CN111558051B - Composite nano-microsphere with rapid mucus penetration effect and preparation method and application thereof - Google Patents

Composite nano-microsphere with rapid mucus penetration effect and preparation method and application thereof Download PDF

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CN111558051B
CN111558051B CN202010651124.1A CN202010651124A CN111558051B CN 111558051 B CN111558051 B CN 111558051B CN 202010651124 A CN202010651124 A CN 202010651124A CN 111558051 B CN111558051 B CN 111558051B
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composite
metal organic
organic framework
zif
black phosphorus
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CN111558051A (en
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李志斌
钱敏
喻学锋
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Shenzhen Institute of Advanced Technology of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
    • A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K9/501—Inorganic compounds
    • 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
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention relates to a composite nano microsphere with a rapid mucus penetration effect, and a preparation method and application thereof, and particularly discloses a composite nano microsphere, which comprises a metal organic framework ZIF-8 and a hydrophilic high polymer modified on the surface of the metal organic framework ZIF-8, wherein the metal organic framework ZIF-8 is loaded with black phosphorus quantum dots and active ingredients, and the hydrophilic high polymer is selected from polyethylene glycol. According to the invention, ZIF-8 is modified by hydrophilic PEG for the first time and is used for increasing the mucus penetrating capability of the composite nano-particles, so that the mucus penetrating capability of the composite nano-particles is improved, and the targeting capability and the capability of penetrating the human body physiological barrier obstruction are improved.

Description

Composite nano-microsphere with rapid mucus penetration effect and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a composite nano microsphere with rapid mucus penetration and drug delivery controlled release effects, and a preparation method and application thereof.
Background
Nanospheres are generally defined as particles in the 1-1000nm scale range that exhibit unique properties of large specific surface area, electromagnetic and optical behavior. The nanometer microsphere can artificially regulate the composition, size and surface property in the preparation process, and synthesize nanometer microsphere structure packaging and protective treatment medicines with specific properties according to needs, so that some medicine molecules with poor water solubility are stably dispersed, and are prevented from being discharged out of a body by various endogenous defense mechanisms in the in vivo circulation process, wherein the mechanisms comprise enzyme catalytic degradation, immune degradation, reticuloendothelial system action, gastric acid hydrolysis, lung mucosa fiber clearing action and the like. In addition, by controlling the shape and size and surface modification of the nano particles, the drug-loaded nano particles can reach a specific pathological change part in a targeted manner and release the drug controllably without affecting normal tissues. Some nanoparticles have excellent magnetism and optical property, and can be used for biological imaging (magnetic resonance, fluorescence imaging and the like) to realize diagnosis and treatment integration.
Drug Delivery System (DDS)[1-5]Refers to improving the in vivo availability of the drug by preventing premature release and enhancing drug uptake, controlling the drug concentration within the therapeutic window by controlling the drug release rate, and reducing side effects by targeting the disease site and cancer cells[6-7]. In 1990, liposomal amphotericin B was marketed as the first drug delivery system approved by the U.S. food administration (FDA). Various DDSs have been used so far for the treatment of various diseases such as cancer, fungal infection and muscular degeneration[8-9]. Over the past decades, the design and synthesis of various biocompatible materials has driven the advancement of DDS. Liposomes[10]Is the first to be used clinically. Most preferablyRecently, some new materials[4]Such as porous silica, ferroferric tetrachloride, carbon materials and Metal Organic Frameworks (MOFs)[11-12]It also shows potential as a DDS carrier. Among them, MOFs have received extensive attention and research because of their good properties, such as good porosity, large surface area and chemical tunability. Horcajada et al reported that MOFs materials synthesized based on ferric iron as suitable nanomaterials for the effective controlled delivery of drugs for the treatment of cancer and AIDS[13](ii) a Sun Keke based on La-MOF, SiO2、Fe2O3The composite material is synthesized to realize targeted drug delivery, and the fluorescence of the composite material is expected to monitor drug delivery. In the field of drug delivery, most of the work of MOFs has focused on MIL compounds. MILs have been functionalized by various methods and modified by post-synthesis to give Nanoparticles (NPs) which are decomposed in water to release their payload by covalent bonding, and the release rate is adjusted by coating the nanoparticles with a layer of silica[14]. These coated nanoparticles are able to cross the cell membrane of HT-29 tumor cells and inhibit cell growth or cell staining depending on the drug function. In addition, MIL-53(Fe) re-detected ibuprofen delivery[15]Drug adsorption was found to induce amplification of the MOFs framework. The desorption time of this material is very slow (20 days) and has zero order kinetics due to the tight binding of the drug molecules to the framework. A 32% drug loading rate was achieved in MIL-100, approximately 5 times higher than currently available drug delivery platforms. The drug-loaded MOFs showed cytotoxicity very similar to free drug; MIL-100 loaded with anti-HIV drugs also showed significant inhibition of viral replication in vitro.
