CN114366722A - Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof - Google Patents

Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof Download PDF

Info

Publication number
CN114366722A
CN114366722A CN202210027143.6A CN202210027143A CN114366722A CN 114366722 A CN114366722 A CN 114366722A CN 202210027143 A CN202210027143 A CN 202210027143A CN 114366722 A CN114366722 A CN 114366722A
Authority
CN
China
Prior art keywords
nps
pcn
arg
gox
mem
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210027143.6A
Other languages
Chinese (zh)
Inventor
庞春丽
杨潇
安海龙
任深圳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hebei University of Technology
Original Assignee
Hebei University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hebei University of Technology filed Critical Hebei University of Technology
Priority to CN202210027143.6A priority Critical patent/CN114366722A/en
Publication of CN114366722A publication Critical patent/CN114366722A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • A—HUMAN NECESSITIES
    • 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
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61K47/54—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 an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61K47/54—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 an organic compound
    • A61K47/55—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 an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/03—Oxidoreductases acting on the CH-OH group of donors (1.1) with a oxygen as acceptor (1.1.3)
    • C12Y101/03004—Glucose oxidase (1.1.3.4)

Abstract

The invention discloses a polyphenol-mediated multifunctional bionic metal-organic framework mixed structure, and preparation and application thereof. That is, L-Arg @ PCN @ GOx-TA @ Mem nanoparticle, wherein L-Arg represents L-arginine and PCN represents ZrOCl2And meso-tetra (4-carboxyphenyl) porphin (TCPP) and Benzoic Acid (BA) as raw materials, wherein the MOFs are prepared by reaction, GOx-TA represents glucose oxidase-tannic acid, and Mem represents a cell membrane of a cancer cell to be targeted. The nanoparticles enable a synergistic cascade of ghrelin therapy, photodynamic therapy and gas therapy for the treatment of tumors/cancers.

