CN115192708A - Nano composite material loaded with anti-tumor drug, nano drug-loaded system, preparation and application - Google Patents
Nano composite material loaded with anti-tumor drug, nano drug-loaded system, preparation and application Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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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
- A61K33/243—Platinum; Compounds thereof
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- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
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- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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Abstract
The invention discloses a nanocomposite for loading an anti-tumor drug, a nano drug-loading system with cancer cell membrane fused with TPE-s COF, and preparation and application thereof. The invention adopts an anti-tumor drug loaded nano composite material which is composed of a sulfhydryl-containing lipophilic covalent organic framework TPE-s COF, a photothermal agent (gold nanoparticle) which is combined with sulfhydryl on the surface of the TPE-s COF by a covalent bond, and an anti-tumor drug (cisplatin) loaded in the TPE-s COF. According to the invention, gold nanoparticles are combined with exposed sulfydryl in a TPE-s COF structure through a covalent bond, cisplatin is loaded inside the TPE-s COF, then HepG2 cells and the nano carrier are co-cultured until fusion is realized, and M @ TPE-s COF-Au @ Cisplatin is formed through low-temperature shock. The invention realizes homologous targeting and specificity. The problem that TPE-s COF materials lack targeting and non-specificity and the problem that a drug delivery system is low in efficiency is effectively solved. The novel combined treatment drug delivery system can be used for specific targeting and efficient chemotherapy/photothermal combined treatment of liver cancer.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an anti-tumor medicine loaded nano composite material, a cancer cell membrane fused TPE-s COF nano medicine carrying system, and preparation and application thereof
Background
Liver Cancer (LC) is the most heterogeneous malignant tumor, with the prevalence being the first global and the mortality being third worldwide. In China, the number of people dying from liver cancer accounts for 45 percent of the world every year, and serious threats are caused to the health and life of residents. The research results of prevention, diagnosis and treatment and relapse prevention of liver cancer are receiving increasing attention. Because early symptoms of liver cancer are not obvious, the early diagnosis rate is less than 15%. This means that most of the patients with liver cancer have metastasized cancer cells when they are found, which is not amenable to surgical treatment. The drug therapy is mainly non-targeted chemotherapy drugs and has respective defects, so that the development of a novel liver cancer drug is urgently needed, and the aim of promoting and achieving the aim of improving the 5-year survival rate of liver cancer patients by 15 percent is fulfilled.
In recent years, based on the concept of 'nature simulation', the bionic nano-carrier has been widely applied due to the advantages of reproducing the characteristics of natural materials. Among them, the bionic nano-carrier derived from cells is a research hotspot because of its natural characteristics of low immunogenicity, long circulation time, strong targeting property, etc. The cell membrane coating carrier is a nano carrier prepared by coating a layer of natural cell membrane with organic/inorganic synthetic Nanoparticles (NPs), can play a role in synthesizing the NPs, and has the natural complex characteristic of source cells. For example, erythrocytes can escape immune monitoring due to the expression of CD47 on cell membranes, but have no targeting ability, while cancer cells have the tendency and homing ability of diseased parts, and different application purposes are realized according to different functions. The main components of cell membranes are phospholipids, glycoproteins, glycolipids and proteins, which allow some lipophilic carriers to be fused specifically with cell membranes, with biocompatibility and biological interfacial properties and specific targeting effects. The phospholipid bilayer lipophilic structure of the cell membrane plays an important role in determining the cell shape and in conferring mechanical robustness to the cell against external mechanical stresses. Therefore, the cell membrane specific fused lipophilic vector has great application prospect in cancer treatment.
