CN115044051B - Platinum cluster radiotherapy sensitizer for relieving tumor hypoxia - Google Patents
Platinum cluster radiotherapy sensitizer for relieving tumor hypoxia Download PDFInfo
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- CN115044051B CN115044051B CN202210584881.0A CN202210584881A CN115044051B CN 115044051 B CN115044051 B CN 115044051B CN 202210584881 A CN202210584881 A CN 202210584881A CN 115044051 B CN115044051 B CN 115044051B
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Abstract
The invention discloses a platinum cluster radiotherapy sensitizer for relieving tumor hypoxia, belonging to the cross field of nano material chemistry and biochemistry. The invention takes levonorgestrel with good biocompatibility as a protective ligand, and synthesizes the alloy nanocluster with high yield and excellent fluorescence performance and accurate atom size by a room-temperature volatilization one-pot method. The chemical formula of the nano alloy cluster is as follows: pt 2 Au 4 C 168 H 216 O 16 (abbreviated as: pt) 2 Au 4 L 8 ) Belonging to trigonal system, the space group is chiral space groupP3221. The nano alloy cluster has a small size (-2 nm) and good dispersibility; the fluorescent material has strong red fluorescence at room temperature, the fluorescence quantum yield is 37.9%, and the fluorescent material can be used for high-quality cell imaging. The nano alloy cluster material can relieve tumor hypoxia, has a radiotherapy sensitization effect when being used as a radiotherapy sensitizer, and has high efficiency of killing tumor cells.
Description
Technical Field
The invention belongs to the cross field of nano material chemistry and biochemistry, particularly relates to a nano alloy cluster material radiotherapy sensitizer with accurate atoms, and particularly relates to a nano alloy cluster material radiotherapy sensitizer capable of relieving tumor hypoxia.
Background
With the rapid development of cluster science, researchers in the field of radiotherapy have proposed an idea of studying high atomic number nanoclusters as next-generation radiosensitizers, due to the strong interaction of the high atomic number nanoclusters with incident radiation. Up to now, au clusters such as Bovine Serum Albumin (BSA) -protected Au 25 Cluster and levonorgestrel protected Au 8 Clustering has been extensively explored in the context of radiosensitization. Studies have shown that metal clusters of 1-3nm size are effectively cleared by the kidney, exhibiting low toxicity. In addition, the nanoclusters with accurate atomic structures provide good opportunities for analyzing the structure-activity relationship of the radiotherapy sensitizer.
Most of the previously reported nano-cluster radiotherapy sensitizers have single functions and cannot overcome the radiation resistance of hypoxic tumors. By breakdown of over-expressed H in the tumor microenvironment 2 O 2 Carrying out in situ generation of O 2 Is a feasible method. In addition, many platinum-related nanomaterials had good catalase-like activity. Therefore, the preparation of platinum-based alloy clusters has great promise for achieving radiosensitization to block the negative effects of hypoxia on cancer treatment.
Disclosure of Invention
The invention aims to provide an atomic-level accurate nano alloy cluster radiotherapy sensitizer capable of relieving tumor hypoxia. Another object is to provide a process for producing the same.
For the purpose of the present invention, the chemical formula of the nano-alloy cluster material is Pt 2 Au 4 C 168 H 216 O 16 The abbreviation is: pt 2 Au 4 L 8 Belonging to the trigonal system; space group is a handThe group of sexual spaces P3221 is,
α＝90°,β＝90°,γ＝120°,/>
l represents levonorgestrel ligand.
In order to realize the aim of the invention, the nano alloy cluster material is prepared by the following steps:
dissolving ligand levonorgestrel in Dichloromethane (DCM), stirring at room temperature to dissolve and clarify; adding a methanol solution of chloroplatinic acid, and stirring at room temperature for reaction; adding triethylamine, and continuously stirring at room temperature; and finally adding tetrahydrothiophene gold chloride, stirring at room temperature, after the reaction is finished, placing the clear solution at room temperature to be protected from light and volatilized to obtain crystals, filtering, washing and drying at room temperature.