Description

Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a light function nano material capable of catalyzing cascade enhanced hunger/photodynamic/gas cooperative therapy and a preparation method thereof, in particular to a polyphenol-mediated multifunctional bionic metal-organic framework mixed structure, a preparation method thereof and application thereof in preparation of a tumor targeted combination therapy drug.
Background
Photodynamic therapy (PDT) is an emerging photochemically-based method of cancer treatment. When irradiated by a specific light, a non-toxic photosensitizer is activated and transfers the energy of the light to surrounding oxygen molecules, inducing the production of a series of cytotoxic reactive oxygen species. In recent years, metal-organic frameworks (MOFs) self-assembled from metal-organic ligands have been widely used in the biomedical field due to their large surface area, suitable size, good biocompatibility and biodegradability. In particular, the porous porphyrin MOFs with the photosensitizer loaded in the MOFs framework has the unique advantages of avoiding self-quenching and high photosensitizer load, and can be used as a nano photosensitizer for PDT. In addition, due to their porous structure, porphyrin MOFs have been used as multifunctional nano-platforms in combination with other therapeutic approaches.
However, many conventional photosensitizers, such as hematoporphyrin, zinc phthalocyanine, chlorin e6, etc., have poor water solubility and low tumor selectivity, resulting in an undesirable therapeutic effect of PDT. In addition, the hypoxic environment and the continued oxygen consumption during PDT would further impair the therapeutic efficacy of the treatment for cancer.
Disclosure of Invention
The invention aims to provide L-Arg @ PCN @ GOx-TA @ Mem nanoparticles (mPAGTP NPs).
The L-Arg @ PCN @ GOx-TA @ Mem nano particle provided by the invention is characterized in that L-Arg represents L-arginine, and PCN represents ZrOCl2MOFs prepared by reaction of meso-tetra (4-carboxyphenyl) porphin (TCPP) and Benzoic Acid (BA) serving as raw materials, GOx-TA represents glucose oxidase-tannic acid, and Mem represents the fine powder of cancer cells to be targetedCell membrane, specifically, cell membrane of breast cancer cell (4T 1);
the L-Arg @ PCN @ GOx-TA @ Mem nano particle is prepared by the following steps:
1) preparation of PCN NPs
With ZrOCl2Reacting meso-tetra (4-carboxyphenyl) porphin (TCPP) and Benzoic Acid (BA) serving as raw materials in N, N-Dimethylformamide (DMF) to obtain PCN NPs (namely PCN-224 NPs);
2) preparation of L-Arg @ PCN NPs, i.e., PA NPs
Adding L-Arg into a PCN NPs aqueous solution for reaction to obtain L-Arg @ PCN NPs, namely PA NPs;
3) preparation of L-Arg @ PCN @ GOx-TA NPs (PAGTNPs)
Adding TA into PA NPs aqueous solution, stirring for reaction at 37 ℃ for 0.5h, then adding GOx, and continuously stirring for reaction at 37 ℃ for 3.5h to obtain L-Arg @ PCN @ GOx-TA NPs (PAGTNPs);
4) preparation of L-Arg @ PCN @ GOx-TA @ Mem NPs, i.e., mPAGT NPs
And (3) wrapping L-Arg @ PCN @ GOx-TA NPs by using a cell membrane of a cancer cell to be targeted to obtain the L-Arg @ PCN @ GOx-TA @ Mem NPs, namely mPAGTNPs.
ZrOCl in step 1) of the above method2The mol ratio of the TCPP to the BA is 1:0.12-0.15:22-25 in sequence;
the reaction is carried out in the dark, the temperature of the reaction can be 85-100 ℃, and the time can be 3-7 hours;
in the step 2) of the method, the mass ratio of the L-Arg to the PCN NPs in the PCN NPs aqueous solution can be 0.5:1-2:1, and specifically can be 1: 1;
the reaction is carried out in the dark at room temperature, and the reaction time can be 20-26h, specifically 24 h;
in the step 3) of the method, the mass ratio of the TA to the PA NPs and GOx in the PA NPs aqueous solution can be 4:10-15:5-8 in sequence, and specifically can be 4:12.5: 6;
the operation of the step 4) of the method is as follows: and collecting cancer cells to be targeted, crushing, centrifuging, taking a supernatant, mixing the obtained supernatant with L-Arg @ PCN @ GOx-TA NPs, and carrying out ultrasonic treatment to obtain the L-Arg @ PCN @ GOx-TA @ Mem NPs, namely mPAGTP NPs.
The L-Arg @ PCN @ GOx-TA NPs prepared in the step 3) also belong to the protection scope of the invention.
The application of the L-Arg @ PCN @ GOX-TA @ Mem nano particle or the L-Arg @ PCN @ GOX-TA NPs in the preparation of the medicine for targeted therapy of tumors/cancers also belongs to the protection scope of the invention.
In the application, the nanoparticles can realize the cascade synergistic treatment of tumors/cancers by hunger therapy, photodynamic therapy and gas therapy, and the types of the tumors/cancers are the same as the sources of Mem cell membranes in L-Arg @ PCN @ GOx-TA @ Mem nanoparticles.
According to the invention, a layer of GOx-TA is coated through the interaction of hydrogen bonds, hydrophobicity and static electricity between protein and polyphenol so as to improve the generation of ROS. The multifunctional nano platform (L-Arg @ PCN @ GOx-TA @ Mem nano particle) prepared by the invention has wide application prospect in the aspect of synergistic treatment of tumors through catalytic cascade enhancement.
Drawings
