CN113855815B - Zinc-containing metal organic framework coated manganese dioxide nanocomposite and preparation and application thereof - Google Patents

Zinc-containing metal organic framework coated manganese dioxide nanocomposite and preparation and application thereof Download PDF

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CN113855815B
CN113855815B CN202111097053.6A CN202111097053A CN113855815B CN 113855815 B CN113855815 B CN 113855815B CN 202111097053 A CN202111097053 A CN 202111097053A CN 113855815 B CN113855815 B CN 113855815B
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zif
zinc
deionized water
manganese dioxide
containing metal
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CN113855815A (en
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刘锡建
管少琪
王星妍
王金霞
张子文
曹东苗
王香
陆杰
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Shanghai University of Engineering Science
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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
    • A61K47/6949—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
    • 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
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    • 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
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    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K49/00—Preparations for testing in vivo
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
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    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/008—Supramolecular polymers

Abstract

The invention relates to a zinc-containing metal organic frame coated manganese dioxide nanocomposite and preparation and application thereof, wherein the preparation process of the composite is as follows: (1) ZIF-90 formed by complexing Zn ions serving as nodes and imidazole-2-formaldehyde serving as an organic ligand; (2) MnO is reacted by oxidation reduction 2 Coating the product on the outer layer to obtain the target product. The zinc-containing metal organic framework coated manganese dioxide nanocomposite material prepared by the invention has a porous dodecahedron structure, provides a space for effectively delivering Doxorubicin (DOX) to tumor tissues, not only can integrate the enhancement of sound dynamics treatment under oxidative stress and the overcoming of chemical resistance of chemical treatment drugs into a whole, realize the cooperative treatment of cancer by sound dynamics treatment/chemical treatment, but also can be used as a contrast agent of MR; in addition, the composite material has double sensitive degradation effects on weak acid environment of tumors and under ultrasonic irradiation, can reduce the long-term toxicity of the composite material to organisms, and has wide application prospect in the field of biomedicine.

Description

Zinc-containing metal organic framework coated manganese dioxide nanocomposite and preparation and application thereof
Technical Field
The invention belongs to the technical field of nano composite particles, and relates to a manganese dioxide nano composite material coated by a zinc-containing metal organic framework, and preparation and application thereof.
Background
With the increasing incidence of cancer worldwide, traditional methods of treatment have failed to meet the clinical needs of patients. For example, multidrug resistance of cancer cells is a major cause of chemotherapy failure (H Wang, Z Gao, X Liu, P Agarwal, S Zhao, D W Conroy, G Ji, J Yu, C P Jaronic, Z Liu, et al, targeted production of reactive oxygen species in mitochondria to overcome cancer drug resistance, nature Communications 2018,9,562), and recognition of P-glycoproteins and other related transporters on the plasma membranes of some cancer cells. These transporters can recognize and catalyze various anticancer drugs and expel them outside the cancer cells. While ATP is indispensable for the transporter. ATP is synthesized by ATP synthase driven by an intra-mitochondrial proton concentration gradient, which is produced by an Electron Transport Chain (ETC), zn 2+ The failure of the transporter by the lack of ATP supply can be overcome by inhibiting ETC (Y Liu, Y Wang, W Zhen, Y Wang, S Zhang, Y Zhao, S Song, Z Wu, H Zhang. Defect modified zinc oxide with augmenting sonodynamic reactive oxygen species generation. Biomaterials 2020,251,120075.). In addition, due to high tumor specificity and low treatment depth limitations, sonodynamic therapy (SDT) is increasingly being investigated as an emerging non-invasive tumor treatment strategy, however, common organic sonosensitizers (such as porphyrins and their derivatives) have severe skin photosensitivity, low chemical/biological stability and poor tumor aggregation (D Wang, D-B Cheng, L Ji, L-J Niu, X-H Zhang, Y Cong, R-H Cao, L Zhou, F Bai, Z-Y Qiao, et al, precise magnetic resonance imaging-guided sonodynamic therapy for drug-resistant bacterial deep in section.biomaterials 2021,264,120386.). Inorganic sonosensitizers such as commonly used semiconducting titanium dioxide (TiO 2) also suffer from poor biodegradability, relatively low ROS quantum yield, poor biocompatibility, and the like (X Wang, X Wang, X Zhong, G Li, Z Yang, Y Gong, Z Liu, L Cheng.V-TiO2 nanospindles with regulating tumor microenvironment performance for enhanced sonodynamic cancer therapy.Applied Physics Reviews 2020,7,041411.)。
Whereas Zn is to 2+ And MnO 2 The combination therapy for enhancing SDT and inhibiting multidrug resistance under amplified oxidative stress has not been reported. The present invention has been made based on this.