In addition, great progress has been made in the construction of multifunctional nanomaterials that enable the integration of multiple therapeutic modalities into a single nanoplatform. The aggregation luminescent covalent organic framework (TPE-s COF) is used as a multifunctional nano carrier, has the excellent characteristics of high stability, low density, large specific surface area, multi-dimension, porosity and high ordered structure, can be used as a drug loading system to keep loaded drugs delivered in a stable form in vivo, and can be aggregated in tumors to specifically control and release the drugs. The TPE-s COF can be used as a multifunctional carrier, and simultaneously carries an anti-tumor drug, a photosensitizer and a photothermal agent, so that the synergistic effect of chemotherapy and other therapies is realized. Moreover, the TPE-s COF has a pi-conjugated structure through structural design, so that the photo-thermal absorption and the photo-stability are obviously improved, and the TPE-s COF has high-efficiency ROS generation and photo-thermal conversion capacity under near-infrared external light irradiation.
Combination therapy generally significantly improves the therapeutic effect compared to monotherapy. The combination of chemotherapy and photothermal therapy arouses great interest of researchers, the advanced cooperative treatment method not only can keep the advantages of non-invasiveness, low toxicity and convenient administration of photothermal therapy, but also solves the problems of non-selectivity, multi-drug resistance and the like of the traditional chemotherapy, and obtains good treatment effect. In order to deliver chemical/photothermal drugs to the tumor area simultaneously for synergistic effect, a highly efficient and safe drug delivery platform is urgently needed. The TPE-s COF nanocomposite in the previous research achieves a remarkable effect in the combined chemo/photothermal therapy treatment, but the TPE-s COF nanocomposite delivery platform needs to be further improved in the aspects of targeting, specific recognition, long-term blood circulation and immune escape functions.
Disclosure of Invention
The invention aims to provide a combined therapy combining chemotherapy and photothermal therapy for treating malignant tumors, particularly liver cancer, wherein the combined therapy is applied by adopting a nanocomposite material loaded with anti-tumor drugs, and the nanocomposite material consists of lipophilic covalent organic frameworks (TPE-s COFs) containing sulfydryl, photothermal agents (Au NPs) combined with sulfydryl groups on the surfaces of the TPE-s COFs by covalent bonds and the anti-tumor drugs loaded in the TPE-s COFs; the photothermal agent adopts gold nanoparticle Au NPs, and the anti-tumor drug adopts Cisplatin Cisplatin.
The nano composite material comprises the synthesis of a TPE-s COF material, the synthesis of TPE-s COF-Au, and the synthesis of TPE-s COF-Au @ Cisplatin. The TPE-s COF material is synthesized by subjecting tetra-aldehyde tetraphenylethylene and 3,3 '-dimercapto-4,4' -biphenyldiamine to Schiff base reaction under the catalysis of 1,4-dioxane, mesitylene and acetic acid, and standing at 100-140 ℃ for 2-5 days; the synthesis of the TPE-s COF-Au is to mix the TPE-s COF material with HAuCl 4 Mixing and reacting to obtain; the synthesis of the TPE-s COF-Au @ Cisplatin is obtained by mixing and reacting TPE-s COF-Au with chemotherapeutic drug Cisplatin Cisplatin. Further, in the synthesis of the TPE-s COF material, the molar ratio of tetra-aldehyde tetraphenyl ethylene to 3,3 '-dimercapto-4,4' -biphenyldiamine is 1.4-2.2, preferably 1:2, the volume usage ratio of 1,4 dioxane to mesitylene is 5-20, preferably 1:1; the TPE-s COF in the synthesis of TPE-s COF-Au is prepared into TPE-s COF water dispersion with the concentration of 2-8mg/ml water, preferably 4-6mg/ml water and HAuCl 4 TPE-s COF aqueous dispersion and HAuCl at a concentration of 8-12mM 4 A volume ratio of 10-40, preferably 20; preferably, the TPE-s COF material is synthesized by mixing TPE-s COF water with HAuCl 4 Mixing and stirring, then adjusting the pH =10-13 with 0.4-0.8M NaOH solution, then slowly adding a small amount of NaBH dropwise 4 Reducing to light blackAnd dialyzing and purifying the product to obtain the product. The mass ratio of TPE-s COF-Au to Cisplatin in the synthesis of TPE-s COF-Au @ Cisplatin is 4-6:1-3, preferably 5:3. Preferably, the synthesis of the TPE-s COF-Au @ Cisplatin is to disperse the TPE-s COF-Au with 1,4-dioxane, add the chemotherapeutic drug Cisplatin Cisplatin, dropwise add 7ml of water, stir for reaction for 2h, dialyze and freeze-dry to obtain the product.