FIG. 1(A) is a schematic diagram of the nanoparticle preparation process prepared in example 1 of the present invention; (B) TEM image of the L-Arg @ PCN @ GOx-TA @ Mem nanoparticles prepared in example 1, with 50nm scale; (C) nano particle ultraviolet absorption spectrum; (D) change in the particle size dispersion coefficient of L-Arg @ PCN @ GOx-TA @ Mem nanoparticles in water, PBS (pH 7.4), or 10% cell culture medium.
FIG. 2(A) is pHt-pH0Dependent concentration of mPGT NPs. (B) Of different samples probed with DPBF1O2Generating (C) NO release from mPAGT NPs under different treatment conditions.
Figure 3(a) CLSM image shows 4T1 cells incubated with mPAGT NPs for 0.5, 1, 2 and 4 h. (B) Cell proliferation rates under laser irradiation of different treatment groups. (C) Apoptosis rates of different treatment groups.
Figure 4(a) groups of tumor volumes were treated in darkness or under laser irradiation. (B) The weights of the groups varied. (C) In vitro fluorescence imaging of organs and tumors of mice 12h after mPAGT NPs injection.
FIG. 5 is a diagram showing the results of SDS-PAGE qualitative analysis of Mem, GOx and mPAGT.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The examples provided below serve as a guide for further modifications by a person skilled in the art and do not constitute a limitation of the invention in any way.
The experimental procedures in the following examples, unless otherwise indicated, are conventional and are carried out according to the techniques or conditions described in the literature in the field or according to the instructions of the products. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of L-Arg @ PCN @ GOx-TA @ Mem nanoparticles (mPAGT NPs)
First, ZrOCl2·8H2O (150mg,0.465mmol), TCPP (50mg,0.065mmol) and BA (1.4g,11.5mmol) were dissolved in 50mL DMF. The mixture was then gently stirred in the dark at 90 ℃ for 5 hours. Finally, the PCN-224(PCN) nanoparticles were purified by centrifugation (15000 rpm) for 20 minutes and then washed 3 times with DMF. L-Arg (10mg) was added to an aqueous solution of PCN-224NPs (1mg/mL,10 mL). After stirring in the dark at room temperature for 24h, the PA NPs (L-Arg @ PCN) were centrifuged (15000 rpm) for 20 min and then washed 3 times with water. Finally, the product was redispersed in water and stored at 4 ℃ in a refrigerator protected from light. TA (4mg) was added to a solution of the obtained PA NPs (2.5mg/mL,5mL), stirred at 37 ℃ for 0.5h, and then GOx (6mg) was added. Stirring was continued for 3.5h at 37 ℃ and PAGTP NPs (L-Arg @ PCN @ GOx-TA) were collected by centrifugation and suspended in water. Mouse breast cancer (4T1) cells were incubated, collected, suspended in PBS for 2 minutes, centrifuged (5000 rpm), then water was added, disrupted with a cell disruptor, then, disrupted 4T1 cells were centrifuged at 8000rpm for 5min, and the supernatant was taken. mPAGTT NPs are then prepared by ultrasonically coating PAGTT NPs with 4T1 cell membranes.
FIG. 1(A) is a schematic diagram of a nanoparticle preparation process; (B) TEM image of nanoparticles; (C) nano particle ultraviolet absorption spectrum; (D) variation in the particle size dispersion coefficient of nanoparticles in water, PBS (pH 7.4) or 10% cell culture medium.
As can be seen from fig. 1C: the UV-Vis absorption spectrum clearly shows the characteristic peaks of TCPP, indicating the successful synthesis of PCN NPs.
As can be seen from fig. 1D: the hydrodynamic diameter and polydispersity index in water, PBS and growth media did not change significantly within 5 days, indicating that our nano-platform has satisfactory colloidal properties and is suitable for biological applications.
The qualitative analysis of SDS-PAGE of Mem, GOx and mPAGT (FIG. 5) was performed and confirmed that the mPAGT cell membranes and GOx were coated by comparing the protein composition of 4T1 membrane in SDS-PAGE and most of the cell membrane proteins and GOx were preserved in the mPAGT band.
Example 2 Cascade catalysis Effect experiment
The PCN @ GOx-TA NPs, i.e., PGT NPs, used in the following experiments were prepared as follows:
adding TA into PCN NPs aqueous solution, stirring for reaction at 37 ℃ for 0.5h, then adding GOx, and continuously stirring for reaction at 37 ℃ for 3.5h to obtain PCN @ GOx-TA NPs (PGT NPs);
the PCN @ Mem NPs, L-Arg @ PCN @ Mem NPs and PCN @ GOx-TA @ Mem NPs, i.e., mCN NPs, mPA NPs and mPGT NPs, used in the following experiments were prepared by the following methods:
the PCN NPs, PA NPs and PGT NPs are wrapped by the cell membrane of the cancer cell to be targeted to obtain mPCN NPs, mPA NPs and mPGT NPs.
The cell membrane extraction method comprises incubating mouse breast cancer (4T1) cells, collecting, suspending in PBS for 2 min, centrifuging (5000 rpm, 4 min), adding water, breaking with cell breaker, centrifuging broken 4T1 cells at 8000rpm for 5min, and collecting supernatant. Then, PCN NPs, PA NPs and PGT NPs are ultrasonically wrapped by 4T1 cell membranes. Namely, the mixture was ultrasonically iced in an ice bath for 90 minutes, and then collected by centrifugation.