Disclosure of Invention
The invention aims to provide a zinc-containing metal organic framework coated manganese dioxide nanocomposite, and preparation and application thereof, so as to solve the defects that SDT efficiency is low, drug resistance of cancer cells to a chemotherapeutic drug Doxorubicin (DOX) is low, and/or imaging guided cooperative treatment is difficult to realize in the prior art.
The aim of the invention can be achieved by the following technical scheme:
one of the technical proposal of the invention provides a zinc-containing metal organic framework coated manganese dioxide nanocomposite material which comprises ZIF-90 and MnO deposited on the ZIF-90 2 A mesoporous dodecahedron structure is formed.
Further, the average particle diameter of the composite material is 160-200nm.
Further, the preparation process of the ZIF-90 nano particles specifically comprises the following steps:
(A) Zn (NO) 3 ) 2 4H 2 O is dissolved in tertiary butanol and deionized water to obtain solution A;
(B) PVP and imidazole-2-formaldehyde are dissolved in glycerin and deionized water, and the temperature is raised and maintained to obtain a solution B.
(C) Rapidly adding the solution A into the solution B, stirring vigorously, maintaining at normal temperature, centrifuging, washing, and drying to obtain ZIF-90 nanoparticles;
further, zn (NO 3 ) 2 4H 2 The addition amount ratio of the sum of O, tertiary butanol and deionized water (the volume ratio of the O to the tertiary butanol is 1:0.8-1.2, and the preferred volume ratio is 1:1) is (350-400) mg: (15-25) mL. .
In the step (B), PVP, imidazole-2-formaldehyde and the sum of glycerol and deionized water (the volume ratio of the PVP to the imidazole-2-formaldehyde is 1:0.8-1.2, and the preferable ratio of the added amount of the glycerol to the deionized water is 1:1) are (20-70) mg: (450-550) mg: (15-25) mL.
In the step (B), after dispersing the raw materials in glycerol and deionized water, heating to 50-70 ℃ and keeping for 30-60 min, and cooling to normal temperature after uniform dispersion to obtain the solution B.
In the step (C), the process conditions maintained at normal temperature are as follows: the temperature is 25 ℃, the intense stirring rotating speed is 900rpm/min, and the stirring time is 1-30 min. Meanwhile, the addition amounts of the solution A and the solution B satisfy the following conditions: zn (NO) 3 ) 2 .4H 2 The mass ratio of O to PVP is (350-400): (20-70).
The second technical proposal of the invention provides a preparation method of the manganese dioxide nanocomposite coated by the zinc-containing metal organic framework, which is characterized in that ZIF-90 nano particles are firstly taken and dissolved in deionized water, and KMnO is added dropwise 4 And (5) stirring the aqueous solution to obtain the target product. In the invention, aldehyde groups and KMnO on ZIF-90 nano particles 4 And carrying out oxidation-reduction reaction to obtain the manganese dioxide nanocomposite coated with the zinc-containing metal organic framework. The material has a porous dodecahedron structure and can be loaded with a chemotherapeutic drug doxorubicin. In addition, ZIF-90 nanoparticles, KMnO 4 And deionized water are limited in addition amount, temperature and stirring time, so that MnO with uniform load can be obtained 2 Dodecahedron structure, too high temperature and over reaction when the maintaining time is more than 2h, resulting in collapse of dodecahedron structure, mnO when the maintaining time is less than 0.5h 2 The form wrapping was unsuccessful.
Further, ZIF-90, KMnO 4 And deionized water in an amount of (5-10) mg: (1-5) mg: (5-10) mL.
Further, ZIF-90 and KMnO 4 The stirring reaction process is carried out at normal temperature, and the stirring time is 0.5-2 h.
Further, the preparation process of the ZIF-90 nano particles specifically comprises the following steps:
(1) Zn (NO) 3 ) 2 4H 2 O is dissolved in a mixed solvent consisting of tertiary butanol and deionized water to obtain a solution A;
(2) PVP and imidazole-2-formaldehyde are dissolved in glycerin and deionized water, and the temperature is raised to obtain a solution B.