The chemotherapy and photothermal therapy combined therapy adopts a cancer cell membrane fused TPE-s COF nano drug-carrying system, which is obtained by co-culturing and fusing a cancer cell HepG2 cell and the nano composite material and then performing low-temperature shock; the low-temperature shock is to place the co-cultured and fused cells in a cell freezing medium and freeze the cells in liquid nitrogen for more than 8 hours; the cancer cells are endocytosed and fused with the nano composite material to form a nano drug-loading system with autologous cancer cell membranes fused with TPE-s COF, namely M @ TPE-s COF-Au @ Cisplatin. The cancer cells are HepG2 cells, and can be autologous cancer cells or purchased from professional microbial product companies.
According to the invention, the cell membrane fusion fluorescent TPE-s COF nano composite material is used as a drug carrier, so that a specific targeted chemotherapy/photothermal combined treatment effect is achieved. The M @ TPE-s COF Au @ Cisplatin cell fusion nano-carrier in the system eliminates the pathogenicity of tumor cells through simple liquid nitrogen treatment, but retains the homing capability of the cells to the tumor part and good biocompatibility. In addition, the targeting of the M@TPE-s COF Au @ Cisplatin can reduce the consumption of the Cisplatin in the in-vivo circulation process, thereby reducing side effects. The M @ TPE-s COF-Au @ Cisplatin realizes excellent in-vivo anti-tumor treatment effect through combined drug treatment of photo-thermal/chemotherapy. Compared with a common photo-thermal agent, the M @ TPE-s COF-Au @ Cisplatin nano composite material has a plurality of unique advantages: high homologous targeting and specificity, water solution stability, high photothermal conversion efficiency and higher aggregation of Au NPs at the tumor part. Meanwhile, the system has the characteristics of fluorescence imaging, living body pharmacokinetics monitoring and the like, forms a novel autologous cell membrane specificity fusion lipophilic fluorescence TPE-s COF delivery system with efficient combination therapy, and can promote the development of a multi-therapy diagnosis nano platform. The invention can adopt the covalent organic framework TPE-s COF nano composite material which has the advantages of lipophilicity and double-function aggregation-induced emission (AIE) structure and is fused with autologous cell membrane specificity, the system has good dispersibility in water, good photo-thermal property and fluorescent tracing characteristic, and can be used for enhancing targeting and specificity recognition to realize efficient combined treatment effect.
The photothermal agent gold nanoparticles (Au NPs) are combined with the exposed sulfydryl in a TPE-S COF structure through covalent bonds, and the antitumor drug Cisplatin (Cisplatin) is loaded inside the lipophilic fluorescent TPE-S COF to form a TPE-S COF-Au @ Cisplatin carrier. Then co-culturing the HepG2 cell and the nano-carrier until fusion is realized, and forming the M @ TPE-s COF-Au @ Cisplatin carrier by a low-temperature shock method. At the moment, hepG2 cells lose the proliferation capacity and pathogenicity, but still maintain the homing capacity, and realize homologous targeting and specificity. The problems that TPE-s COF materials lack targeting property and non-specificity and a drug delivery system is low in efficiency are effectively solved. After intravenous administration, the TPE-s COF nanocomposite is fused with the cell specificity to specifically target a tumor part, after the tumor part is irradiated by laser, the temperature is increased, the M @ TPE-s COF-Au @ Cisplatin nanocomposite is broken, and the TPE-s COF-Au @ Cisplatin carrier is released at the tumor part, so that the photothermal-chemical combination therapy is realized. We successfully develop a novel combined treatment drug delivery system based on bionic autologous cell membrane specific fusion lipophilic fluorescent TPE-s COF, and the system is used for liver cancer specific targeting and efficient chemotherapy/photothermal combined treatment.
Drawings
FIG. 1 is a schematic diagram of the synthesis process of the porous composite material (TPE-s COF, TPE-s COF-Au @ Cisplatin) in example 1.