The nano drug-loaded system can effectively exert the protective effect of the material on the drug, assist the drug to cross the mucosal barrier, and pass through Enhanced Permeability and Retention (EPR)[16-18]The effect enhances the accumulation of the drug at the target site, changes the distribution of the drug in the body, reduces the systemic toxicity, and is the current direction of modern drugs. Metal-organic frameworks (MOFs) are an emerging porous hybrid material, and are compatible with the traditional materialsCompared with nanomaterials, the MOFs have adjustable composition and topology, highly ordered voids, large surface area, and excellent physicochemical properties, and are widely used in a plurality of fields such as catalysis, chemical sensing, gas adsorption, and the like, and especially have great attention in the aspects of drug loading and delivery. Zeolite imidazole framework material (ZIF-8)[19-20]The metal Zn ion is the most representative one of MOFs materials, and the framework structure of the metal Zn ion is a tetrahedral structure formed by the connection of metal Zn ions and N atoms in dimethyl imidazole. Besides the advantages of MOFs, ZIF-8 also has better drug loading capacity, chemical stability, good biocompatibility and sensitive pH responsiveness, so that the loaded drug can be controllably and accurately released at a tumor part, and the requirements of a novel nano material drug loading system on various aspects such as drug loading capacity, stability, drug release and the like are met.
The synthesis of ZIF-8 essentially depends on the coordination capability of the metal center and the organic bond. Compared with the traditional zeolite, the ZIF-8 has better flexibility and controllability, and the size and the adsorption performance of the ZIF-8 can be adjusted by changing or chemically modifying the anionic imidazole linker. However, the mucus barrier in human body, such as the high secretion of respiratory mucus in common respiratory diseases, makes it difficult for the nanoparticles to penetrate effectively, reducing the therapeutic effect of the drug. To solve this problem, there is an urgent need to develop a drug delivery vehicle having mucus penetrating ability.
The main references:
[1]Berger A.Drug Delivery System May Combat Cancer.British Medical Journal,2001,322(7278):72-72.
[2]Brown L,Langer R.Transdermal Delivery of Drugs.Annual Review of Medicine.1988,39(39):221-229.
[3]Towari G,Towari R,Sriwastawa B,et al.Drug Delivery System:An Updated Review.International Journal of Pharmaceutical Investigation.2012,2(1):2-11.
[4]Sayed E,Haj-Ahmad R,Ruparelia K,et al.Porous Inorganic Drug Delivery System-A Review.Aaps Pharmscitech,2017,18(5):1507-1525.
[5]He J J,Qi X X,Maio Y P,et al.Application of Smart Nanostructures in Medicine.Nanomedicine,2010, 5(7):1129-1138.
[6]Aberoumandi S M,Mohammadhosseini M,Abasi E,et al.An Update on Application of Nanostructured Drug Delivery System in Cancer Therapy:A Review.Artificial Cells Nanomedicine and Biotechnology,2017,45(6):1058-1068.
[7]Saini S,Kumar S,Choudhary M,et al.Microspheres as Controlled Drug Delivery System:An Updated Review.International Journal Pharmaceutical Sciences and Research,2018,9(5):1760-1768.
[8]Zhang Y,Chan H F,Leong K M.Advanced Materials and Processing for Drug Delivery:The Past and the Future.Advanced Drug Delivery Reviews,2013,65(1):104-120 .
[9]Allen T M,Cullis P R.Drug Delivery System:Entering the Mainstream.Science,2004, 303(5665):1818-1822.
[10]Tarahovsky Y S.“Smart”Liposomal Nanocontainers in Biology and Medicine.Biochemistry-Moscow, 2010,75(7):811-824.
[11]Yaghi O M,Li H.Hydrothermal Synthesis of a Metal-Organic Framework Containing Large Rectangular Channels.Journal of the American chemical Society,1995,117(41):10401-10402.
[12]Li H,Eddaoudi M,O’Keeffe M,et al.Design and Synthesis of an Exceptionally Stable and Highly Porous Metal-organic Framework.Nature,1999,402(6759):276-279.
[13]Horcajada P,Chalati T,Serre C,et al.Porous Metal-Organic-Framework Nanoscale Carriers as a Potential Platform for Drug Delivery and Imaging.Nature Materials,2010,9(2):172-178.
[14]Taylor-Pashow K M L,Della Rocca J,Xie Z G,et al.Postsynthetic Modification of Tron-Carboxylate Nanoscale Metal-organic Frameworks for Imaging and Drug Delivery.Journal of the American chemical Society, 2009,131(40):14261-14263.
[15]Horcajada P,Serre C,Maurin G,et al.Flexible Porous Metal-organic Frameworks for a Controlled Drug Delivery.Journal of the American chemical Society,2008,130(21):6774-6780.
[16]Perche F,Torchilin V P,Recent Trends in Multifunctional Liposomal Nanocarriers for Enhanced Tumor Targeting.J.Drug Delivery 2013,705265DOI:10.1155/2013/705265 .
[17]Nishihara H.Human Pathological Basis of Blood Vessels and Stromal Tissue for Nanotechnology.Adv.Drug Delivery Rev.74,19-27.
[18]Yokoi K,Kojic M,Milosevic M,Tanei T,Ferrari M,Ziemys A.Capillary-Wall Collagen as a Biophysical Marker of Nanotherapeutic Permeability into the Tumor Microenvironment.Cancer Res.74,4239-46.
[19]Noh K,Lee J,Kim J.Compositions and Structures of Zeolitic Imidazolate Frameworks.Israel Journal of chemistry,2018,58(9-10):1075-1088.