(3) And (3) rapidly adding the solution A into the solution B, stirring, maintaining at normal temperature, centrifuging, washing and drying to obtain the ZIF-90 nano particles.
Further, in the step (1), zn (NO 3 ) 2 .4H 2 The ratio of the addition amount of O to the mixed solvent is (350-400) mg: (15-25) mL;
further, in the step (1), the volume ratio of the tertiary butanol to the deionized water in the mixed solvent is 1:0.8-1.2, preferably 1:1.
Further, in the step (2), the mass ratio of PVP to imidazole-2-formaldehyde is (20-70): (450-550).
Further, in the step (2), the volume ratio of the glycerol to the deionized water is 1:0.8-1.2, preferably 1:1.
Further, in the step (2), the heating process is specifically: heating to 50-70 deg.c for 30-60 min. Because imidazole-2-formaldehyde cannot be uniformly dispersed in the room temperature environment, most of imidazole-2-formaldehyde ligand deposition cannot be reacted, and the obtained ZIF-90 is oversized and nonuniform in size.
Further, in the step (3), the addition amounts of the solution a and the solution B satisfy: zn (NO) 3 ) 2 .4H 2 The mass ratio of O to PVP is (350-400): (20-70).
During the reaction, zn (NO 3 ) 2 4H 2 The amounts of O, imidazole-2-carbaldehyde, PVP and solvent added are limited to obtain nanoparticles with a particle size of about 160-200nm, and the particle size is increased by excessive temperature and prolonged stirring.
The third technical scheme of the invention provides application of the manganese dioxide nanocomposite coated by the zinc-containing metal organic framework, and the composite can be used for preparing an anticancer drug release carrier. Preferably, the corresponding anticancer drug may be doxorubicin.
The invention also provides application of the zinc-containing metal organic framework coated manganese dioxide nanocomposite in enhancing acoustic dynamic treatment under oxidative stress, overcoming chemical resistance of chemotherapeutic drugs, dual sensitive degradation in weak acid environment of tumor and ultrasonic irradiation or MR imaging.
The invention firstly passes through Zn 2+ Complexing with imidazole-2-formaldehyde to prepare ZIF-90 dodecahedron mesoporous structure, and then oxidizing and reducing MnO based on ZIF-90 2 Coating the zinc-containing metal organic frame coated manganese dioxide nano composite material on the outer layer. The material has a porous dodecahedron structure, and can provide space for effectively delivering Doxorubicin (DOX) to tumor tissues; the composite material can release a large amount of DOX and simultaneously release Zn under the double degradation of weak acid environment of tumor and ultrasonic irradiation 2+ And MnO 2 。MnO 2 Catalytic H 2 O 2 Can produce O 2 Overcoming tumor hypoxia environment for enhancing SDT effect, and generating Mn 2+ Not only can oxidize GSH in cells, but also can effectively improve separation of electron holes under US irradiation to enhance SDT. In addition, released Zn 2+ Can inhibit ETC, and can prevent and treat drug resistance due to dysfunction of discharge pump on plasma membrane.
Compared with the prior art, the invention has the following advantages:
(1) The zinc-containing metal organic framework coated manganese dioxide nanocomposite material prepared by the method has a porous structure, and provides a space for effectively delivering Doxorubicin (DOX) to tumor tissues.
(2) The zinc-containing metal organic frame coated manganese dioxide nanocomposite prepared by the method has double sensitive degradation effects under the weak acid environment of tumors and ultrasonic irradiation, and can effectively release DOX and simultaneously release Zn after degradation 2+ And MnO 2 。
(3) The zinc-containing metal organic framework coated manganese dioxide nanocomposite prepared by the invention releases MnO after degradation 2 And H is 2 O 2 Reaction to produce O 2 Can improve hypoxia of Tumor Microenvironment (TME) to enhance SDT, mn formation 2+ Not only can oxidize GSH in cells to enlarge oxidative stress, but also can effectively improve separation of electron holes under US irradiation to enhance SDT.
(4) The zinc-containing metal organic frame coated manganese dioxide nanocomposite prepared by the method has double-dependence degradation on weak acid environment of tumors and under ultrasonic irradiation, so that the toxic and side effects of the nanocomposite on organisms can be reduced.