FIG. 2 is a representation of the composite obtained in example 1. Wherein a) a TEM image of TPE-s COF-Au transmission electron microscope, b) a fluorescence spectrogram of TPE-s COF, TPE-s COF-Au @ cissplatin, c) a pore size distribution diagram of TPE-s COF and TPE-s COF-Au, and d) an AA-stacking structure diagram of TPE-s COF.
FIG. 3 is a Scanning Electron Microscope (SEM) image of live cells and shock cells evaluated for proliferation characteristics of shock cells, surface potentials of live cells and shock cells by the tetramethylazozolium salt (MTT) method, and flow cytometry analysis (FSC, forward scatter; SSC, side scatter) of the live cells and shock cells at the same voltage in example 2.
FIG. 4 is a laser confocal observation of the fusion of a cell membrane and a TPE-s COF composite (a) and a TEM image of a cut HepG2 cell fused with a TPE-s COF (b) shown in example 3.
FIG. 5 is a fluorescence image of the porous composite material described in example 4 (product of example 2) injected into a mouse for 2-96 hours in vivo, reflecting the metabolism of the composite material in the mouse (upper panel). And tissue fluorescence images of tumor-bearing mice after euthanasia three days after tail vein administration (lower panel).
FIG. 6 shows the apoptosis of HepG2 cells of different composite nano-materials, drugs or laser groups after the Annexin V-FITC cell apoptosis test is administrated.
FIG. 7 shows the temperature change of the laser irradiated tumor site half an hour after the nanocomposite material is irradiated.
FIG. 8 is a graph of tumor volume change, tumor beat and tumor weight in different groups 27 days after treatment.
Detailed Description
The following examples are further illustrative of the present invention as to the technical content of the present invention, but the essence of the present invention is not limited to the following examples, and one of ordinary skill in the art can and should understand that any simple changes or substitutions based on the essence of the present invention should fall within the protection scope of the present invention.
Instruments and reagents
All wet samples of TPE-s COF were dried in a DX 120-50-01 supercritical CO2 extractor using supercritical CO 2. Fourier transform infrared spectroscopy (FT-IR) spectra were collected using a Bruker Tenson-27 FT-IR spectrometer. Solid state using a Bruker AVIII NMR spectrometer (400 MHz) 13 C nuclear magnetic resonance measurement. Scanning Electron Microscope (SEM) (Gemini SEM 300 (Carl Zeiss, germany.) Transmission Electron Microscope (TEM) and SAED images were obtained on a Talos L120C G2 Electron microscope (Thermo Fisher, america) at an accelerating voltage of 120kV at LSM-80Laser scanning confocal images were recorded on a 0 (Zeiss inc., germany) microscope. The UV-visible spectrum was obtained on a UV-1800 (PC) UV-visible spectrophotometer (Mapada, china). Powder X-ray diffraction (PXRD) and in-situ temperature change PXRD (VTPXRD) patterns are prepared by equipping Cu Ka source
D8 Advance record of (1). The nitrogen adsorption isotherm at 77K was measured using a JW-BK200B positive displacement gas adsorber equipped with a liquid nitrogen container. All samples were degassed under vacuum at 120 ℃ for 4-6 hours. Fluorescence spectra were recorded using a FluoroMax-4 fluorescence spectrophotometer (HORIBA Scientific, japan) with excitation and emission slit widths of 5nm. BD FACScelesta (BD celesta) was used for flow cytometry analysis. The molecular structure of TPE-s COF was constructed using Materials Studio (MS) software package and geometry optimized by Dmol3 module equipped in MS (function: local Density Approximation (LDA) within Perew-Wang Parameterization (PWC); convergence tolerance: energy: 2.0e-5Ha; maximum force:
maximum displacement:
maximum number of iterations: 200 of a carrier; maximum step size:
)
example 1
The preparation method of TPE-s COF-Au @ Cisplatin comprises the following steps:
(1) Monomer tetra aldehyde tetraphenylethylene and 3,3 '-dimercapto-4,4' -biphenyldiamine (molar ratio 1:2) were added to the Pyrex tube. 1,4-dioxane, mesitylene and 6M aqueous acetic acid (10. Freezing with liquid nitrogen, then evacuating, thawing again, repeating the above operations three times, and removing oxygen from the system. The Pyrex tube was then sealed with an alcohol torch and placed in a constant temperature oven. Stored at 120 ℃ for 3 days. After thorough washing with tetrahydrofuran, methanol and acetone by soxhlet extraction, TPE-s COF was separated into yellow powder with a yield of 45% which was insoluble in common organic solvents and water.
