtain a BPNSs-PAMAM-PD-1/PMT system;
s4 synthesizing a targeting nano drug-loading system: dropwise adding the solution F into the solution G, reacting at room temperature to obtain a solution H, and dialyzing the solution H in water to remove impurities to obtain a solution I; adding the solution I into the BPNSs-PAMAM-PD-1/PMT system obtained in the step S3, and mixing and reacting to obtain the targeted BPNSs-PAMAM-PD-1-Ang2/PMT nano drug-loaded system;
wherein the solution F contains EDC, NHS and PEG-DNH2A DMSO solution of (1); the solution G is an aqueous solution of Angiopep-2.
2. The method of claim 1, wherein the concentration of black phosphorus in step S1 is 0.1mg/mL to 5 mg/mL.
3. The method of claim 1, wherein the concentration of PAMAM in step S2 is 1 mg/mL.
4. The method of claim 1, wherein the PAMAM-PMT solution C in the step S3 is prepared by: preparing PMT solution, adding EDC and NHS into PMT solution according to the molar ratio of 1:1.5, stirring and reacting for 4 hours at room temperature, finally adding PAMAM solution, and stirring overnight to obtain PAMAM-PMT solution C.
5. The method of claim 1, wherein the PAMAM-PD-1 solution D in step S3 is prepared by: preparing a PD-1 aqueous solution, adding EDC and NHS into the PD-1 aqueous solution according to the molar ratio of 1:1.5, stirring and reacting at room temperature for 4 hours, finally adding a PAMAM solution, and stirring overnight to obtain a PAMAM-PD-1 solution D.
6. The method of claim 1, wherein the solution F is prepared by: mixing ethylene glycol diamine (PEG-DNH)2) Dissolving in DMSO to obtain solution E; and adding EDC and NHS into the solution E in a molar ratio of 1:1.5, and stirring for reacting for 4 hours to obtain a mixed solution F.
7. The method of claim 1, wherein the solution G is prepared by: angiopep-2 was dissolved in water to obtain solution G.
8. The nano drug-carrying system prepared by the preparation method of the black phosphorus nanosheet-based targeted drug-carrying system as defined in any one of claims 1 to 7.
9. The black phosphorus nanoplate-based targeted drug delivery system of claim 8, comprising a nano delivery carrier material that is BPNSs-PAMAM-PD-1.
10. Use of a black phosphorus nanoplate-based targeted drug delivery system of claim 8 in the preparation of a drug for the treatment of a tumor.
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