CN109464672B - Platinum drug/black phosphorus compound and preparation method and application thereof - Google Patents

Platinum drug/black phosphorus compound and preparation method and application thereof Download PDF

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CN109464672B
CN109464672B CN201811360336.3A CN201811360336A CN109464672B CN 109464672 B CN109464672 B CN 109464672B CN 201811360336 A CN201811360336 A CN 201811360336A CN 109464672 B CN109464672 B CN 109464672B
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black phosphorus
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CN109464672A (en
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邓文斌
刘赣
梅林�
曾小伟
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Sun Yat Sen University
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Abstract

The invention discloses a platinum drug/black phosphorus compound and a preparation method and application thereof, wherein the platinum drug/black phosphorus compound is a product obtained by coordination and complexation of two-dimensional black phosphorus and a platinum drug active component; the method for stabilizing the black phosphorus material by using the platinum drug active ingredient is simple and efficient, and can be safely and risk-free applied to clinic; the platinum drug/black phosphorus compound can stably realize the photothermal and chemotherapy combined treatment of tumors, can also be used as a stable black phosphorus carrier system to further load other drugs, and has good application prospect in the aspect of preparing antitumor drugs.

Description

Platinum drug/black phosphorus compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biomedical materials. In particular to a platinum drug/black phosphorus compound and a preparation method and application thereof.
Background
Cancer is one of the major diseases throughout the world that endanger human life and health. According to the data of the world cancer research foundation, cancer becomes one of the main causes of human death, the worldwide cancer incidence rate increases by 3-5% every year, 1270 ten thousand of newly increased cancer patients are added worldwide in 2008, and 2100 ten thousand of newly increased cancer patients are expected in 2030. Traditional cancer treatment strategies have included surgical resection, chemotherapy, radiation therapy, and biological therapy. In recent years, near-infrared photothermal therapy has been widely considered as a potential alternative or supplement to conventional cancer treatment methods due to its various advantages, such as high efficiency and non-invasiveness.
Black Phosphorus (BP), a new two-dimensional material, has been the focus of research for rapid outbreaks in recent two years as a near-infrared photothermal conversion agent for cancer treatment. BP is composed of a multi-layer folded honeycomb structure formed by single P element, P-P covalent bonds are arranged in layers, Van der Waals weak interaction is utilized between layers, and a liquid phase stripping method is utilized to prepare black phosphorus nanosheets, black phosphorus quantum dots and black phosphorus micron sheets. As a metal-free layered semiconductor, the energy gap of black phosphorus changes with the number of layers, increasing from 0.3 eV for bulk materials to 2 eV for single-layer phospholenes, and thus its absorption range is wide, with absorption from the ultraviolet to the near infrared. In addition to excellent optical properties, another very unique advantage of black phosphorus material in biomedical field is its very good biocompatibility and biodegradability. Research shows that the black phosphorus material can react with oxygen and water in water to degrade, and the final degradation product is phosphate radical which exists widely in the body and is non-toxic. Therefore, the black phosphorus material has a great prospect of clinical application due to the excellent photothermal effect and biocompatibility.
However, the black phosphorus material is very reactive to oxygen and water in the external environment, resulting in degradation of material components and significant degradation of optical properties. The black phosphorus is a folded honeycomb structure, each P atom of the black phosphorus is connected with three adjacent P atoms in the layer through covalent bonds, a pair of lone-pair electrons is exposed, the lone-pair electrons are very active and can react with oxygen to generate PxOy, and P0 is exposed again to enable the P0 to be oxidized continuously, so that the degradation of the black phosphorus is initiated. Therefore, trying to stabilize the lone pair of electrons is a potential strategy for inhibiting BP degradation, and although there are reports that covalent modification, transition metal ion coordination, or surface adsorption of organic molecules with electron-withdrawing groups are used to stabilize the lone pair of electrons of BP and further inhibit BP oxidation, for practical biomedical applications, it is still urgent to select a BP stabilization method which is efficient and has real clinical prospects.