(2) 5mg of the product of step 1 are dispersed in 1ml of water with 0.05ml of 10mM HAuCl 4 Mix in a 5ml round bottom flask. Under magnetic stirring, 0.5M NaOH solution was added and the pH was adjusted to 12 with slow stirring. Then slowly dropwise adding a small amount of NaBH 4 The color of the solution was reduced from an initial yellow to a reddish brown and finally to a light black, and the product was purified by (3000 Da) dialysis bag. Then slowly dropwise adding a small amount of NaBH 4 The color of the solution was reduced from an initial yellow to a reddish brown and finally to a light black, and the product was purified by (3000 Da) dialysis bag.
(3) The product of step 2 was purified and dried, dispersed with 2ml of 1, 4-dioxane, and placed in a round bottom flask with magnetons. Then adding the chemotherapeutic drug Cisplatin (the mass ratio of TPE-s COF-Au to Cisplatin is 5:3) in proportion, stirring for 2 hours, and dropwise adding 7ml of ultrapure water by using a peristaltic pump. After completion of the dropwise addition, the mixture was stirred for 2 hours and dialyzed. And freeze-drying to obtain the TPE-s COF-Au @ Cisplatin material.
Physical property characterization of TPE-s COF-Au @ Cisplatin:
sampling and performing characterization detection on the product in the step 2. As shown in fig. 2, transmission Electron Microscope (TEM) images showed regular uniform lamellar morphology with gold nanoparticles uniformly dispersed on TPE-s COF sheets. The average hydrodynamic diameter of the TPE-s COF-Au nanoparticles is about 100nm. From the fluorescence spectrogram, it can be analyzed that after TPE-s COF-Au is combined, the fluorescence is obviously enhanced, i.e. the peak intensity of TPE-s COF-Au is higher than that of the original TPE-s COF, while the peak intensity of TPE-s COF-Au @ Cisplatin is lower than that of the original TPE-s COF, which is probably the result caused by the interaction between TPE-s COF and Au, cisplatin. The pore diameter distribution curve shows that the pore diameter of TPE-s COF-Au is obviously reduced compared with that of TPE-s COF, and further proves that the synthesis of TPE-s COF-Au is successful.
Example 2
Synthesis of M @ TPE-s COF-Au @ Cisplatin
Adding a proper amount of the freeze-dried product TPE-s COF-Au @ Cisplatin into a culture bottle of the logarithmic growth adherent HepG2 cells (Shanghai leaf Biotech Co., ltd.)Mixing (cell density 1X 10) 6 -1×10 7 /ml), followed by co-cultivation for 6 hours. After the HepG2 cells were subsequently digested, centrifuged and resuspended, the cells were placed in a non-rate-controlled cell cryopreservation solution and the cell cryopreservation tubes were immersed in liquid nitrogen for 12 hours. Before use, the cryopreserved tubes were thawed in a 37 ℃ water bath and centrifuged for 3 minutes. After washing the cells with a PBS solution of pH =7.4, they were suspended in PBS and kept at 4 ℃.
The physical property characterization of the material M @ TPE-s COF-Au @ Cisplatin is as follows:
as shown in fig. 3, the results of the tetramethylazodicarbonyl blue (MTT) assay showed that shock cells did not exhibit proliferative activity compared to live cancer cells. Flow cytometry measured Forward Scatter (FSC) values confirm the reduction in cell size of the shock cells, while similar Side Scatter (SSC) values indicate that the internal structure of the shock cells remains unchanged. These results indicate that the cells after shock exhibit no proliferative activity.