To evaluate the effect of cascade catalysis, we performed an in vitro experiment, expecting a cascade reaction involving GOx catalyzed oxidation of glucose, H2O2And ROS-mediated oxidation of L-Arg to release NO, and based on nano-photosensitizers1O2And (4) generating. First, mPGT NPs of different concentrations were mixed with 0.05M glucose, stirred to react, and the change was observed with a pH meter, and GOx was evaluated by detecting the change in pHCatalytic performance. The significant decrease in pH as shown in figure 2A also indicates that mPGT NPs can accelerate the decomposition of glucose and have a concentration and time dependence. As a result, glucose is completely consumed, and the supply of nutrients is cut off, thereby implementing the starvation therapy. Then, we selected 1, 3-Diphenylisobenzofuran (DPBF) as a chemical probe, and further examined our nano-platform generation by monitoring the decrease in absorption intensity at 424nm1O2. DPBF was then mixed with different nanocomposite solutions (concentration 50. mu.g/mL) (mPCN, mPA, mPGT, mPAGT + glucose) and irradiated under a 650nm laser for different times to obtain absorption spectra. As shown in FIG. 2B, the decrease in absorbance intensity for mPAGT + glucose is more pronounced. Finally, in the NO generation experiment using the typical Griess method, as can be seen from FIG. 2C, a large amount of NO was generated under laser irradiation, and the concentration further increased with the addition of Glu, confirming the generation of NO during PDT1O2Can oxidize the L-Arg molecule to release NO. In summary, our nano-platform can initiate a cascade catalytic reaction to accelerate1O2And continuously reacts with L-Arg to release NO.
The effect on cell proliferation of 4T1 cells was determined by cell proliferation assay (MTT method was used to determine its effect on cell proliferation of 4T1 cells. 4T1 cells were cultured in 96-well plates for 24 h. then incubated for 4h with various samples (mPCN NPs, mPA NPs mPAGTT NPs and mPAGTT NPs + Glu) at concentrations of 50. mu.g/mL, 100. mu.g/mL and 200. mu.g/mL followed by irradiation (650nm,100 mW/cm)2) For 5 minutes. After 24h, 20 μ L of MTT (5 mg/ml) was added to each well. After 4h incubation, the supernatant was aspirated and dissolved with 150 μ L DMSO. The absorption wavelength at 570nm was measured with a microplate reader. The cell viability was defined as OD (sample)/OD (control). times.100%, where OD (control) and OD (sample) represent the absorbance at 570nm in the presence or absence of the sample, respectively), and the decrease in cell proliferation rate under laser irradiation was found from FIG. 3B, and the cell uptake behavior of the nanoparticles was investigated using CLSM. Cells were seeded in 6-well plates, cultured for 24 hours, then cultured for 4 hours, 2 hours, 1 hour, and 0.5 hour in equal amounts to mPAGTP NPs (100. mu.g/mL), washed 3 times, and then fluorescence was observed by CLSM. Fluorescence was observed by CLSM and from figure 3A it can be seen that mPAGT NPs were efficiently taken up by 4T1 cells over time. By flow cytometryAnalyzing apoptosis, inoculating cells into 6-well plate, culturing for 24 hr, adding mPCN NPs, L-arg, mPA NPs, mPAGTT and mPAGTT + Glu (100 μ g/mL), culturing for 4 hr, and irradiating (650nm,100 mW/cm)2) 5min, cells were collected, stained with V-FITC and PI, and examined by flow cytometry, and FIG. 3C shows an increase in apoptosis rate. The nano platform can initiate a series of cascade reactions under laser irradiation, including GOx catalytic oxidation of glucose and ROS mediated release of NO, so that proliferation of tumor cells is effectively inhibited, and apoptosis of the tumor cells is promoted.
The results of in vivo experiments further confirm the slight systemic toxicity and cascade enhancement of mPAGT NPs for tumor-targeted combination therapy. (BALB/c mice 6-8 weeks old BALB/c mice, 4T1 cells (1X 10)7Cells were seeded in 150 μ L PBS). The tumor volume reaches 100mm3Thereafter, mice were randomly divided into 8 groups (n ═ 5), and PBS (150 μ L), L-Arg (150 μ L,0.45mg/kg), mPCN NPs (150 μ L,5mg/kg), mPA NPs (150 μ L,5mg/kg) and mPAGT (150 μ L,5mg/kg) were injected intravenously every 2 d. 24h after injection, mice in the group of mPCN NPs mPA NPs and mPAGT were given 650nm, 600mW/cm2Irradiation for 10 min). As can be seen from fig. 4A, significant inhibition of tumor growth is likely associated with cascade enhanced tumor-targeted combination therapy. As shown in fig. 4B, the body weight of the mice was monitored every other day, and no significant change was observed in 8 groups, indicating that the nanoplatform has good biocompatibility. As shown in fig. 4C, in vitro imaging results demonstrate that mPAGT NPs can accumulate efficiently in tumor tissue 12 hours after injection.
Therefore, the prepared multifunctional nano platform has wide application prospect in the aspect of synergistic treatment of tumors through catalytic cascade enhancement.
The present invention has been described in detail above. It will be apparent to those skilled in the art that the invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with reference to specific embodiments, it will be appreciated that the invention can be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. The use of some of the essential features is possible within the scope of the claims attached below.