(5) Zn released by the zinc-containing metal organic framework coated manganese dioxide nanocomposite material prepared by the invention after degradation 2+ Can inhibit ETC, and cause dysfunction of efflux pump on plasma membrane to overcome DOX resistance of cancer cells, thereby effectively killing cancer cells.
(6) The manganese dioxide nanocomposite coated on the zinc metal organic frame prepared by the method can realize the effect of MR imaging guided sound dynamics treatment/chemotherapy synergistic treatment of cancer.
Drawings
FIG. 1 shows ZIF-90 and ZIF-90@MnO according to example 1 of the present invention 2 Scanning electron microscope and transmission electron microscope pictures of the nanocomposite;
FIG. 2 is a schematic diagram of ZIF-90@MnO in example 1 of the present invention 2 Specific surface area and pore size map of nanocomposite;
FIG. 3 is a schematic diagram of ZIF-90@MnO in example 1 of the present invention 2 Element map of nanocomposite;
FIG. 4 shows ZIF-90@MnO in example 1 of the present invention 2 Particle size distribution of the nanocomposite;
FIG. 5 shows ZIF-90@MnO in example 1 of the present invention 2 ROS detection map of nanocomposite;
FIG. 6 is a schematic diagram of ZIF-90@MnO in example 1 of the present invention 2 Reduction map of nanocomposite to GSH;
FIG. 7 is a schematic diagram of ZIF-90@MnO according to example 1 of the present invention 2 An oxygen generation map of the nanocomposite;
FIG. 8 is a schematic diagram of ZIF-90@MnO in example 1 of the present invention 2 A degradation experiment diagram of the nanocomposite;
FIG. 9 is a schematic diagram of ZIF-90@MnO in example 1 of the present invention 2 Zn of nanocomposite 2+ Releasing the graph;
FIG. 10 is a schematic diagram of ZIF-90@Mn in example 1 of the present inventionO 2 Ultraviolet absorbance of the/DOX nanocomposite;
FIG. 11 is a schematic diagram of ZIF-90@MnO in example 1 of the present invention 2 Drug release profile of the/DOX nanocomposite;
FIG. 12 is a schematic diagram of ZIF-90@MnO in example 1 of the present invention 2 Contrast images of pre-and post-DOX nanocomposite injection into mice.
Detailed Description
The invention will now be described in detail with reference to the drawings and specific examples. The present embodiment is implemented on the premise of the technical scheme of the present invention, and a detailed implementation manner and a specific operation process are given, but the protection scope of the present invention is not limited to the following examples.
In the following examples, unless otherwise indicated, the starting materials or processing techniques are all conventional commercially available in the art.
Example 1:
preparation of Zinc-containing Metal organic framework coated manganese dioxide nanocomposite (i.e., ZIF-90@MnO) 2 Nanoparticles
(1) Preparation of ZIF-90 nanoparticles
370mg Zn (NO) 3 ) 2 4H 2 O is dissolved in 20mL of tertiary butanol and deionized water with the volume ratio of 1:1 to obtain a solution for standby; 50mg PVP and 480mg imidazole-2-formaldehyde are taken and dissolved in 20mL of glycerin and deionized water with the volume ratio of 1:1, the temperature is raised to 60 ℃, and the mixture is cooled after being kept for 40 minutes, so as to obtain a solution B. Rapidly adding the solution B into the solution A under intense stirring, maintaining at normal temperature for 10min, centrifuging, washing with methanol for 3 times, and vacuum drying at 60deg.C for 6 hr to obtain ZIF-90 nanoparticles with dodecahedron structure as shown in figure 1 a;
(2) Preparation of ZIF-90@MnO 2 Nanoparticles
Weighing 5mg of ZIF-90 nano particles, dissolving in 5mL of deionized water, dropwise adding 2mg of KMnO4 aqueous solution, stirring at normal temperature of 25 ℃ for 1h, centrifuging, taking precipitate, and respectively ultrasonically washing with ethanol and deionized water for 3 times to obtain a target product (figure 1 b). Testing ZIF-90@MnO 2 The adsorption/desorption isotherms of the nanocomposite appear as typical type IV isotherms,the mesoporous nature is demonstrated. And the specific surface area and the average pore diameter are 282.93m respectively 2 g -1 And 6.933nm, indicating ZIF-90@MnO 2 The nanocomposite has a mesoporous dodecahedron structure and is suitable for drug delivery (fig. 2). ZIF-90@MnO 2 The elemental profile of the nanocomposite showed the presence of Zn, mn, O, C, N (FIG. 3), and dynamic light scattering demonstrated ZIF-90@MnO 2 The size of the nanocomposite material was about 230nm (FIG. 4), which can be an indication of ZIF-90@MnO 2 The nanocomposite material was successfully prepared and the size was uniform.
