Cobalt manganese oxide nano particle and preparation method and application thereof

Abstract

The invention discloses cobalt manganese oxide nanoparticles and a preparation method and application thereof, the preparation method comprises the following steps: dispersing cobalt salt and manganese salt in ethylene glycol, stirring until the cobalt salt and the manganese salt are dissolved, heating to 180 DEG C, refluxing for 1-2 hours, centrifuging, washing and drying to obtain a brown CMO precursor; the CMO precursor is subjected to heat treatment for 8.0-24 h at the temperature of 150-250 DEG C, and black CMO is obtained; dispersing CMO into deionized water, and carrying out ultrasonic crushing to obtain CMO nanoparticles; hyaluronic acid is added into the CMO nano particle dispersion liquid for surface modification, and the magnetic resonance nano contrast agent with good biocompatibility and T1-T2 double-weighted enhancement is obtained. The CMO nanoparticles obtained by the invention have T1-T2 double-weighted enhanced magnetic resonance imaging performance, and the method is simple, safe, environment-friendly, low in cost and easy to operate, and has a wide application prospect in diagnosis and imaging of cancers.

Description

Technical Field

[0001] The invention belongs to the technical field of nano materials, and specifically relates to cobalt manganese oxide nano particles and a preparation method and application thereof. Background Art

[0002] Non-invasive magnetic resonance imaging (MRI) is an important imaging technique in clinical medicine. Its excellent tissue penetration has great advantages in the detection of various diseases, especially malignant tumors. It is an important tool for tumor localization and TNM staging at this stage.

[0003] Traditional magnetic resonance (MR) contrast agents mainly include T1-weighted gadolinium complexes and T2-weighted superparamagnetic iron oxide nanoparticle contrast agents. However, T1- and T2-weighted imaging each reflects different physical and chemical properties of tissues, and a single T1- or T2-weighted signal may affect the accuracy of early tumor diagnosis due to a single enhancement pattern. Contrast agents with T1-T2 weighted performance can simultaneously integrate the advantages of two imaging sequences, highlight lesion characteristics, and provide more comprehensive diagnostic information. Summary of the invention

[0004] Based on this, the main purpose of the present invention is to provide a method for preparing cobalt manganese oxide nanoparticles, the required raw materials are easily available, the price is low, and the synthesis method is mild.

[0005] Another object of the present invention is to provide a cobalt manganese oxide nanoparticle having T1-T2 double-weighted properties.

[0006] Another object of the present invention is to provide the use of the cobalt manganese oxide nanoparticles in the preparation of T1-T2 dual-weighted enhanced magnetic resonance nanocontrast agents, which have good biocompatibility and magnetic resonance imaging performance.

[0007] To achieve the above object, the present invention adopts the following technical solution:

[0008] The present invention provides a method for preparing cobalt manganese oxide nanoparticles, comprising the following steps:

[0009] (1) dispersing cobalt salt and manganese salt in ethylene glycol, stirring until dissolved, heating to 180° C. and reflux for 1 to 2 hours, centrifuging, washing, and drying to obtain a brown cobalt manganese oxide (CMO) precursor;

[0010] (2) heat treating the CMO precursor in step (1) at 150-250° C. for 8.0-24 h to obtain black CMO;

[0011] (3) Dispersing the CMO obtained in step (2) in deionized water and subjecting it to ultrasonic grinding with an ultrasonic power of 50 to 300 W and an ultrasonic time of 10 to 60 min to obtain the product.

[0012] Preferably, in step (1), the cobalt salt and the manganese salt are selected from one or more of nitrates, acetates or chlorides.

[0013] Preferably, in step (1), the molar ratio of the cobalt salt to the manganese salt is x:3-x, 0≤x≤3.

[0014] Preferably, in step (1), the molar volume ratio of the cobalt salt, the manganese salt and the ethylene glycol is x:3-x:30-120 mL, 0≤x≤3.

[0015] Preferably, in step (2), the atmosphere for heat treatment of the CMO precursor is selected from one or more of air, nitrogen or argon.

[0016] Preferably, in step (3), the ultrasonic pulverization is carried out in an ice bath.

[0017] Preferably, in step (3), the concentration of CMO dispersed in deionized water is 0.5 to 20 mg / mL.

[0018] The present invention also provides a CMO nanoparticle, which is prepared by the preparation method of the CMO nanoparticle and has an average particle size of 10 to 300 nm.

[0019] Preferably, the CMO nanoparticles have no effect on cell survival rate within a concentration range of 0 to 100 ug / mL and have good biocompatibility.

[0020] The present invention also provides the use of the CMO nanoparticles in preparing T1-T2 dual-weighted enhanced magnetic resonance nano contrast agents.

[0021] The present invention also provides a T1-T2 dual-weighted enhanced magnetic resonance nano contrast agent, which is obtained by adding hyaluronic acid to the dispersion of the CMO nanoparticles for surface modification.

[0022] Preferably, the T1-T2 dual-weighted enhanced magnetic resonance nanocontrast agent exhibits concentration-dependent longitudinal and transverse relaxation rates.

[0023] Preferably, the mass ratio of the CMO nanoparticles to hyaluronic acid is 1:5-200.

[0024] Compared with the prior art, the beneficial effects of the present invention are that the CMO nanoparticles prepared by the present invention can be applied to the diagnosis of cancer or other diseases, and the preparation method has the advantages of being environmentally friendly, the required raw materials are easily available, the price is low, and the operation process is simple. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1This is the XRD pattern of the CMO nanoparticles prepared in Example 1.