Claims (9)

  1. L-Arg @ PCN @ GOx-TA @ Mem nanoparticle, wherein L-Arg represents L-arginine and PCN represents ZrOCl2And meso-tetra (4-carboxyphenyl) porphine and benzoic acid are used as raw materials to react to prepare MOFs, GOx-TA represents glucose oxidase-tannic acid, and Mem represents a cell membrane of a cancer cell to be targeted.
  2. 2. A process for the preparation of L-Arg @ PCN @ GOx-TA @ Mem nanoparticles according to claim 1, comprising the steps of:
    1) preparation of PCN NPs
    With ZrOCl2Reacting meso-tetra (4-carboxyphenyl) porphin, benzoic acid and N, N-dimethylformamide serving as raw materials to obtain PCN NPs;
    2) preparation of L-Arg @ PCN NPs, i.e., PA NPs
    Adding L-Arg into a PCN NPs aqueous solution, and reacting to obtain L-Arg @ PCN NPs, namely PA NPs;
    3) preparation of L-Arg @ PCN @ GOx-TA NPs (PAGTNPs)
    Adding TA into PA NPs aqueous solution, stirring for reaction at 37 ℃ for 0.5h, then adding GOx, and continuously stirring for reaction at 37 ℃ for 3.5h to obtain L-Arg @ PCN @ GOx-TA NPs (PAGTNPs);
    4) preparation of L-Arg @ PCN @ GOx-TA @ Mem NPs, i.e., mPAGT NPs
    And (3) wrapping L-Arg @ PCN @ GOx-TA NPs by using a cell membrane of a cancer cell to be targeted to obtain the L-Arg @ PCN @ GOx-TA @ Mem NPs, namely mPAGTNPs.
  3. 3. The method of claim 2, wherein: in step 1), ZrOCl2The mol ratio of the TCPP to the BA is 1:0.12-0.15:22-25 in sequence;
    the reaction is carried out in the dark, the temperature of the reaction is 85-100 ℃, and the time is 3-7 hours.
  4. 4. A method according to claim 2 or 3, characterized in that: in the step 2), the mass ratio of the L-Arg to the PCN NPs in the PCN NPs aqueous solution is 0.5:1-2: 1;
    the reaction is carried out in the dark at room temperature, and the reaction time is 20-26 h.
  5. 5. The method according to any one of claims 2-4, wherein: in the step 3), the mass ratio of the TA to the PA NPs and GOx in the PA NPs aqueous solution is 4:10-15:5-8 in sequence.
  6. 6. The method according to any one of claims 2-5, wherein: the operation of the step 4) is as follows: and collecting cancer cells to be targeted, crushing, centrifuging, taking a supernatant, mixing the obtained supernatant with L-Arg @ PCN @ GOx-TA NPs, and carrying out ultrasonic treatment to obtain the L-Arg @ PCN @ GOx-TA @ Mem NPs, namely mPAGTP NPs.
  7. 7. PAGTNPs, L-Arg @ PCN @ GOx-TA NPs, produced by step 3) of the process of claim 2.
  8. 8. Use of the L-Arg @ PCN @ GOx-TA @ Mem nanoparticles of claim 1 or the L-Arg @ PCN @ GOx-TA NPs of claim 7 for the preparation of a medicament for the targeted treatment of tumors/cancers.
  9. 9. Use according to claim 8, characterized in that: in the application, the medicine can realize cascade synergistic treatment of hunger therapy, photodynamic therapy and gas therapy.
CN202210027143.6A 2022-01-11 2022-01-11 Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof Pending CN114366722A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210027143.6A CN114366722A (en) 2022-01-11 2022-01-11 Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210027143.6A CN114366722A (en) 2022-01-11 2022-01-11 Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof

Publications (1)

Publication Number Publication Date
CN114366722A true CN114366722A (en) 2022-04-19

Family

ID=81143650

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210027143.6A Pending CN114366722A (en) 2022-01-11 2022-01-11 Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof

Country Status (1)