The nano alloy cluster material is composed of two platinum atoms, four gold atoms and eight organic ligands (shown in figure 1), six metal atoms form an octahedral inner core through the interaction of metal bonds, each platinum atom is coordinated with a carbon atom on terminal alkyne in the four ligands through sigma bonds, and each gold atom is coordinated with a carbon atom on terminal alkyne in the two ligands through pi bonds (shown in figure 2).
The nanoalloy cluster materials have an ultra-small size (2 nm) and good dispersion (shown in figures 3 and 4). Under the condition of room temperature, the fluorescent material has strong red fluorescence, and the optimal emission wavelength position is 663nm (the excitation wavelength is 390 nm) (shown in figure 5); the fluorescence quantum yield at room temperature was 37.9%. With tris (4, 7-diphenyl-1, 10-phenanthroline) ruthenium (II) dichloride ([ Ru (dpp) 3 ]Cl 2 Based on O 2 Fluorescent quencher) to detect O as a function of time 2 Concentration to indicate whether or not O is produced 2 . At H 2 O 2 In the presence of Pt 2 Au 4 L 8 Group [ Ru (dpp) 3 ]Cl 2 The fluorescence intensity of (A) is dependent on the inverseSignificant decrease with time (shown in FIG. 6), indicating Pt 2 Au 4 L 8 Can catalyze the decomposition of hydrogen peroxide into O 2 I.e. it has catalase-like properties, is doped with other metals (e.g. Ag and Cu), and has no catalase-like activity. The material is used for cell cloning experiments, and is subjected to treatment under different conditions in the experiment process, wherein Pt is used for 2 Au 4 L 8 Cell necrosis was most pronounced in the radiographic group (shown in figure 7).
The invention has the beneficial effects that: the nano alloy cluster material has strong red fluorescence at room temperature, has good dispersibility and biocompatibility, can be used for high-quality cell imaging and regulating tumor hypoxia, has a radiotherapy sensitization effect as a radiotherapy sensitizer, and has high efficiency of killing tumor cells. Provides a potential platform for further analyzing the structure-activity relationship of the alloy cluster radiotherapy sensitizer and opens up a new way for constructing an atomic-scale accurate nano-drug to block the negative influence of hypoxic on tumor radiosensitivity.
Drawings
FIG. 1 is a single crystal structure of the nano alloy cluster material of the present invention.
FIG. 2 is a diagram of the core structure and ligand coordination mode of the nano-alloy cluster material of the present invention.
FIG. 3 is a transmission electron micrograph of the nanoalloy cluster material of the present invention.
FIG. 4 is a dynamic light scattering diagram of the nano-alloy cluster material of the present invention.
FIG. 5 is a graph of the excitation curve and emission curve of the nano-alloy cluster material of the present invention and a fluorescent photograph of the material at 365 nm.
FIG. 6 shows a nano-alloy cluster material of the present invention in H 2 O 2 In the presence of [ Ru (dpp) 3 ]Cl 2 Graph of fluorescence intensity versus time.
FIG. 7 is a diagram showing the results of cell cloning experiments using the nano-alloy cluster material of the present invention as a radiosensitizer.
Detailed Description
The invention is further illustrated by the following examples:
example 1: synthesis of the Nano alloy Cluster Material of the invention
Dissolving ligand levonorgestrel in Dichloromethane (DCM), stirring at room temperature to dissolve and clarify; adding a methanol solution of chloroplatinic acid, and stirring at room temperature for reaction; then triethylamine is added, and stirring is continued at room temperature; and finally adding tetrahydrothiophene gold chloride, stirring for 15 minutes at room temperature, after the reaction is finished, placing the reaction solution at room temperature to be protected from light and volatilized, obtaining yellow strip crystals after 2-3 days, filtering, washing with acetonitrile, obtaining the yield of 69.87%, and airing at room temperature for a property test material.
Example 2: the nano alloy cluster material of the invention is used as a radiation sensitizer
The nano alloy cluster material sample prepared in the embodiment 1 is taken, firstly dissolved in a small amount of DMSO (dimethyl sulfoxide), added into a culture medium and subjected to uniform ultrasound, the culture medium containing the material is used for cell cloning experiments, and X-ray treatment is performed on different groups. The results are shown in FIG. 7, where it can be seen that Pt 2 Au 4 L 8 The + X-ray experimental group showed the most significant cell necrosis.