Platinum-based antitumor drugs are first-line antitumor drugs widely used in clinical practice at present, and among them, Cisplatin (cissplatin) and Oxaliplatin (Oxaliplatin) are the most representative. After entering cells, active components formed by hydrolysis and DNA bases form an intra-chain cross-linking product in a coordination mode, so that the replication and transcription of DNA are blocked, and cancer cells are apoptotic. At present, reports on the utilization of platinum drugs to enhance the stability of BP in external environment and to be used for resisting tumors are not found.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the prior art, prepares the platinum drug/black phosphorus compound by coordination and complexation of the platinum drug active ingredient and the two-dimensional black phosphorus material, realizes the clinical photothermal and chemotherapy combined treatment of tumors while enhancing the stability of the two-dimensional black phosphorus material by using the platinum drug active ingredient, and has a wide application prospect.
The first purpose of the invention is to provide a platinum drug/black phosphorus compound.
The second purpose of the invention is to provide a preparation method of the platinum drug/black phosphorus compound.
The third purpose of the invention is to provide the application of the platinum drug/black phosphorus compound in the preparation of a black phosphorus carrier system.
The fourth purpose of the invention is to provide the application of the platinum drug/black phosphorus compound in preparing anti-tumor drugs.
The above purpose of the invention is realized by the following technical scheme:
a platinum drug/black phosphorus compound is a product obtained by coordination complexing two-dimensional black phosphorus and a platinum drug active component. Specifically, the complex is obtained by carrying out coordination and complexation on P of lone pair electrons of two-dimensional black phosphorus and Pt atoms of platinum active ingredients with electron deficiency.
The platinum drug/black phosphorus compound of the invention is prepared by the coordination complexation of the Pt lacking electrons in the active component of the platinum drug and the P of lone pair electrons of two-dimensional black phosphorus, and the black phosphorus material is stabilized by using the drug itself. Therefore, the active ingredients of the platinum drugs containing electron-deficient Pt can enhance the stability of the two-dimensional black phosphorus through coordination complexation.
Preferably, the platinum drug active ingredient is (1, 2-cyclohexanediamine) platinum (DACHPt) and/or diammineplatinum [ Pt (NH) ] 3 ) 2 ]。
Particularly preferably, the platinum drug/black phosphorus complex is BP/DACHPt and/or BP/Pt (NH) 3 ) 2 。
Preferably, the two-dimensional black phosphorus is one or more of black phosphorus nanosheets, black phosphorus quantum dots, or black phosphorus micron sheets.
Particularly preferably, the size of the black phosphorus nanosheet is 20-500 nm, and the thickness of the nanosheet is 1-20 nm; the size of the black phosphorus quantum dot is 2-15 nm, and the thickness of the black phosphorus quantum dot is 1-5 nm; the size of the micron sheet is 1-20 μm.
The preparation method of the platinum drug/black phosphorus compound comprises the steps of uniformly mixing the active components of the platinum drug and the two-dimensional black phosphorus in an organic solvent, carrying out a complexing reaction for 12-48 h, centrifuging, and precipitating to obtain the platinum drug/black phosphorus compound.
Preferably, the mass ratio of the two-dimensional black phosphorus to the platinum drug active ingredient is 1 (0.5-10).
More preferably, the mass ratio of the two-dimensional black phosphorus to the platinum drug active ingredient is 1 (0.5-8).
More preferably, the mass ratio of the two-dimensional black phosphorus to the platinum active ingredient is 1 (0.5-4).
Preferably, the addition amount of the two-dimensional black phosphorus is 0.1-1% of the mass of the organic solvent.
Preferably, the organic solvent is one or more of N-methylpyrrolidone, dioxane, acetonitrile or N, N-dimethylformamide.
Further preferably, the preparation method of the black phosphorus nanosheet is: dispersing BP powder in an organic solvent by 0.1-1%, adjusting a probe amplifier to be 25%, performing ultrasonic treatment for 4-8 hours with a switching period of 5s/5s, centrifuging the obtained dispersion liquid at 3000-4000 rpm for 8-12 min, removing large BP precipitates without stripping, collecting supernatant BP nanosheets, and centrifuging the supernatant at 6000-8000 rpm for 8-12 min to obtain the BP nanosheets.