Country Link
CN (1) CN114366722A (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030068355A1 (en) * 2001-08-20 2003-04-10 Shanley John F. Therapeutic agent delivery device with protective separating layer
CN108210931A (en) * 2016-12-15 2018-06-29 深圳大学 Nanometer diagnosis and treatment agent, preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030068355A1 (en) * 2001-08-20 2003-04-10 Shanley John F. Therapeutic agent delivery device with protective separating layer
CN108210931A (en) * 2016-12-15 2018-06-29 深圳大学 Nanometer diagnosis and treatment agent, preparation method and application

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
SEHER ALTUN ET AL.: "A facile and effective immobilization of glucose oxidase on tannic acid modified CoFe2O4 magnetic nanoparticles", 《COLLOIDS AND SURFACES B: BIOINTERFACES》 *
WAN ET AL.: "ROS-induced NO generation for gas therapy and sensitizing photodynamic therapy of tumor", 《BIOMATERIALS》 *
刘涛 等: "用于肿瘤诊疗的金属-多酚网络多功能材料", 《功能高分子学报》 *
杨美华主编: "《中药质量控制与分析》", 31 May 2020, 中国协和医科大学出版社 *

Similar Documents

Publication Publication Date Title
CN112245579B (en) Photodynamic therapeutic agent for relieving tumor hypoxia and preparation method and application thereof
CN112940278B (en) Sound-sensitive active oxygen-generating metalloporphyrin coordination polymer and preparation and application thereof
Wang et al. Biomineralized DNA nanospheres by metal organic framework for enhanced chemodynamic therapy
Zhou et al. Oxygen-deficient tungsten oxide (WO x) nanobelts with pH-sensitive degradation for enhanced sonodynamic therapy of cancer
Wang et al. Biomimetic nanoarchitectonics of hollow mesoporous copper oxide-based nanozymes with cascade catalytic reaction for near infrared-II reinforced photothermal-catalytic therapy
Jiang et al. A tumor microenvironment-responsive Co/ZIF-8/ICG/Pt nanoplatform for chemodynamic and enhanced photodynamic antitumor therapy
Ren et al. A versatile nanoplatform based on multivariate porphyrinic metal–organic frameworks for catalytic cascade-enhanced photodynamic therapy
Kang et al. Synthesis of red/black phosphorus-based composite nanosheets with a Z-scheme heterostructure for high-performance cancer phototherapy
Cheng et al. A multifunctional nanocomposite based on Pt-modified black phosphorus nanosheets loading with l-arginine for synergistic gas-sonodynamic cancer therapy
Zheng et al. Fabrication of denatured BSA-hemin-IR780 (dBHI) nanoplatform for synergistic combination of phototherapy and chemodynamic therapy
Xu et al. Raspberry-like AgBiS 2@ PVP nanoparticles for enhanced sonodynamic and chemodynamic cancer therapy
Zhang et al. Sonoactivated cascade Fenton reaction enhanced by synergistic modulation of electron–hole separation for improved tumor therapy
CN112121154A (en) Tumor microenvironment response CO gas therapeutic agent and preparation and application thereof
CN114366722A (en) Polyphenol-mediated multifunctional bionic metal-organic framework mixed structure and preparation and application thereof
CN115252644B (en) Preparation method and application of anti-tumor nano-drug enhanced by synergistic starvation therapy/chemodynamic therapy
CN114344482B (en) Multifunctional nanoparticle based on metal-organic framework and preparation method and application thereof
Shi et al. A small pore black TiO 2/-large pore Fe 3 O 4 cascade nanoreactor for chemodynamic/photothermal synergetic tumour therapy
WO2022067885A1 (en) Application of doped titanium dioxide in manufacturing of sonosensitizer
CN110642865B (en) Application of high-charge cationic porphyrin in preparation of PDT nano photosensitizer
CN113144175A (en) Tumor microenvironment response CO gas therapeutic agent and preparation method and application thereof
Faustova et al. Polymer particles containing Fe-based metalloporphyrin as a highly efficient stimulator of reactive oxygen species formation in vitro and in vivo
Feng et al. Covalent organic framework-based nanozyme for cascade-amplified synergistic cancer therapy
CN108421041B (en) Photodynamic therapy compound and preparation method and application thereof
Zhang et al. Hypoxia mitigation by manganese-doped carbon dots for synergistic photodynamic therapy of oral squamous cell carcinoma
CN110548141A (en) Preparation method and application of titanyl porphyrin complex-folic acid liposome nanoparticles

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20220419