Example 3
Focusing effect diagram of M @ TPE-s COF-Au @ Cisplatin cell nanocomposite
After the M @ TPE-s COF-Au @ Cisplatin cell nanocomposite and the HepG2 cell are co-cultured for 6h, blue fluorescence of the TPE-s COF on the HepG2 cell is observed by a confocal microscope (shown in figure 4 a), and is highly consistent with red fluorescence of a cell membrane fluorescence probe Dil, which indicates that the M @ TPE-s COF-Au @ Cisplatin cell nanocomposite is endocytosed and fused on a cell membrane. The cut-open TEM image after fixation of the co-cultured cells (fig. 4 b) shows that the material entered the cells and adhered to the membrane, and partially appeared in an aggregated state (as indicated by yellow arrows) without entering the nuclei.
Example 4
Real-time monitoring of in vivo imaging after drug administration
The distributed metabolism of the TPE-s COF composite in mice was followed for 2-96h after intravenous injection of the samples into tumor-containing mice via tail vein. The fluorescence distribution in each tissue organ was second tested by directly tracking the intrinsic fluorescence of TPE-s COF in the isolated organ. As shown in fig. 5, a distinct fluorescent signal was observed at the tumor site of the product mice of examples 1, 2, indicating that the nanocomplexes were aggregated at the tumor site. And after 6h, the product of example 2 is imaged in mice to show that the fluorescence intensity is strongest, and strong fluorescence is still observed at the tumor part after 96h along with the prolonging of time. The tissue anatomy also shows that the nanocomposite of TPE-s COF mainly aggregates at the tumor and liver sites.
Example 5
Annexin V-FITC apoptosis
First, hepG2 cells were seeded at a cell density of 1X 10 5 6 well cell culture plates per well. After 24 hours of culture, the cells were incubated for 24 hours with complete cell culture containing the product of example 1, 2 (200. Mu.g/mL). After washing with fresh complete medium, with or without a 808nm laser (1.0W/cm) 2 5 minutes) and then incubated for 6 hours. Cells were harvested and stained with Annexin V-FITC (5. Mu.L) and PI (10. Mu.L) for 20 min in the dark. Finally, the stained cells were analyzed by Flow Cytometry (FC) and the recorded data were statistically analyzed using FlowJo 10.0 software. As shown in FIG. 6, the TPE-s COF-Au group produced only very slight cytotoxicity even after incubation for 48h at concentrations as high as 200. Mu.g mL-1, while the material plus laser irradiated group showed enhanced apoptosis. The cell survival rate of the group of M @ TPE-s COF-Au @ Cisplatin + laser is only 14%, which indicates that the M @ TPE-s COF-Au @ Cisplatin + laser has strong killing effect on tumor cells in vitro.
Example 6
MTT assay
HepG2 cells were cultured on cell culture plates for 24 hours. Cytotoxicity was measured after incubating HepG2 cells with different concentrations of the products of examples 1 and 2 (different concentration ranges: 12.5-200. Mu.g/mL) for 48 hours at 37 ℃. After 48 hours of incubation, the cells were washed with fresh complete medium and then with or without a 808nm laser (1.0W/cm) 2 5 minutes) of irradiation. Cell viability was measured using standard MTT methods and further analyzed. And detecting the absorbance at 450nm by using a microplate reader. The MTT detection result is consistent with the Annexin V-FITC apoptosis detection result.