[20]Yao J F,Wang H T.Zeolitic Imidazolate Frameworks Composite Membranes and Thin Films:Synthesis and Applications.Chemistry Society Review,2014,43(13):4470-4493.
disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the preparation and the application of the composite nano microsphere with the functions of rapid mucus penetration and drug delivery controlled release. The black phosphorus quantum dots and the therapeutic drug composite nano microspheres coated by the metal organic framework ZIF-8 have good drug loading capacity and wide application range, can load various therapeutic drugs, can improve the therapeutic effect of the drugs, and reduce adverse toxic and side effects; and after surface modification is carried out by using the electrically neutral high molecular weight polyethylene glycol (PEG), the surface charge of the composite nano-microsphere can be reduced, so that the composite nano-microsphere has mucus inertia and can quickly permeate a mucus layer. Meanwhile, the preparation process of the nano-microsphere is simple, the reproducibility is good, and the large-scale preparation can be rapidly realized.
In order to achieve the purpose, the invention adopts the following technical scheme:
on one hand, the invention provides a composite nano microsphere, which takes a metal organic framework ZIF-8 as a nano microsphere main body, wherein black phosphorus quantum dots and active ingredients are wrapped inside the composite nano microsphere, and hydrophilic high molecular polymer is used for surface modification outside the composite nano microsphere;
the hydrophilic high molecular polymer is selected from polyethylene glycol (PEG).
On the other hand, the invention provides a preparation method of the black phosphorus metal organic framework ZIF-8 composite nano material, which comprises the following steps:
1) mixing the metal organic framework ZIF-8 with the black phosphorus quantum dots and the active ingredients to obtain the metal organic framework ZIF-8 loaded with the black phosphorus quantum dots and the active ingredients;
2) carrying out surface modification on the product prepared in the step 1) by using a hydrophilic high molecular polymer to obtain the composite nano-microsphere.
In yet another aspect, the present invention provides a drug delivery composition comprising the composite nanosphere described above.
In still another aspect, the present invention provides a detection reagent, which comprises the composite nanoparticle.
In still another aspect, the present invention provides the use of the composite nanospheres of the present invention for the preparation of a medicament for the treatment of a respiratory disease.
In still another aspect, the invention provides the use of the composite nanospheres of the present invention as a drug detection reagent for detecting respiratory diseases.
Advantageous effects
1) According to the invention, ZIF-8 is modified by hydrophilic PEG for the first time and is used for increasing the mucus penetrating capability of the composite nano-particles, so that the mucus penetrating capability of the composite nano-particles is improved, and the targeting capability and the capability of penetrating the human body physiological barrier obstruction are improved.
2) According to the invention, the black phosphorus quantum dots and the active ingredients are loaded in the ZIF-8 together, and are converted into heat through an external intervention mode, such as near infrared light conversion irradiation, so that the nano microsphere structure is damaged to promote the ZIF-8 to release the active ingredients, the effect of actively selecting release time and release positions can be realized, and active targeting and accurate release are realized.
3) The components of the nano material are mutually matched, have synergistic interaction and can efficiently play the role of drug therapy; the nanosphere has good drug loading capacity and wide application range, can load various therapeutic drugs, can improve the therapeutic effect of the drugs and reduce adverse toxic and side effects; and has good biocompatibility.
Drawings
FIG. 1 is a scanning electron microscope image of PEG-modified composite nanospheres loaded with black phosphorus quantum dots and a therapeutic agent of a metal organic framework ZIF-8 according to example 1 of the present invention;
FIG. 2 is a scanning electron microscope image of a metal organic framework ZIF-8 nanosphere of example 4 of the present invention;
FIG. 3 is a scanning electron microscope image of PEG-modified composite nanospheres of metal organic frameworks ZIF-8 loaded with black phosphorus quantum dots and therapeutic drugs in example 2 of the present invention;
FIG. 4 is a schematic representation of each sample dispersed in PBS buffer for 5 h; a is the metal organic framework ZIF-8 of example 4; b is a therapeutic agent DOX; c is black phosphorus, d is the PEG-modified black phosphorus quantum dot-coated ZIF-8 composite nanosphere prepared in example 3; e is the PEG-modified ZIF-8 composite nano-microsphere wrapping the black phosphorus quantum dots and the therapeutic drug DOX prepared in the embodiment 1;
FIG. 5 is an observation of the ability of each sample to penetrate the artificial mucus layer at different time periods; a is the metal organic framework ZIF-8 of example 4, b is the metal organic framework ZIF-8 modified by PEG of example 5, c is the metal organic framework ZIF-8 loaded with the black phosphorus quantum dot and the therapeutic drug of example 6, d is the metal organic framework ZIF-8 modified by PEG and loaded with the black phosphorus quantum dot and the therapeutic drug of example 1;
FIG. 6 is a comparison of release efficiency of PEG-modified ZIF-8 composite nanospheres encapsulating black phosphorus quantum dots and therapeutic agent DOX without or with near infrared laser irradiation at different time periods;
FIG. 7 is a graph showing the inhibitory effect of each sample on Escherichia coli by plate counting; a is a blank control group; b is the metal organic framework ZIF-8 of example 4; c is a metal organic framework ZIF-8 modified by PEG and loaded with the black phosphorus quantum dots and the therapeutic drugs in the embodiment 1; d is the metal organic framework ZIF-8+ near infrared ray modified by PEG and loaded with the black phosphorus quantum dots and the therapeutic drugs in the embodiment 1And (5) laser illumination. The near infrared laser illumination condition is that 808 nanometer laser (1W/cm) is used2) Irradiating for 10 minutes;
FIG. 8 is a graph showing the inhibitory effect of each sample on Staphylococcus aureus, as observed by plate counting; a is a blank control group; b is the metal organic framework ZIF-8 of example 4; c is a metal organic framework ZIF-8 modified by PEG and loaded with the black phosphorus quantum dots and the therapeutic drugs in the embodiment 1; d is the metal organic framework ZIF-8+ near infrared laser illumination modified by PEG and loaded with the black phosphorus quantum dots and the therapeutic drugs in the embodiment 1. The near infrared laser illumination condition is that 808 nanometer laser (1W/cm) is used2) Irradiating for 10 minutes;
FIG. 9 is a graph showing the biocompatibility of each sample with Hok cells observed using a live/dead cell staining kit (a is a blank control group, b is black phosphorus, c is a metal organic framework ZIF-8, and d is a PEG-modified black phosphorus quantum dot-encapsulated ZIF-8 composite nanosphere); the scale size in the figure is 10 μm;
FIG. 10 is a graph showing the biocompatibility of each sample with Cal-27 cells observed using a live/dead cell staining kit (a is a blank control group, b is black phosphorus, c is a metal organic framework ZIF-8, and d is a PEG-modified black phosphorus quantum dot-encapsulated ZIF-8 composite nanosphere); the scale size in the figure is 10 μm.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below, but the present invention is not to be construed as being limited to the implementable range thereof.