Further preferably, the preparation method of the black phosphorus quantum dot comprises the following steps: dispersing BP powder in an organic solvent by 0.1-1%, adjusting a probe amplifier to be 25%, performing ultrasonic treatment for 6-10 hours at a switching period of 5s/5s, performing constant-temperature ultrasonic treatment for 8 hours at 16 ℃, centrifuging supernatant liquid of the obtained dispersion liquid at 6000-8000 rpm for 8-12 min, removing large BP precipitates without stripping, collecting supernatant liquid BP quantum dots, and centrifuging the supernatant liquid at 20000 rpm for 10 min to obtain the BP quantum dots.
Further preferably, the preparation method of the black phosphorus micron sheet comprises the following steps: dispersing BP powder in an organic solvent by 0.1-1%, and carrying out ice-bath ultrasonic treatment for 4-6 hours under the conditions of 40 kHz frequency and 80% power; centrifuging the obtained dispersion liquid at 3000-4000 rpm for 8-12 min, removing large BP precipitates without stripping, collecting supernatant BP micron sheets, and centrifuging the supernatant BP micron sheets at 6000-8000 rpm for 8-12 min to obtain the BP nanosheets.
Preferably, the organic solvent is one or more of N-methylpyrrolidone, dioxane, acetonitrile or N, N-dimethylformamide.
Further preferably, the preparation method of the active ingredient DACHPt of oxaliplatin comprises the following steps: 0.5 to 5% of dichloro (1, 2-cyclohexanediamine) platinum DACHPtCl 2 Dissolving in water, and reacting with 2 equivalents of silver nitrate at normal temperature in the dark for 1 day; centrifuging to remove silver chloride precipitate, filtering the supernatant with 0.22 μm filter, and lyophilizing.
Further preferably, the active ingredient of cisplatin is Pt (NH) 3 ) 2 The preparation method comprises the following steps: dissolving Diamminedichloroplatinum (CDDP) in water, and reacting with 2 equivalents of silver nitrate at normal temperature in dark for 1 day; centrifuging to remove silver chloride precipitate, filtering the supernatant with 0.22 μm filter, and lyophilizing.
The active component of the platinum drug in the platinum drug/black phosphorus compound is complexed with BP nanosheets containing lone pair electrons, and the stability of BP in an external environment is enhanced, so that the strategy of self-constructing a stable BP carrier system by utilizing the drug can avoid potential clinical application risks and realize photothermal and chemotherapy combined treatment on tumors.
Therefore, the application of the platinum drug/black phosphorus compound in the preparation of the black phosphorus carrier system is also within the protection scope of the invention.
Meanwhile, the application of the platinum drug and the black phosphorus compound in the preparation of the anti-tumor drug with stable photo-thermal property and chemotherapy toxicity is also within the protection scope of the invention.
In addition, the application of the platinum drug active ingredient in improving the stability of the two-dimensional black phosphorus material is also within the protection scope of the invention.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a platinum drug/black phosphorus compound, which utilizes the active ingredients of the platinum drug to enhance the stability of a two-dimensional black phosphorus material, and the method for stabilizing the black phosphorus material by utilizing the drug is simple and efficient, and can be safely and risk-free applied to clinic; the platinum drug/black phosphorus compound can stably realize the photothermal and chemotherapy combined treatment of tumors, can also be used as a stable black phosphorus carrier system to further load other drugs, and has good application prospect in the aspect of preparing antitumor drugs.
Drawings
FIG. 1 is a schematic representation of the formation of a complex BP/DACHPt of a black phosphorus material and a platinum drug active ingredient DACHPt.
FIG. 2 shows the drug loading of BP at different DACHPt/BP feed ratios.
FIG. 3 is a TEM image of a transmission electron microscope of BP/DACHPt nanosheet.
FIG. 4 is a TEM image of a transmission electron microscope of BP/DACHPt quantum dots.
FIG. 5 is a Raman scattering Raman plot of pure BP and BP/DACHPt.
FIG. 6 is an XPS plot of X-ray photoelectron spectra of pure BP, BP/DACHPt and DACHPt. Wherein, A is P spectrum, B is Pt spectrum.
FIG. 7 is a graph of UV-Vis-NIR absorption of pure BP and BP/DACHPt over time in an ambient environment.
FIG. 8 shows pure BP, BP/DACHPt and BP/DACHPtCl 2 An in vitro near-infrared photothermal conversion temperature rise graph which changes along with time.