Example 2
ZIF-90@MnO 2 Determination of ROS in ultrasound of nanocomposite particles
The ZIF-90, ZIF-90@MnO obtained in example 1 was taken 2 1mL of each of (200. Mu.g/mL) and deionized water was placed in 3 10mL centrifuge tubes, and H was added separately 2 O 2 (870. Mu.L, 100 mM) +DPBF (130. Mu.L, 1 mg/mL). The same set (3 centrifuge tubes) was prepared again according to the above procedure, and the two sets were treated by the presence and absence of ultrasound, and the supernatant was removed by centrifugation and its absorption spectrum was measured with an ultraviolet-visible spectrophotometer, monitoring the attenuation trend at 652nm at different time points. As a result, as shown in FIG. 5, ZIF-90@MnO 2 +H 2 O 2 The attenuation trend of the +US group is strongest, indicating ZIF-90@MnO 2 The nanocomposite can generate a large amount of ROS through ultrasonic action.
Example 3
ZIF-90@MnO 2 Consumption experiment of nanocomposite on GSH
ZIF-90, ZIF-90@MnO obtained in example 1 2 Dispersing the nano composite particles in deionized water, and adding PBS (pH 7.4), ZIF-90, ZIF-90@MnO to reduced GSH (1 mL, 2M) respectively 2 (200μg/mL)、H 2 O 2 (200 mM) 1mL each, reacted for 30min, centrifuged to obtain supernatant, 10. Mu.L of DTNB (DMSO, 100 mM) was added, and the mixture was shaken on a shaker for 30min, and the absorbance spectrum at 410nm was detected by ultraviolet. As a result, as shown in FIG. 6, ZIF-90@MnO 2 The result is the same as that of the positive control group, which shows that ZIF-90@MnO 2 GSH can be reduced.
Example 4
ZIF-90@MnO 2 Oxygen production detection of nanocomposite
The ZIF-90@MnO obtained in example 1 was taken 2 (0 or 200. Mu.g/mL), PBS (pH 6.5,2 mL) and H 2 O 2 (1 mL,100 mM) were placed in 50mL centrifuge tubes, respectively, and then stirred at 37℃for 10 minutes. The oxygen content was measured with a dissolved oxygen meter. As a result, as shown in FIG. 7, ZIF-90@MnO 2 Can catalyze H 2 O 2 Generates a large amount of oxygen, indicating ZIF-90@MnO 2 The nanocomposite can relieve hypoxia of tumor microenvironment.
Example 5
ZIF-90@MnO 2 Degradation Properties of nanocomposite
The ZIF-90@MnO obtained in example 1 was taken 2 Dispersed in PBS solution (pH=6.5 and 7.4) and stirred with shaking in a shaker for 8h, respectively, in the presence or absence of ultrasound. ZIF-90@MnO is adopted by a transmission electron microscope 2 The degradation behavior of (2) was evaluated. The results are shown in FIG. 8, where ZIF-90@MnO is present at pH=6.5 2 Gradually crushing, and under the combined action of pH=6.5+US, ZIF-90@MnO 2 More remarkable degradation, indicating ZIF-90@MnO 2 Can be degraded doubly in tumor environment and under US.
Example 6
ZIF-90@MnO 2 Zn released after degradation of nanocomposite 2+ Testing
The ZIF-90@MnO obtained in example 1 was taken 2 Dispersed in PBS solution at pH5.0, 6.5, 7.4, and oscillated at 200 rpm/min. Supernatant obtained by centrifugation at 0,2, 4, 8, 12, 24, 48, 36 and 72h and Zn measured by inductively coupled plasma spectrometry (ICP-OES) 2+ Is released. The results are shown in FIG. 9, where ZIF-90@MnO is present at pH=6.5 2 Releasing more than 50% of Zn 2+ Whereas ZIF-90@mno in ph=5.0 2 98% of Zn is released 2+ Indicating Zn 2+ Can be released in large amounts with multidrug resistance for inhibiting cancer cells.