The specific embodiment of the invention provides a composite nano microsphere, which comprises a metal organic framework ZIF-8 and a hydrophilic high molecular polymer modified on the surface of the metal organic framework ZIF-8, wherein the metal organic framework ZIF-8 is loaded with black phosphorus quantum dots and active ingredients, and the hydrophilic high molecular polymer is selected from polyethylene glycol (PEG).
In some embodiments of the invention, the particle size of the composite nanospheres is 50-1000nm, preferably 50-300nm, such as 50nm, 70nm, 100nm, 150nm, 180nm, 200nm, 220nm, 250nm or 300 nm. The composite nano-microsphere has the defects that the nano-performance is reduced due to overlarge particle size, the capability of penetrating through a biological barrier is reduced, the insufficient penetrating capability of the prepared nano-medicament is quickly eliminated by an organism due to the overlarge particle size, and the medicament effect is poor.
In some embodiments of the invention, the polyethylene glycol has a molecular weight of 1000-3000kD, preferably 1500-2500 kD.
In some embodiments of the invention, the black phosphorus quantum dots have a particle size of 2-10nm, such as 2nm, 3nm, 4 nm, 5nm, 6nm, 7nm, 8nm, 9nm, or 10nm, and the like. The reason that the particle size of the black phosphorus quantum dot is selected to be 2-10nm is that the size of the black phosphorus quantum dot needs to have better stability and quantum dot effect in the interval.
In some embodiments of the present invention, the mass ratio of the black phosphorus quantum dots to the metal organic framework ZIF-8 is 1:4 to 10, preferably 1:5 to 8.
In some embodiments of the invention, the mass ratio of active ingredient to metal-organic framework ZIF-8 is comprised between 1:4 and 12, preferably between 1:5 and 10.
In some embodiments of the invention, the active ingredient is any ingredient having a therapeutic or prophylactic effect, including, but not limited to, antineoplastic agents, antibiotic agents, antiviral agents, hormones, agents that act on respiratory diseases. The anti-tumor drug is preferably a chemical drug affecting DNA structure, such as adriamycin (DOX), alkylating drugs, interfering transcription and protein drugs.
In some embodiments of the present invention, the composite nanoparticle may further label a label selected from a fluorescent molecule selected from Fluorescein Isothiocyanate (FITC), rhodamine, and the like. The nanosphere can be positioned, traced, observed, detected in concentration and the like through the surface mark.
The specific embodiment of the invention also provides a preparation method of the composite nano microsphere, which comprises the following steps:
1) mixing the metal organic framework ZIF-8 with the black phosphorus quantum dots and the active ingredients to obtain a metal organic framework ZIF-8 aqueous solution loaded with the black phosphorus quantum dots and the active ingredients;
2) carrying out surface modification on the product prepared in the step 1) by using a hydrophilic high molecular polymer to obtain composite nano microspheres;
the hydrophilic high molecular polymer is selected from polyethylene glycol.
In some embodiments of the present invention, the surface modification method in step 2) includes adding a hydrophilic high molecular polymer to the aqueous solution obtained in step 1), mixing uniformly, and centrifuging to remove excess hydrophilic high molecular polymer.
In some embodiments of the present invention, in step 2), the hydrophilic high molecular weight polymer is added to the aqueous solution obtained in step 1) in a concentration of excess PEG, preferably 4mg/mL or more.
The metal organic framework ZIF-8 used in the present invention is a metal organic framework material having a zeolite framework structure, which is the most important of zeolitic imidazolate framework materials (ZIFs). The transition metal in the zeolite imidazole ester framework material is Zn, and imidazole or imidazole derivatives are organic connecting ligands. The imidazole ester is a five-membered ring with conjugated property, and forms an M-Im-M bond angle close to 145 degrees by losing a proton energy and a metal ion ligand, and the connection mode of the imidazole ester is just corresponding to the Si-O-Si structure in the traditional zeolite. The ZIF-8 used in the present invention can be obtained by any method known in the art.
In some embodiments of the present invention, the metal organic framework ZIF-8 is obtained by dissolving a zinc salt and an imidazolyl ligand, respectively, and mixing the imidazolyl ligand solution and the zinc salt ligand solution, and separating the precipitate.