FIG. 9 shows BP/CDDP and BP/Pt (NH) 3 ) 2 An in vitro near-infrared photothermal conversion temperature rise graph changing along with time.
FIG. 10 is an atomic force microscope AFM morphology of the surface of pure BP and BP/DACHPt micron sheet after 24 hours.
FIG. 11 is a microscopic image of photothermal killing of HeLa tumor cells at different concentrations of pure BP and BP/DACHPt after exposure to ambient conditions for 0 and 72 hours.
FIG. 12 shows the quantitative results of the combined photo-thermal and chemotherapy treatments at different concentrations to kill HeLa tumor cells after pure BP and BP/DACHPt were placed in the external environment for 72 hours.
FIG. 13 shows in vivo photothermal and chemotherapeutic anti-tumor effects of BP/DACHPt; wherein G1 is normal saline water + NIR, G2 is pure black phosphorus subjected to 72 h pretreatment + NIR, G3 is BP/DACHPt, and G4 is BP/DACHPt + NIR.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. The reagents, methods and apparatus employed in the present invention are conventional in the art, except as otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 preparation of three different morphologies of two-dimensional Black phosphorus Material
1. Method of producing a composite material
The preparation method of the black phosphorus nanosheet comprises the following steps: grinding the BP crystal into BP powder in a mortar, then dispersing the BP powder in N-methylpyrrolidone at a rate of 0.2%, adjusting a probe amplifier to be 25%, carrying out ultrasonic treatment for 4 hours at a switching period of 5s/5s, centrifuging the obtained dispersion liquid at 3500 rpm for 10 min, removing large BP precipitates without stripping, collecting supernatant BP nanosheets, and centrifuging the supernatant at 7000 rpm for 10 min to obtain the BP nanosheets.
The preparation method of the black phosphorus quantum dot comprises the following steps: grinding the BP crystal into BP powder in a mortar, then dispersing the BP powder in N-methylpyrrolidone at the rate of 0.2%, adjusting a probe amplifier to be 25%, performing ultrasonic treatment at the switching period of 5s/5s for 8 hours, then performing ultrasonic treatment at the constant temperature of 16 ℃ for 8 hours, centrifuging the obtained dispersion liquid at 7000 rpm for 10 min, removing large BP precipitates without stripping, collecting supernatant BP quantum dots, and centrifuging the supernatant liquid at 20000 rpm for 10 min to obtain the BP quantum dots.
The preparation method of the black phosphorus micron tablet comprises the following steps: the BP crystals were ground into BP powder in a mortar, then the BP powder was dispersed in N-methylpyrrolidone at 0.2% and subjected to ultrasonic treatment in an ice bath at a frequency of 40 kHz and a power of 80% for 4 hours, the resulting dispersion was centrifuged at 3000 rpm for 10 min, large BP precipitates without peeling were removed and supernatant BP micron pieces were collected, and the supernatant was centrifuged at 7000 rpm for 10 min to obtain BP micron pieces.
2. Results
The size of the black phosphorus nanosheet prepared by the method is 77 nm, and the thickness of the black phosphorus nanosheet is 12 nm; the size of the black phosphorus quantum dot is 4.3 nm, and the thickness of the black phosphorus quantum dot is 1.5 nm; the size of the black phosphorus quantum dots is 8 μm.
Example 2 preparation of three different morphologies of two-dimensional Black phosphorus Material
The present embodiment is substantially the same as embodiment 1, except that the organic solvent N-methylpyrrolidone used in the preparation process of the three different forms of two-dimensional black phosphorus materials is respectively replaced by dioxane, acetonitrile and N, N-dimethylformamide, and black phosphorus nanosheets, black phosphorus quantum dots and black phosphorus micron sheets with the same size range can be prepared.
EXAMPLE 3 preparation of platinum pharmaceutical active ingredient
1. Preparation of active ingredient (1, 2-cyclohexanediamine) platinum (DACHPt) of oxaliplatin
0.5% of dichloro (1, 2-cyclohexanediamine) platinic chloride DACHPtCl 2 Dissolving in water, reacting with 2 equivalents of silver nitrate at normal temperature in dark place for 1 day, centrifuging to remove silver chloride precipitate, filtering the supernatant with 0.22 μm filter, and lyophilizing.