Example 7
(1) Drug loading
Taking 4mg ZIF-90@MnO obtained in example 1 2 The nanocomposite particles were mixed with 1mL of 1mg/mL DOX and shaken in a shaker at room temperature for 24h. After centrifugation, the centrifuged product was collected and its absorption peak at near infrared was measured by UV-visible spectrophotometer, and the result was shown in FIG. 10, ZIF-90@MnO 2 The nano composite particles have obvious DOX absorption peak at 480 nm.
(2) Drug release
Taking the prepared 4mg ZIF-90@MnO 2 DOX was dispersed in 5mL of PBS (pH 6.5 and 7.4), respectively, and the supernatant was collected for UV measurement of the released drug content at a predetermined time with or without sonication. As a result, as shown in FIG. 11, ZIF-90@MnO 2 The maximum percentage of DOX released by DOX under the irradiation of pH 6.5+US indicates ZIF-90@MnO 2 the/DOX nanocomposite can release the maximum amount of the chemotherapeutic DOX under dual stimulation of tumor environment and US irradiation.
Example 8
ZIF-90@MnO is injected in vivo into HeLa tumor-bearing mice 2 In vivo T1-weighted MRI of/DOX nanocomposite (200. Mu.L, 2 mg/mL) with ZIF-90@MnO injection as shown in FIG. 12 2 The tumor area of the mice after the DOX nano composite material is obviously lightened, which shows that ZIF-90@MnO 2 The DOX nanocomposite has a nuclear magnetic imaging guiding effect.
Comparative example 1:
compared with example 1, the method is largely the same except that MnO in step (2) is omitted 2 Is a load of (a). As shown in FIG. 4, the synthesized ZIF-90@MnO 2 Is much stronger than ZIF-90, proving that ZIF-90@MnO 2 The sound power treatment effect is better. As shown in FIG. 5, ZIF-90@MnO does not significantly affect GSH as compared to ZIF-90 which has the same effect as the negative control 2 GSH can be consumed and MnO as shown in FIG. 6 2 Contribute to the generation of oxygen, all of which indicate MnO obtained in example 1 2 The nanocomposite can amplify oxidative stress for enhancing the photodynamic therapy effect.
Example 8:
multifunctional ZIF-90@MnO 2 A method of preparing a nanocomposite comprising the steps of:
(1) Preparation of ZIF-90 nanoparticles
350mg Zn (NO) 3 ) 2 4H 2 O is dissolved in 15mL of tertiary butanol and deionized water with the volume ratio of 1:1 to obtain a solution for standby; 20mg PVP and 450mg imidazole-2-formaldehyde are taken and dissolved in 15mL of glycerin and deionized water with the volume ratio of 1:1, the temperature is raised to 50 ℃, and the mixture is cooled after being kept for 60 minutes, so as to obtain a solution B. Rapidly adding the solution B into the solution A under intense stirring, maintaining at normal temperature for 1min, centrifuging, washing with methanol for 3 times, and vacuum drying at 60deg.C for 6 hr to obtain ZIF-90 nanoparticles;
(2) Preparation of ZIF-90@MnO 2 Nanoparticles
Weighing 5mg ZIF-90 nanoparticles, dissolving in 5mL deionized water, and dripping 1mg KMnO 4 Stirring the aqueous solution at the normal temperature of 25 ℃ for 2 hours, centrifuging, taking the precipitate, and respectively ultrasonically washing the precipitate with ethanol and deionized water for 3 times to obtain the target product.
Example 9:
multifunctional ZIF-90@MnO 2 A method of preparing a nanocomposite comprising the steps of:
(1) Preparation of ZIF-90 nanoparticles
400mg Zn (NO) 3 ) 2 4H 2 O is dissolved in 25mL of tertiary butanol and deionized water with the volume ratio of 1:1 to obtain a solution for standby; 70mg PVP and 550mg imidazole-2-formaldehyde are taken and dissolved in 25mL of glycerin and deionized water with the volume ratio of 1:1, the temperature is raised to 70 ℃, and the mixture is cooled after being kept for 30 minutes, so as to obtain a solution B. Rapidly adding the solution B into the solution A under intense stirring, maintaining at normal temperature for 10min, centrifuging, washing with methanol for 3 times, and vacuum drying at 60deg.C for 6 hr to obtain ZIF-90 nanoparticles;
(2) Preparation of ZIF-90@MnO 2 Nanoparticles
Weighing 10mg ZIF-90 nanoparticles, dissolving in 5mL deionized water, and dripping 5mg KMnO 4 Stirring the aqueous solution at the normal temperature of 25 ℃ for 30min, centrifuging, taking the precipitate, and respectively ultrasonically washing the precipitate with ethanol and deionized water for 3 times to obtain the target product.