In some preferred embodiments of the present invention, the zinc salt used in the process for preparing the metal-organic framework ZIF-8 is selected from the group consisting of zinc nitrate, zinc nitrate hexahydrate, zinc acetate, zinc sulfate, preferably zinc nitrate, zinc nitrate hexahydrate.
In some preferred embodiments of the present invention, the imidazolyl ligand used in the preparation of the metal organic framework ZIF-8 is selected from the group consisting of 2-methylimidazole.
In some preferred embodiments of the present invention, the solvent used in the process of preparing the metal organic framework ZIF-8 is anhydrous methanol, anhydrous ethanol or anhydrous propanol.
In some preferred embodiments of the invention, the molar ratio of zinc salt to imidazolyl ligand is 20 to 50:1, preferably 30 to 40: 1.
Preferably, in the process of preparing the metal organic framework ZIF-8, the concentration of ZIF-8 in the metal organic framework ZIF-8 solution is 20-32mg/mL, such as 20mg/mL, 22mg/mL, 24mg/mL, 26mg/mL, 28mg/mL, 30mg/mL, 32mg/mL, and the like.
The concentration of the ZIF-8 can influence the preparation of the metal organic framework ZIF-8, and the reason why the concentration is selected to be within the range of 20-32mg/mL is that the concentration is higher than the concentration value, the nano particles are agglomerated, the dispersibility of the nano particles in the solution is poor, and the concentration lower than the concentration value is not favorable for the formation of the nano particles by the metal organic framework ZIF-8.
In some embodiments of the invention, the black phosphorus quantum dots are prepared by methods known in the art or are commercially available.
In some embodiments of the present invention, the black phosphorus quantum dots are obtained by grinding the black phosphorus blocks in a vacuum environment, dispersing the ground black phosphorus blocks in a first organic solvent, mixing the dispersion with a second organic solvent and sodium hydroxide, heating, cooling, centrifuging the mixture, and collecting the supernatant to obtain the black phosphorus quantum dot dispersion.
Preferably, the particle size of the black phosphorus block is 10-200 μm, such as 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, or 200 μm.
Preferably, the first organic solvent includes any one of N-methylpyrrolidone, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, methanol, isopropanol, chloroform, or dichloromethane, or a combination of at least two thereof, such as a combination of N-methylpyrrolidone and dimethylformamide, a combination of dimethylsulfoxide and tetrahydrofuran, a combination of methanol and isopropanol, and the like.
Preferably, the concentration of the dispersion is 3-4mg/mL, such as 3mg/mL, 3.2mg/mL, 3.4mg/mL, 3.5 mg/mL, 3.6mg/mL, 3.7mg/mL, 3.8mg/mL, or 4 mg/mL.
Preferably, the second organic solvent is N-methylpyrrolidone.
Preferably, the heating temperature is 100-.
Preferably, the heating time is 18-24h, such as 18h, 19h, 20h, 21h, 22h, 23h or 24 h.
Preferably, said cooling means cooling to 16-24 ℃, such as 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃ or 24 ℃.
In still another aspect, the present invention provides a use of the composite nanosphere of the present invention in preparation of a medicament for treating respiratory diseases.
In still another aspect, the present invention provides a use of the composite nanoparticle of the present invention as a drug detection reagent for detecting respiratory diseases.
Example 1 PEG-modified and Black phosphorus Quantum dots and therapeutic drug loaded Metal organic frameworks ZIF-8
The embodiment provides a composite nano microsphere, which takes a metal organic framework ZIF-8 as a main body of the nano microsphere, the composite nano microsphere is internally wrapped with black phosphorus quantum dots and therapeutic drugs, and the surface of the composite nano microsphere is modified by PEG. The preparation method comprises the following steps:
(1) grinding block black phosphorus with the particle size of 80 mu m in a vacuum environment, dispersing the ground block black phosphorus into a mixed solvent of N-methyl pyrrolidone and dimethylformamide, mixing a dispersion liquid with the concentration of 2mg/mL with the N-methyl pyrrolidone and sodium hydroxide, heating the mixed liquid at 130 ℃ for 18 hours, cooling to 24 ℃, centrifuging, and collecting a supernatant to obtain a black phosphorus quantum dot dispersion liquid;
(2) the preparation method of the metal organic framework ZIF-8 comprises the following steps: 0.31g of zinc nitrate hexahydrate was weighed out and completely dissolved in 5mL of anhydrous methanol. 3g (48.72mmol/L) of 2-methylimidazole are accurately weighed out and dissolved in another 8ml portion of anhydrous methanol, and the solution is dropped into the former portion of methanol solution and stirred at room temperature for 10 min. The resulting white precipitate was washed 3 times with anhydrous methanol and deionized water, respectively, and centrifuged in a centrifuge at 9000 rpm. Drying the obtained white solid in a vacuum drying oven;
(3) mixing the metal organic framework ZIF-8 prepared in the step (2) with prepared black phosphorus quantum dots and treatment drug adriamycin (DOX), adding the mixture into a 20mL glass bottle, and stirring for reaction to obtain a composite nano material of the metal organic framework ZIF-8 loaded with the black phosphorus quantum dots and the treatment drug, wherein the mass ratio of the black phosphorus quantum dots to the metal organic framework ZIF-8 is 1:6 after mixing; the mass ratio of the adriamycin to the metal organic framework ZIF-8 is 1: 7.5.