The active ingredient (1, 2-cyclohexanediamine) platinum (DACHPt) of the oxaliplatin is successfully prepared by the method, and the chemical structural formula is shown as follows:
Figure 296932DEST_PATH_IMAGE001
。
2. diammineplatinum [ Pt (NH) ] as active component of cisplatin 3 ) 2 ]Preparation of
Dissolving Diamminedichloroplatinum (CDDP) in water, and reacting with 2 equivalents of silver nitrate at normal temperature in dark for 1 day; centrifuging to remove silver chloride precipitate, filtering the supernatant with 0.22 μm filter, and lyophilizing.
The active ingredient diammine platinum [ Pt (NH) of the cisplatin is successfully prepared by the method 3 ) 2 ]The chemical structural formula is shown as follows:
Figure 948494DEST_PATH_IMAGE002
。
EXAMPLE 4 preparation of platinum drug/Black phosphorus Complex
1. Method of producing a composite material
In N-methylpyrrolidineIn the ketone, 0.1% of black phosphorus nanosheet, quantum dot or micron sheet by mass percentage is respectively mixed with (0.5, 1, 2, 3, 4, 5, 6, 7 and 8 times) of platinum drug active ingredient DACHPt or Pt (NH) by mass percentage 3 ) 2 Mix overnight. The mixture was then centrifuged at 12000 rpm for 20 min and the precipitate collected to give BP/DACHPt and BP/(NH) 3 ) 2 And (c) a complex.
2. As a result, the
(1) The loading results are shown in FIG. 2, where the BP loading was saturated after a DACHPt/BP loading ratio of 4, and the loading was 2. And Pt (NH) 3 ) 2 the/BP also reached saturation after a feed ratio of 5 and the drug loading was 2.5.
(2) When the DACHPt/BP feeding ratio is 5, the TEM result of a transmission electron microscope of the prepared BP/DACHPt compound is shown in figures 3-4, the figure 3 can intuitively prove the morphology and the size of the BP/DACHPt nano-sheet and the compounding of the active components of the platinum drug, the figure 3A can observe that the morphology is irregular and the size is 50-100 nm, the figure 3B shows that the lattice fringe spacing is 0.223 nm, which is the lattice characteristic of BP, the structure of the BP is proved to be unchanged after compounding, and the figure 3C shows the distribution of P and Pt in the compound, so that the DACHPt is proved to be compounded with the BP uniformly and compactly; from FIG. 4, the morphology size of the BP/DACHPt quantum dot is compounded with platinum active ingredients, the Pt active ingredients are regular round particles, and the size of the Pt active ingredients is 2-6 nm.
(3) In addition, Raman scattering detection is carried out on pure BP and BP/DACHPt to verify whether the platinum drug and the black phosphorus are successfully compounded; the experimental result is shown in fig. 5, the raman scattering characteristic peak of BP shows red shift after being compounded with the drug, which shows that the coordination of BP and DACHPt inhibits the vibration of surface P atoms and reduces the raman scattering energy.
Further, the result of the detection by the X-ray photoelectron spectroscopy on pure BP and BP/DACHPt is shown in FIG. 6, and it can be seen from FIG. 6-A that the P element in BP/DACHPt is significantly oxidized, which indicates that BP and DACHPt are significantly coordinated and complexed; FIG. 6-B shows: the Pt binding energy of BP/DACHPt is reduced relative to that of a platinum drug active ingredient, because P containing a lone pair of electrons coordinates with an electron deficient Pt atom and donates an electron, and the above results all demonstrate that BP and DACHPt are efficiently complexed to form a BP/DACHPt complex.
EXAMPLE 5 preparation of platinum drug and Black phosphorus complexes
This example is essentially the same as the process described in example 3, except that the organic solvent N-methylpyrrolidone used was replaced with any of dioxane, acetonitrile and N, N-dimethylformamide, and similar drug loading results were obtained, indicating that the type of solvent had little effect on the drug loading.