Example 10:
multifunctional ZIF-90@MnO 2 A method for preparing a nanocomposite material comprisingThe method comprises the following steps:
(1) Preparation of ZIF-90 nanoparticles
350mg Zn (NO) 3 ) 2 4H 2 O is dissolved in 15mL of tertiary butanol and deionized water with the volume ratio of 1:1 to obtain a solution for standby; 50mg PVP and 550mg imidazole-2-formaldehyde are taken and dissolved in 25mL of glycerin and deionized water with the volume ratio of 1:1, the temperature is raised to 70 ℃, and the mixture is cooled after being kept for 30 minutes, so as to obtain a solution B. Rapidly adding the solution B into the solution A under intense stirring, maintaining at normal temperature for 20min, centrifuging, washing with methanol for 3 times, and vacuum drying at 60deg.C for 6 hr to obtain ZIF-90 nanoparticles;
(2) Preparation of ZIF-90@MnO 2 Nanoparticles
Weighing 5mg ZIF-90 nanoparticles, dissolving in 10mL deionized water, and dripping 1mg KMnO 4 Stirring the aqueous solution at the normal temperature of 25 ℃ for 2 hours, centrifuging, taking the precipitate, and respectively ultrasonically washing the precipitate with ethanol and deionized water for 3 times to obtain the target product.
Example 11:
multifunctional ZIF-90@MnO 2 A method of preparing a nanocomposite comprising the steps of:
(1) Preparation of ZIF-90 nanoparticles
400mg Zn (NO) 3 ) 2 4H 2 O is dissolved in 25mL of tertiary butanol and deionized water with the volume ratio of 1:1 to obtain a solution for standby; 50mg PVP and 450mg imidazole-2-formaldehyde are taken and dissolved in 15mL of glycerin and deionized water with the volume ratio of 1:1, the temperature is raised to 50 ℃, and the mixture is cooled after being kept for 60 minutes, so as to obtain a solution B. Rapidly adding the solution B into the solution A under intense stirring, maintaining at normal temperature for 20min, centrifuging, washing with methanol for 3 times, and vacuum drying at 60deg.C for 6 hr to obtain ZIF-90 nanoparticles;
(2) Preparation of ZIF-90@MnO 2 Nanoparticles
Weighing 5mg ZIF-90 nanoparticles, dissolving in 5mL deionized water, and dripping 1mg KMnO 4 Stirring the aqueous solution at the normal temperature of 25 ℃ for 2 hours, centrifuging, taking the precipitate, and respectively ultrasonically washing the precipitate with ethanol and deionized water for 3 times to obtain the target product.
Example 12
Multifunctional ZIF-90@MnO 2 Nanometer scaleThe preparation method of the composite material comprises the following steps:
(1) Preparation of ZIF-90 nanoparticles
370mg Zn (NO) 3 ) 2 4H 2 O is dissolved in 20mL of tertiary butanol and deionized water with the volume ratio of 1:1 to obtain a solution for standby; 50mg PVP and 480mg imidazole-2-formaldehyde are taken and dissolved in 20mL of glycerin and deionized water with the volume ratio of 1:1, the temperature is raised to 70 ℃, and the mixture is cooled after being kept for 40 minutes, so as to obtain a solution B. Rapidly adding the solution B into the solution A under intense stirring, maintaining at normal temperature for 10min, centrifuging, washing with methanol for 3 times, and vacuum drying at 60deg.C for 6 hr to obtain ZIF-90 nanoparticles;
(2) Preparation of ZIF-90@MnO 2 Nanoparticles
Weighing 10mg ZIF-90 nanoparticles, dissolving in 10mL deionized water, and dripping 1mg KMnO 4 Stirring the aqueous solution at the normal temperature of 25 ℃ for 2 hours, centrifuging, taking the precipitate, and respectively ultrasonically washing the precipitate with ethanol and deionized water for 3 times to obtain the target product.