(4) Modifying the composite nano material obtained in the step 3) with PEG, wherein the molecular weight of PEG is 2000KD, the feeding ratio of PEG to the composite nano material is 5mg/mL, namely, excessive PEG is added, and after the PEG is uniformly mixed, the PEG is centrifuged for 3 minutes at 8000r/min and is washed by deionized water to remove the unmodified PEG.
Example 2 PEG-modified Metal organic framework ZIF-8 loaded with Black phosphorus Quantum dots and therapeutic drugs
A metal organic framework ZIF-8 nano microsphere is prepared, and the preparation method is only different from that of the example 1 in that in the step (2), 0.31g of zinc nitrate hexahydrate is replaced by 0.2g of zinc nitrate, and the rest is kept unchanged.
Example 3 PEG-modified Black phosphorus Quantum dot-Supported Metal organic framework ZIF-8
A metal organic framework ZIF-8 nanosphere was prepared, and the preparation method thereof was different from example 1 only in that the therapeutic agent in step (3) was omitted.
EXAMPLE 4 Metal organic framework ZIF-8
A metal organic framework ZIF-8 nano microsphere is prepared only by adopting the step (2) in the example 1.
Example 5 PEG-modified Metal organic framework ZIF-8
Preparing a metal organic framework ZIF-8 nano microsphere,
(1) grinding block black phosphorus with the particle size of 80 mu m in a vacuum environment, dispersing the ground block black phosphorus into a mixed solvent of N-methyl pyrrolidone and dimethylformamide, mixing a dispersion liquid with the concentration of 2mg/mL with the N-methyl pyrrolidone and sodium hydroxide, heating the mixed liquid at 130 ℃ for 18 hours, cooling to 24 ℃, centrifuging, and collecting a supernatant to obtain a black phosphorus quantum dot dispersion liquid;
(2) the preparation method of the metal organic framework ZIF-8 comprises the following steps: 0.31g of zinc nitrate hexahydrate was weighed out and dissolved completely in 5mL of anhydrous methanol. 3g (48.72mmol/L) of 2-methylimidazole are accurately weighed out and dissolved in another 8ml portion of anhydrous methanol, and the solution is dropped into the former portion of methanol solution and stirred at room temperature for 10 min. The resulting white precipitate was washed 3 times with anhydrous methanol and deionized water, respectively, and centrifuged in a centrifuge at 9000 rpm. Drying the obtained white solid in a vacuum drying oven; obtaining the metal organic framework ZIF-8.
(3) Modifying metal organic framework ZIF-8 with PEG, wherein the molecular weight of the PEG is 2000KD, the feeding ratio of the PEG to the metal organic framework ZIF-8 is 5mg/mL, after the PEG is uniformly mixed, centrifuging at 8000r/min for 3 minutes, and cleaning with deionized water to remove the unmodified PEG.
Example 6 Metal organic framework ZIF-8 loaded with Black phosphorus Quantum dots and therapeutic drugs
Prepared by the steps (1) to (3) in example 1.
Example 7 scanning Electron microscopy and Dispersion testing
In this embodiment, a scanning electron microscope is used to observe the composite nano-microsphere prepared by the present invention and morphological characteristics thereof during cracking. Scanning electron microscope observation is performed on the PEG-modified ZIF-8 composite nanospheres wrapping the black phosphorus quantum dots and the therapeutic drug DOX prepared in examples 1 and 2, as shown in FIG. 1 and FIG. 3. FIG. 2 is a metal organic framework ZIF-8 nanosphere of example 4.
As can be seen from fig. 1-3: the particle size of the prepared nanosphere is about 100-350nm, and after the black phosphorus quantum dots and the therapeutic drugs are encapsulated, the surface modification is carried out through PEG, so that the particle size and the shape of the nanosphere are not obviously changed.
Each sample was dispersed in PBS buffer, and the mixture was allowed to stand for 5 hours and then observed. The results are shown in FIG. 4, wherein a is the metal organic framework ZIF-8 of example 4; b is a therapeutic agent DOX; c is a black phosphorus quantum dot, d is the PEG-modified black phosphorus quantum dot-coated ZIF-8 composite nanosphere prepared in example 3; e is the PEG-modified ZIF-8 composite nano-microsphere wrapping the black phosphorus quantum dots and the therapeutic drug DOX prepared in the embodiment 1;
as can be seen from fig. 4: in phosphate buffer solution, the prepared composite nano-microsphere has good dispersion performance, and does not generate agglomeration even under high concentration.
Example 8 testing of the ability to penetrate the mucus barrier
Simulating a human mucus barrier in vitro, and detecting the capability of the prepared composite nano-microsphere to permeate the mucus barrier. Wherein, the in vitro simulated human mucus is prepared by mixing mucus, DNA and yolk emulsion in water solution to obtain artificial mucus, and placing on solidified agarose gel. Meanwhile, dyeing the prepared sample by using Coomassie brilliant blue dye, then carefully adding the sample to the surface of the artificial mucus layer respectively, and observing the capability of the nano microspheres for penetrating into the mucus layer at different time periods.
The experimental groups were respectively: a: example 4 metal organic framework ZIF-8, b: example 5 PEG-modified metal organic framework ZIF-8, c: example 6 metallo-organic framework ZIF-8, d: example 1 PEG-modified and black phosphorus quantum dots and therapeutic drug loaded metal organic frameworks ZIF-8.