Example 7
The temperature change of the tumor part of the nude mice irradiated with the laser after half an hour after the administration is shown in figure 7. We further investigated the photothermal effect in vivo. Half an hour after administration of each group of mice, 5 minutes under 808nm laser irradiation (1W cm-2), IR thermography showed that the PBS solution group showed a slight temperature change (FIG. 7), and the temperature at the tumor site was gradually increased in TPE-s COF-Au @ Cisplatin and M @ TPE-s COF-Au @ Cisplatin groups. The TPE-s COF-Au @ Cisplatin and M @ TPE-s COF-Au @ Cisplatin nano composite material has a remarkable PTT effect in vivo. The temperature of the tumor site reached 45.0 ℃ in the TPE-s COF-Au @ Cisplatin group and 48.2 ℃ in the M @ TPE-s COF-Au @ Cisplatin group within 5 minutes of laser irradiation, probably due to the excellent photothermal properties of Au NPs. Wherein the temperature of the M @ TPE-s COF-Au @ Cisplatin is obviously higher than that of the TPE-s COF-Au @ Cisplatin group, mainly due to the specific targeting effect of the cell membrane. The cell membrane is targeted to the tumor part, the temperature is rapidly increased under the laser irradiation, the cell membrane is broken to release Au NPs and cisplatin drugs (right picture of SEM in figure 3), the Au NPs play a role in photo-thermal treatment of the tumor part, and the cisplatin plays a role in chemotherapy, so that the combined treatment effect and the efficient tumor inhibition effect are realized.
Example 8
In-vivo anti-tumor effect of M @ TPE-s COF-Au @ Cisplatin nano composite material on tumor-bearing mice
To fully evaluate the combined anti-tumor efficiency of TPE-s COF-au @ cissplatin and m @ TPE-s COF-au @ cissplatin nanocomposites, we monitored the experiment for 27 days (fig. 8) and randomly grouped tumor-bearing mice into the following 7 groups (n = 6): PBS, 2.Cisplatin, 3.Laser, 4.TPE-s COF-Au, 5.TPE-s COF-Au @ Cisplatin, 6.TPE-s COF-Au @ Cisplatin + laser and 7.M @ TPE-s COF-Au @ Cisplatin + laser. Dosing and laser irradiation were performed every three days and the body weight, tumor volume and size of the mice were followed. Changes in tumor volume during 27 days of treatment were recorded for these groups separately (fig. 8). In groups 1 and 4, tumor volume increased rapidly without laser irradiation. The volumes of groups 4 and 5 were slightly smaller than those of groups 2, 3 and 1, but not statistically significant, indicating that laser irradiation or chemotherapy alone did not induce anti-tumor effects. The treatment effect of group 5 was significantly better than that of group 1, presumably due to the good drug loading properties of TPE-s COF. Similar tumor growth kinetics indicate that TPE-s COF-Au exhibits negligible anti-tumor effects. In contrast, TPE-s COF-Au @ Cisplatin + laser treatment group significantly inhibited tumor growth under 808nm laser irradiation, and the tumor inhibition rate was over 90%. It is worth noting that the anti-tumor effect of the treatment group of M @ TPE-s COF-Au @ Cisplatin + laser is the best, the inhibition rate is up to 100%, and the tumor completely disappears after 27 days of chemotherapy/photothermal synergistic treatment. In addition, all tumors were collected and weighed at day 27 post-treatment, and tumor mass and tumor volume were consistent with the tumor growth curve (fig. 8).
According to the invention, the Au NPs and the mercapto groups on the surface of the TPE-s COF are combined in a covalent bond mode for the first time, and a stable TPE-s COF-Au carrier is formed by the strong anchoring capability between the Au NPs and the mercapto groups, so that the Au NPs have dispersibility, stability and photo-thermal performance on the surface of the TPE-s COF. Meanwhile, TPE-s COF-Au is used for loading a traditional chemotherapeutic drug cis-platinum (cissplatin), and an Au-TPE-s COF @ cissplatin nano carrier is formed. Then co-culturing with liver cancer cells (HepG 2) until cell membranes fuse lipophilic TPE-s COF, forming a fusion body of Au-TPE-s COF @ Cisplatin nano particles wrapped by the cell membranes by a low-temperature shock method, wherein the HepG2 cells after the low-temperature shock keep complete structures, but lose the proliferation capacity and pathogenicity. Meanwhile, the HepG2 cells after low-temperature shock keep the homing capability and the homologous targeting effect, so that the drug delivery carrier of the TPE-s COF-Au @ Cisplatin has a biological interface and specific targeting characteristics, and in addition, the TPE-s COF structure has fluorescence characteristics, and the targeting release and metabolic processes of the TPE-s COF material are traced through in-vivo imaging. Therefore, we constructed a novel lipophilic fluorescent TPE-s COF delivery system based on autologous cell membrane specific fusion to realize high-efficiency combined treatment effect for the first time. The nano drug-loaded system can realize accurate liver cancer combined treatment due to homologous targeting and specific cell membrane specific fusion. In conclusion, we developed cell membrane specific fused fluorescent TPE-s COF nanocomposites that can be used both as drug delivery vehicles and specific targeted combined chemical/photothermal therapy.