Example 13
Multifunctional ZIF-90@MnO 2 A method of preparing a nanocomposite comprising the steps of:
(1) Preparation of ZIF-90 nanoparticles
370mg Zn (NO) 3 ) 2 4H 2 O is dissolved in 20mL of tertiary butanol and deionized water with the volume ratio of 1:1 to obtain a solution for standby; 50mg PVP and 480mg imidazole-2-formaldehyde are taken and dissolved in 20mL of glycerin and deionized water with the volume ratio of 1:1, the temperature is raised to 70 ℃, and the mixture is cooled after being kept for 40 minutes, so as to obtain a solution B. Rapidly adding the solution B into the solution A under intense stirring, maintaining at normal temperature for 10min, centrifuging, washing with methanol for 3 times, and vacuum drying at 60deg.C for 6 hr to obtain ZIF-90 nanoparticles;
(2) Preparation of ZIF-90@MnO 2 Nanoparticles
Weighing 5mg ZIF-90 nanoparticles, dissolving in 5mL deionized water, and dripping 5mg KMnO 4 Stirring the aqueous solution at the normal temperature of 25 ℃ for 30min, centrifuging, taking the precipitate, and respectively ultrasonically washing the precipitate with ethanol and deionized water for 3 times to obtain the target product.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.

Claims (6)

1. A zinc-containing metal organic framework coated manganese dioxide nanocomposite material is characterized by comprising a zinc-containing metal organic framework coated manganese dioxide nanocomposite material formed by ZIF-90 and MnO deposited on the ZIF-90 2 A mesoporous dodecahedron structure is formed;
the nanocomposite is prepared by the following steps:
dissolving ZIF-90 nanoparticles in deionized water, and dripping KMnO 4 Stirring the aqueous solution to obtain a target product;
ZIF-90、KMnO 4 and deionized water in an amount of (5-10) mg: (1-5) mg: (5-10) mL;
stirring is carried out at normal temperature, and the stirring time is 0.5-2 h;
the preparation process of the ZIF-90 nano particles specifically comprises the following steps:
(1) Zn (NO) 3 ) 2 4H 2 O is dissolved in a mixed solvent consisting of tertiary butanol and deionized water to obtain a solution A;
(2) PVP and imidazole-2-formaldehyde are dissolved in glycerin and deionized water, and the temperature is raised to obtain a solution B;
(3) Rapidly adding the solution A into the solution B, stirring, maintaining at normal temperature, centrifuging, washing and drying to obtain ZIF-90 nano particles;
in the step (2), the heating process is specifically as follows: heating to 50-70 ℃ and keeping for 30-60 min;
in the step (3), the addition amounts of the solution A and the solution B satisfy the following conditions: zn (NO) 3 ) 2· 4H 2 The mass ratio of O to PVP is (350-400): (20-70).
2. The zinc-containing metal organic framework coated manganese dioxide nanocomposite of claim 1, wherein the composite has an average particle size of 160-200nm.
3. The method for preparing the zinc-containing metal organic framework coated manganese dioxide nanocomposite according to claim 1 or 2, wherein ZIF-90 nanoparticles are firstly dissolved in deionized water, and KMnO is added dropwise 4 And (5) stirring the aqueous solution to obtain the target product.
4. The method of preparing a zinc-containing metal-organic framework coated manganese dioxide nanocomposite according to claim 3, wherein in step (1), zn (NO 3 ) 2· 4H 2 The ratio of the addition amount of O to the mixed solvent is (350-400) mg: (15-25) mL;
in the mixed solvent, the volume ratio of the tertiary butanol to the deionized water is 1:0.8-1.2.
5. The method for preparing the zinc-containing metal organic framework coated manganese dioxide nanocomposite according to claim 3, wherein in the step (2), the mass ratio of PVP to imidazole-2-formaldehyde is (20-70): (450-550);
the volume ratio of the glycerol to the deionized water is 1:0.8-1.2.
6. Use of the zinc-containing metal organic framework coated manganese dioxide nanocomposite according to claim 1 or 2 for the preparation of an anticancer drug delivery vehicle, or a medicament for enhanced photodynamic therapy under oxidative stress, dual sensitive degradation under weak acid environment of tumors and ultrasound irradiation, or MR imaging.
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