The experimental results are shown in fig. 5 and 6, and the experimental results show that the PEG modification can reduce the surface charge of the nanospheres, prevent the nanospheres from adsorbing mucus, have mucus inertia, obviously improve the ability of the nanospheres to penetrate through a mucus layer, and can quickly penetrate through the mucus layer. As shown in fig. 5, both the PEG-modified ZIF-8 composite nanospheres and the PEG-modified black phosphorus quantum dot-coated ZIF-8 composite nanospheres showed stronger mucus layer permeability. After the nano-microspheres penetrate through the mucus layer, the loaded drugs can be released in a short time through near infrared light irradiation. As shown in figure 6, the PEG-modified ZIF-8 composite nano-microspheres wrapping the black phosphorus quantum dots and the therapeutic drug DOX only release a small amount of DOX drug in the PBS solution, when 808 nanometer laser (1W/cm) is used2) After 5 minutes of irradiation, the black phosphorus quantum dots in the nano-microspheres can quickly convert near-infrared light into heat energy, destroy the ZIF-8 nano-microsphere structure and quickly release the therapeutic drug DOX in the nano-microspheres. The experimental result shows that the maximum-88.2 percent of the therapeutic drug DOX in the nano-microspheres can be irradiated by laser in a single short timeReleasing to realize accurate controlled release of the medicine.
Example 9 evaluation of antibacterial efficacy
In this example, the antibacterial efficacy of the black phosphorus metal organic framework ZIF-8 composite nanomaterial prepared by the present invention was evaluated.
The experimental groups were respectively: a is a blank control group; b is the metal organic framework ZIF-8 of example 4; c is a metal organic framework ZIF-8 modified by PEG and loaded with the black phosphorus quantum dots and the therapeutic drugs in the embodiment 1; d is the metal organic framework ZIF-8+ near infrared laser illumination modified by PEG and loaded with the black phosphorus quantum dots and the therapeutic drugs in the embodiment 1. The near infrared laser irradiation condition is that 808 nanometer laser (1W/cm) is used2) The irradiation was carried out for 10 minutes.
Using Escherichia coli and Staphylococcus aureus as bacterial models, selecting a small amount of bacterial inoculum, adding into a bacterial culture medium containing LB liquid, placing in a shake tube at 37 deg.C, shaking in a 240rmp bacteria constant temperature incubator overnight for culturing, collecting bacteria with a refrigerated centrifuge (5000rmp, 2min), washing the bacteria with sterile normal saline, adjusting the bacteria concentration with normal saline, and detecting with a multifunctional microplate reader to make the bacteria suspension concentration reach OD600 of 0.01 (0.4-0.5). times.106cfu/mL)。
And mixing 100 mu L of each sample with 100 mu L of activated bacterial suspension, uniformly coating the mixture on the surface of a culture dish, uniformly coating the bacterial liquid on the culture dish, placing the culture dish in a bacterial incubator, culturing for 18 hours at 37 ℃ under constant temperature and humidity, and observing the number of bacterial colonies. The light set used 808nm (1W/cm)2) After the near infrared laser irradiates for 10min, the bacterial liquid is evenly coated on a culture dish, the culture dish is placed in a bacterial incubator for culturing for 18h at 37 ℃ under constant temperature and humidity, and the number of colonies is observed. Each sample was replicated 5 times in parallel. Blank control group sample solution was changed to equal volume of saline.
The results of the antimicrobial activity against Escherichia coli in each group are shown in FIG. 7, and the results of the antimicrobial activity against Staphylococcus aureus in each group are shown in FIG. 8, as shown in FIGS. 7 and 8: the metal organic framework ZIF-8 nano microspheres and the metal organic framework ZIF-8 nano microspheres wrapped with the black scale quantum dots in the reference blank control group have weak antibacterial ability to escherichia coli and staphylococcus aureus, but the antibacterial effect is obviously improved after the near-infrared laser irradiation is used. The result shows that the metal organic framework ZIF-8 can release active ingredients therein after being irradiated by infrared laser, and the fixed-point release effect is realized.
Example 10 evaluation of biocompatibility
In this example, biocompatibility evaluation is performed on the prepared PEG-modified black phosphorus quantum dot-coated ZIF-8 composite nanoparticle.
The experimental groups were respectively: a is a blank control group, b is black phosphorus quantum dots, c is a metal organic framework ZIF-8, d is the metal organic framework ZIF-8 modified by PEG and loaded with the black phosphorus quantum dots and the treatment drugs in the embodiment 1
The specific operation is as follows:
the biocompatibility of the nanosphere is detected by a live/dead cell staining kit (Calcein AM/PI), the characteristic that Calcein AM is an excellent fluorescent staining agent for live cells and can easily penetrate through the live cells is utilized, and when the Calcein AM reaches the cells, the Calcein AM can be hydrolyzed by esterase to be Calcein which is remained in the cells and shows strong green fluorescence; propidium Iodide (PI) in the kit cannot cross live cell membranes, but can cross disordered regions of dead cell membranes to reach cell nuclei, and generates red fluorescence (excitation wavelength of 535nm and emission wavelength of 617nm) after being embedded into DNA helices of cells so that the dead cells show red fluorescence.
Respectively taking oral cancer cells (Cal-27) and epithelial cells (Hok) at logarithmic growth phase at 5 × 104Adding 400 mu L of each well into a 48-well plate, culturing in a cell culture box for 24h, then gently sucking out cell culture medium in each well, adding 400 mu L of cell culture medium containing different components to be tested (metal organic framework ZIF-8, black phosphorus quantum dots and metal organic framework ZIF-8 wrapped with the black phosphorus quantum dots with the concentration of 100 mu g/mL) into the wells, and continuing culturing for 24h, wherein the serum-free culture medium is used as a blank control. The 48-well cell culture plate was removed, the culture medium in the well was aspirated off, the well plate was carefully washed with PBS solution 3 times, then calcein and propidium iodide solutions were added to each well, after incubation for 20 minutes in an incubator, the dye was aspirated off, carefully washed with PBS solution 3 times, and then placed under a fluorescence microscope for observation.