EXAMPLE 6 complexes BP/DACHPt and BP/Pt (NH) 3 ) 2 Stability test of
1. Method of producing a composite material
Oxaliplatin bulk drug DACHPtCl was prepared in a similar manner to example 4 2 The compound of cisplatin original drug CDDP and black phosphorus is prepared by mixing 5 groups of black phosphorus preparations (pure BP, BP/DACHPt, BP/DACHPtCl) 2 BP/CDDP and BP/Pt (NH) 3 ) 2 Pre-dispersed in air exposed water (50 μ g/mL) and stirred for various times (0, 12 h, 24 h, 72 h and 168 h). The UV-VIS-NIR absorption of pure BP and BP/DACHPt from 300 to 800 nm was determined at each time point. 5 groups of formulations were simultaneously examined at each time point for near infrared light at 808 nm (1.0W/cm) 2 ) Photo-thermal stability at 10 min of irradiation. The stability of pure BP and BP/DACHPt microsheets was observed by atomic force microscopy after 24 h exposure to humid air.
2. Results
(1) FIG. 7 is a graph of the change in UV-visible NIR absorption of pure BP and BP/DACHPt over time in an ambient environment, showing that pure black phosphorus rapidly decreases in absorption over time within 7 days, indicating that it degrades rapidly in an ambient environment. This result is consistent with the results widely reported previously. And B picture shows that BP/DACHPt has little absorption reduction in 7 days and still reaches 90% of the initial value, which proves that the stability of the compound is obviously improved. This demonstrates that the complexation of platinum drugs can greatly enhance the stability of BP.
(2) FIG. 8 shows pure BP, BP/DACHPt and BP/DACHPtCl 2 The in vitro near infrared photothermal conversion heating effect changes along with the time, and the result shows that the photothermal conversion heating of pure BPThe capacity decreases rapidly with time, only increasing to 32 degrees after 1 day, and almost completely failing to increase after 7 days. The temperature-rising capability of BP/DACHPt is stable, and even after 7 days, the temperature-rising capability of BP/DACHPt is still remarkable. This again verifies that the complexation of platinum drugs can greatly enhance the stability of BP. In addition, BP and intact DACHPtCl 2 The mixture of (a) also failed to enhance the stability of BP, which suggests that only the platinum drug active ingredient is complexed with BP and enhances the stability of BP from the other side.
(3) FIG. 9 shows BP/CDDP and BP/Pt (NH) 3 ) 2 The temperature rise effect of photo-thermal conversion changes along with time. Like DACHPt, the active ingredient Pt (NH) of cisplatin 3 ) 2 Can obviously enhance the stability of the black phosphorus, but the CDDP of the cisplatin can not be enhanced. These results indicate that the property of the platinum drug active ingredient to enhance BP is universal, both because the platinum drug active ingredient can stabilize lone pair electrons of BP and further inhibit its oxidative degradation.
(4) FIG. 10 is an atomic force microscope AFM morphology of the surface of pure BP and BP/DACHPt nanoplates after 24 hours. The results show that the pure BP micron flakes are significantly oxidized, producing very dense vacuoles on their surface. While the BP/DACHPt micron sheet is not changed. This again demonstrates that complexation of platinum drugs can significantly enhance the stability of BP.
EXAMPLE 7 Complex BP/DACHPt in vitro photothermal and chemotherapeutic toxicity test
1. Method of producing a composite material
(1) Photo-thermal property: human cervical cancer cell HeLa was used to study photo-thermal and chemotherapeutic toxicity of BP/DACHPt, and HeLa cells were cultured in 6-well plates for 24 h. Neat BP and BP/DACHPt were pre-dispersed in air-exposed water for 0 or 72 h prior to testing. Then adding pure BP and BP/DACHPt (50 mu g/mL) which are pretreated before extraction into the HeLa cells, culturing for 4 h, irradiating for 10 min by using near infrared laser with the wavelength of 808 nm, culturing for 30 min, co-staining cells by calcein AM (calcium fluorescein acetoxy methyl ester) and PI (propidium iodide) and further evaluating the photo-thermal killing cell effect of the BP/DACHPt by using a fluorescence microscope.
(2) Chemotherapy toxicity: BP/DACHPt toxicity to HeLa cells was also quantified by MTT assay. HeLa cells (1 x 10) 4 Cells/well) were cured in 96-well plates and cultured overnight. The pure BP and BP/DACHPt (10, 20, 50. mu.g/mL) treated for 72 h were added to HeLa cells and placed under irradiation and non-irradiation of near infrared light, respectively (808 nm laser at 1.0W/cm) 2 for 10 min). After irradiation with near infrared light, the cells were cultured for another 12 h, and then the cell viability was quantified using the MTT assay.