The nano alloy cluster material prepared in the embodiment 1 is taken for further characterization, and the process is as follows:
(1) Determination of Crystal Structure
X-ray single crystal diffraction data of the complexes were determined on a Rigaku XtaLAB Pro single crystal diffractometer using appropriately sized single crystal samples. Mo-Ka ray for data
The diffraction sources were collected by ω -scan at 200K temperature. The structure analysis is to obtain the initial structure by a direct method through a SHELXS-97 program, and then to refine the initial structure by a full matrix least square method through a SHELXL-97 program. The solvent molecules were processed by the mask program in OLEX 2. All non-hydrogen atoms were refined using anisotropic thermal parametric methods. All hydrogen atoms are contained in the ideal positions. Detailed crystal determination data are shown in table 1; the key length data of interest are shown in table 2.
TABLE 1 Main crystallographic data for the Nanoalloy cluster materials of the present invention
TABLE 1 Main crystallographic data
R1＝∑||F o |-|F c |/∑||F o |.wR 2 ＝[∑w(F o 2 -F c 2 ) 2 /∑w(F o 2 ) 2 ] 1/2
TABLE 2 Pt 2 Au 4 L 8 Important bond length
Symmetric code: 1 -Y+X,-Y,1/3-Z
the above examples are merely illustrative of the present invention, and other embodiments of the present invention are possible. However, all the technical solutions formed by equivalent alternatives or equivalent modifications fall within the protection scope of the present invention.
Claims (5)
1. A nanoalloy cluster material, characterized by: the chemical formula is as follows: pt 2 Au 4 C 168 H 216 O 16 The abbreviation is: pt 2 Au 4 L 8 Belonging to the trigonal system; space group is chiral space groupP3221，a = 25.48940(10) Å, b = 25.48940(10) Å, c = 25.13260(10) Å, α =90°, β = 90°, γ = 120°, V = 14141.23(12) Å 3 (ii) a L represents levonorgestrel ligand.
2. The nanoalloy cluster material of claim 1, wherein: the catalyst consists of two platinum atoms, four gold atoms and eight organic ligands, wherein six metal atoms form an octahedral inner core through the interaction of metal bonds, each platinum atom is coordinated with a carbon atom on terminal alkyne in the four ligands through a sigma bond, and each gold atom is coordinated with a carbon atom on terminal alkyne in the two ligands through a pi bond; the organic ligand is levonorgestrel.
3. The nanoalloy cluster material of claim 1 or 2, wherein: the single crystal structure is shown in figure 1.
4. Use of a nanoalloy cluster material as claimed in any one of claims 1 to 3, characterized in that: it is used as radio sensitizer for non-disease diagnosis and treatment.
5. Use of a nanoalloy cluster material as claimed in any one of claims 1 to 3, characterized in that: it is used as a radiotherapy sensitizer for relieving tumor hypoxia in non-disease diagnosis and treatment.
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| CN105980519A (en) * | 2014-02-05 | 2016-09-28 | 默克专利有限公司 | Metal complexes |
| CN112755005A (en) * | 2019-11-04 | 2021-05-07 | 四川大学 | Oral nano drug delivery system mediated by small molecular nutrient substances |
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| US7855021B2 (en) * | 2004-12-22 | 2010-12-21 | Brookhaven Science Associates, Llc | Electrocatalysts having platium monolayers on palladium, palladium alloy, and gold alloy core-shell nanoparticles, and uses thereof |
| US8178463B2 (en) * | 2010-04-05 | 2012-05-15 | Uchicago Argonne, Llc | Highly durable nanoscale electrocatalyst based on core shell particles |
| RU2428769C1 (en) * | 2010-04-08 | 2011-09-10 | Учреждение Российской академии наук Институт катализа им. Г.К. Борескова Сибирского отделения РАН | Preparation method of bimetallic catalyst (versions) and its use for fuel elements |
| CN110204563B (en) * | 2019-06-13 | 2021-08-06 | 郑州大学 | Nano-gold cluster material radiotherapy sensitizer |
| CN111229321A (en) * | 2020-01-16 | 2020-06-05 | 吉林大学 | Glutathione-protected platinum alloy nano-cluster with strong catalytic function, preparation method and application thereof |
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