As shown in fig. 9 and 10, all the samples incubated with the cells exhibited strong green fluorescence compared to the blank control group, indicating that each sample had good biocompatibility, no significant cytotoxicity was detected after 24h incubation of oral cancer cells (Cal-27) at a concentration of 100 μ g/mL, and no significant cytotoxicity was detected even after 24h incubation of epithelial cells (Hok) at a concentration of 100 μ g/mL.
The applicant states that the composite nano-microspheres with rapid mucus penetration and drug delivery controlled release effects and the preparation method and application thereof are illustrated by the above examples, but the invention is not limited to the above examples, and equivalent substitutions of raw materials of the product of the invention, addition of auxiliary components, selection of specific modes and the like fall within the protection scope and the disclosure scope of the invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

Claims (17)

1. The composite nano-microsphere comprises a metal organic framework ZIF-8 and a hydrophilic high molecular polymer modified on the surface of the metal organic framework ZIF-8, wherein the metal organic framework ZIF-8 is loaded with black phosphorus quantum dots and active ingredients, and the hydrophilic high molecular polymer is selected from polyethylene glycol;
the preparation method of the composite nano-microsphere comprises the following steps:
1) mixing the metal organic framework ZIF-8 with the black phosphorus quantum dots and the active ingredients to obtain a metal organic framework ZIF-8 aqueous solution loaded with the black phosphorus quantum dots and the active ingredients;
2) carrying out surface modification on the product prepared in the step 1) by using a hydrophilic high molecular polymer to obtain composite nano microspheres;
the hydrophilic high molecular polymer is selected from polyethylene glycol;
the surface modification method in the step 2) comprises the steps of adding a hydrophilic high molecular polymer into the aqueous solution obtained in the step 1), uniformly mixing, and centrifuging to remove the redundant hydrophilic high molecular polymer to obtain the water-soluble polyurethane resin;
in the step 2), the hydrophilic high molecular polymer is added into the aqueous solution obtained in the step 1), wherein the concentration of the PEG is excessive and is more than 4 mg/mL.
2. The composite nanosphere of claim 1, wherein the particle size of the composite nanosphere is from 50 to 1000 nm.
3. The composite nanosphere of claim 2, wherein the particle size of the composite nanosphere is from 50 to 300 nm.
4. The composite nanoparticle of claim 1, wherein the molecular weight of the polyethylene glycol is 1000-3000 KD.
5. The composite nanosphere of claim 4, wherein the molecular weight of said polyethylene glycol is 1500-.
6. The composite nanosphere of claim 1, wherein the mass ratio of the black phosphorus quantum dots to the metal organic framework ZIF-8 is 1: 4-10.
7. The composite nanosphere of claim 6, wherein the mass ratio of the black phosphorus quantum dots to the metal organic framework ZIF-8 is 1: 5-8.
8. The composite nanosphere of claim 1, wherein the mass ratio of the active ingredient to the metal organic framework ZIF-8 is 1: 4-12.
9. The composite nanosphere of claim 8, wherein the mass ratio of the active ingredient to the metal organic framework ZIF-8 is 1: 5-10.
10. The composite nano-microsphere according to claim 1, wherein the active ingredient is any ingredient having therapeutic or prophylactic effect, including but not limited to antineoplastic drugs, antibiotic drugs, antiviral drugs, hormones, chemical drugs acting on respiratory diseases.
11. The composite nanoparticle of claim 10, wherein the anti-tumor drug is a chemical drug affecting DNA structure, alkylating drug, interfering transcription drug, or protein drug.
12. The composite nanosphere of claim 11, wherein said DNA structure affecting chemical agent is doxorubicin.
13. A method of preparing composite nanospheres according to any of claims 1-12 comprising the steps of:
1) mixing the metal organic framework ZIF-8 with the black phosphorus quantum dots and the active ingredients to obtain a metal organic framework ZIF-8 aqueous solution loaded with the black phosphorus quantum dots and the active ingredients;
2) carrying out surface modification on the product prepared in the step 1) by using a hydrophilic high molecular polymer to obtain composite nano microspheres;
the hydrophilic high molecular polymer is selected from polyethylene glycol;
the surface modification method in the step 2) comprises the steps of adding a hydrophilic high molecular polymer into the aqueous solution obtained in the step 1), uniformly mixing, and centrifuging to remove the redundant hydrophilic high molecular polymer to obtain the water-soluble polyurethane resin;
in the step 2), the hydrophilic high molecular polymer is added into the aqueous solution obtained in the step 1), wherein the concentration of the PEG is excessive and is more than 4 mg/mL.
14. Use of the composite nanospheres of any of claims 1-12 in the preparation of a medicament for treating a respiratory disease or in the preparation of a detection reagent for detecting a respiratory disease.
15. A drug delivery composition comprising the composite nanosphere of any of claims 1-12.
16. A detection reagent comprising the composite nanosphere of any of claims 1-12.
17. The detection reagent of claim 16, wherein the composite nanoparticle is labeled with a label selected from fluorescent molecules.
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