2. As a result, the
(1) As shown in FIG. 11, both pure BP and BP/DACHPt pretreated for 0h were able to kill almost all tumor cells by photothermal at 50 μ g/mL, which is consistent with the previous photothermal effect in vitro. Whereas after 72 h pretreatment pure BP failed to kill tumor cells, indicating essentially complete degradation, consistent with previous results. While BP/DACHPt still maintained killing power at 0h, which intuitively demonstrates photo-thermal stability.
(2) As shown in fig. 12, the cell viability exceeded 90% with and without BP addition, both with and without near infrared light, due to the loss of photothermal capacity of BP after degradation. While the cells added with 20. mu.g/mL BP/DACHPt were significantly killed by light irradiation, the cells added with 50. mu.g/mL BP/DACHPt were able to kill almost all cells. This again demonstrates that BP/DACHPt has very good photo-thermal stability. In addition, after BP/DACHPt is added, the cell viability is still reduced obviously even if laser is not irradiated, which indicates that BP/DACHPt also has chemotherapeutic toxicity, which is derived from the active ingredient DACHPt of platinum drug.
EXAMPLE 8 Complex BP/DACHPt in vivo antitumor Effect test
1. Method of producing a composite material
Female SCID nude mice of 4-5 weeks old were purchased from the center of laboratory animals of Zhongshan university and bred in SPF (specific pathogen-free) grade animal houses. All animal experiments were performed under the compliance of the regulations of the animal research administration committee of the university of zhongshan. Each nude mouse was injected subcutaneously on the right side with 5X 10 6 HeLa cells, mice were randomly divided into 4 groups for intratumoral injection of saline, 72 h pretreated neat black phosphorus, 72 h pretreated BP/DACHPt and BP/DACHPt (20 μ L0.5 mg/mL platinum and/or N-acetyl-D-alanine) after tumor volume reached palpable sizeCorresponding BP dose). Groups 1, 3, 4 then irradiated the tumor site at 808 nm after anesthesia, during which time tumor size was weighed and measured every two days and relative tumor volume was calculated for 14 days.
2. Results
The combined photothermal and chemotherapy antitumor effects of BP/DACHPt are shown in FIG. 13, and it can be seen that after treatment, group G4 can completely inhibit tumor growth, even achieve tumor ablation effect; whereas G1 and G2 groups had little effect on tumor growth; g3 has partial tumor growth inhibiting effect, which is caused by the chemotherapy effect of DACHPt, and the results prove the photo-thermal stability and excellent combined photo-thermal and chemotherapy anti-tumor effect of BP/DACHPt on animal level.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (5)

1. The platinum drug/black phosphorus compound is characterized in that the compound is a product obtained by coordination complexing two-dimensional black phosphorus and platinum drug active ingredients; the platinum drug active ingredient is (1, 2-cyclohexanediamine) platinum and/or diammine platinum; the two-dimensional black phosphorus is one or more of black phosphorus nanosheets, black phosphorus quantum dots or black phosphorus micron sheets; the mass ratio of the two-dimensional black phosphorus to the active components of the platinum drug is 1 (0.5-10).
2. The preparation method of the platinum drug/black phosphorus compound as claimed in claim 1, wherein the platinum drug active ingredient and the two-dimensional black phosphorus are mixed uniformly in an organic solvent, subjected to a complexation reaction for 12-48 hours, centrifuged, and precipitated to obtain the platinum drug/black phosphorus compound; the mass ratio of the two-dimensional black phosphorus to the active components of the platinum medicament is 1 (0.5-10); the addition amount of the two-dimensional black phosphorus is 0.1-1% of the mass of the organic solvent.
3. The method according to claim 2, wherein the organic solvent is one or more of N-methylpyrrolidone, dioxane, acetonitrile, or N, N-dimethylformamide.
4. Use of the platinum drug/black phosphorus complex of claim 1 in the preparation of a black phosphorus carrier system.
5. Use of the platinum drug and the black phosphorus compound as defined in claim 1 for the preparation of an antitumor drug having stable photothermal and chemotherapeutic toxicity.
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