It should be noted that the technical contents described above are only explained and illustrated to enable those skilled in the art to know the technical spirit of the present invention, and therefore, the technical contents are not to limit the scope of the present invention. The scope of the invention is defined by the appended claims. It should be understood by those skilled in the art that any modification, equivalent replacement, and improvement made based on the spirit of the present invention should be considered to be within the spirit and scope of the present invention.
Claims (10)
1. The nanometer composite material loaded with antitumor medicine consists of hydrophobic aggregation luminescent covalent organic frame TPE-s COF containing sulfhydryl, photothermal agent combined with the surface sulfhydryl group of TPE-s COF via covalent bond, and antitumor medicine loaded in TPE-s COF.
2. The nanocomposite of claim 1, wherein the photothermal agent is gold nanoparticles and the anti-tumor drug is cissplatin.
3. The method of claim 2, comprising the synthesis of TPE-s COF material, the synthesis of TPE-s COF-Au, and the synthesis of TPE-s COF-Au @ Cisplatin.
4. The preparation method of claim 3, wherein the TPE-s COF material is prepared by subjecting tetra-aldehydic tetraphenylethylene and 3,3 '-dimercapto-4,4' -biphenyldiamine to Schiff base reaction in the presence of 1,4-dioxane, mesitylene and acetic acid as a catalyst, and standing at 100-140 ℃ for 2-5 days; the synthesis of the TPE-s COF-Au is to mix the TPE-s COF material with HAuCl 4 Mixing and reacting to obtain; the synthesis of the TPE-s COF-Au @ Cisplatin is obtained by mixing and reacting TPE-s COF-Au with chemotherapeutic drug Cisplatin Cisplatin.
5. The preparation method of claim 3, wherein the TPE-s COF material is synthesized by using tetraphenylethylene tetraaldehyde and 3,3 '-dimercapto-4,4' -biphenyldiamine in a molar ratio of 1.4-2.2, preferably 1Selecting 1:2; the TPE-s COF is prepared into TPE-s COF dispersion liquid, TPE-s COF dispersion liquid and HAuCl in the synthesis of TPE-s COF-Au 4 The volume ratio is 10-40, preferably 20; the mass ratio of TPE-s COF-Au to cissplatin in the synthesis of TPE-s COF-Au @ cissplatin is 4-6:1-3, preferably 5:3.
6. A drug delivery system for cancer cell membrane fusion TPE-s COF, which is obtained by co-culturing and fusing cancer cells and the nanocomposite material of any one of claims 1-2 or the nanocomposite material obtained by the preparation method of any one of claims 3-5, and then performing low-temperature shock.
7. The Nanocarrier system of claim 6, wherein the low temperature shock is achieved by placing the co-cultured fused cells in a cell freezing medium and freezing the cells in liquid nitrogen for more than 8 hours.
8. The nano drug-carrying system of claim 6, wherein the cancer cell endocytosis fuses the nano composite material to form a nano drug-carrying system of cancer cell membrane fusion TPE-s COF, namely M @ TPE-s COF-Au @ Cisplatin.
9. Use of a nanocomposite material according to any one of claims 1 to 2 or obtained by a preparation method according to any one of claims 3 to 5 for the preparation of a pharmaceutical system for the treatment of liver cancer.
10. Use of the Nanocarrier system of any of claims 6-8 for the preparation of a pharmaceutical system for the treatment of liver cancer.
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