[0026] Figure 2 TEM image of CMO nanoparticles prepared in Example 1.

[0027] Figure 3 4 is the Fourier infrared spectrum of the CMO nanoparticles prepared in Example 1 before and after hyaluronic acid modification.

[0028] Figure 4 MR performance of CMO nanoparticles prepared in Example 1.

[0029] Figure 5 The cytotoxicity data of the CMO nanoparticles prepared in Example 1. DETAILED DESCRIPTION

[0030] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0031] Example 1

[0032] (1) Disperse 1 mmol of cobalt acetate and 2 mmol of manganese acetate in 60 mL of ethylene glycol, stir until dissolved, heat to 180° C. and reflux for 2 h, centrifuge, wash, and dry to obtain a brown CMO precursor;

[0033] (2) heat treating the CMO precursor in step (1) at 220° C. for 8.0 h to obtain black CMO;

[0034] (3) dispersing the CMO obtained in step (2) into deionized water and subjecting it to ultrasonic grinding: ultrasonic power: 200 W; ultrasonic time: 40 min, to obtain CMO nanoparticles with controllable particle size;

[0035] (4) Adding hyaluronic acid (final concentration of 10 mg / mL) to the CMO nanoparticle dispersion (2 mg / mL), stirring overnight, and performing surface modification to obtain a cobalt manganese oxide nanocontrast agent with good biocompatibility.

[0036] The XRD pattern of the CMO nanoparticles prepared in Example 1 is as follows: Figure 1 As shown in the TEM image Figure 2 As shown in Figure 2, the Fourier transform infrared spectra before and after hyaluronic acid modification are as follows: Figure 3 As shown, where:

[0037] Figure 1 The product is cubic cobalt manganese oxide, which corresponds to the standard card (JCPDS 32-0297).

[0038] Figure 2 The product is nanoparticles with a particle size of about 12 nm.

[0039] Figure 3 The Fourier transform infrared spectroscopy (FTIR) showed that compared with the CMO without hyaluronic acid modification (upper curve), the modified sample (lower curve) had a higher peak at 1045 cm -1 A significant signal appears at the stretching vibration of COC, indicating that the product has been successfully modified by hyaluronic acid.

[0040] Example 2

[0041] (1) Disperse 2 mmol of cobalt acetate and 1 mmol of manganese acetate in 60 mL of ethylene glycol, stir until dissolved, heat to 180° C. and reflux for 2 h, centrifuge, wash, and dry to obtain a brown CMO precursor;

[0042] (2) heat treating the CMO precursor in step (1) at 220° C. for 8.0 h to obtain black CMO;

[0043] (3) dispersing the CMO obtained in step (2) into deionized water and subjecting it to ultrasonic grinding: ultrasonic power: 200 W; ultrasonic time: 40 min, to obtain CMO nanoparticles with controllable particle size;

[0044] (4) Adding hyaluronic acid (final concentration of 10 mg / mL) to the CMO nanoparticle dispersion (2 mg / mL), stirring overnight, and performing surface modification to obtain a cobalt manganese oxide nanocontrast agent with good biocompatibility.

[0045] Example 3

[0046] (1) Disperse 1 mmol of cobalt chloride and 2 mmol of manganese chloride in 60 mL of ethylene glycol, stir until dissolved, heat to 180° C. and reflux for 2 h, centrifuge, wash, and dry to obtain a brown CMO precursor;

[0047] (2) heat treating the CMO precursor in step (1) at 220° C. for 8.0 h to obtain black CMO;

[0048] (3) dispersing the CMO obtained in step (2) into deionized water and subjecting it to ultrasonic grinding: ultrasonic power: 200 W; ultrasonic time: 40 min, to obtain CMO nanoparticles with controllable particle size;

[0049] (4) Adding hyaluronic acid (final concentration of 10 mg / mL) to the CMO nanoparticle dispersion (2 mg / mL), stirring overnight, and performing surface modification to obtain a cobalt manganese oxide nanocontrast agent with good biocompatibility.

[0050] Example 4

[0051] (1) Disperse 1 mmol of cobalt acetate and 2 mmol of manganese acetate in 60 mL of ethylene glycol, stir until dissolved, heat to 180° C. and reflux for 2 h, centrifuge, wash, and dry to obtain a brown CMO precursor;

[0052] (2) heat treating the CMO precursor in step (1) at 180° C. for 24.0 h to obtain black CMO;

[0053] (3) dispersing the CMO obtained in step (2) into deionized water and subjecting it to ultrasonic grinding: ultrasonic power: 200 W; ultrasonic time: 40 min, to obtain CMO nanoparticles with controllable particle size;

[0054] (4) Adding hyaluronic acid (final concentration of 10 mg / mL) to the CMO nanoparticle dispersion (2 mg / mL), stirring overnight, and performing surface modification to obtain a cobalt manganese oxide nanocontrast agent with good biocompatibility.

[0055] Example 5

[0056] The in vitro MR properties of the CMO nanoparticles obtained in Example 1 were measured.

[0057] First, a CMO nanoparticle dispersion with a gradient concentration (0-3.2 mM) was prepared, and then the relaxation time of the CMO dispersion with different concentrations was tested on a 3.0-T magnetic resonance scanner. The results are as follows: Figure 4 As shown, A is the T1, T2 weighted images and weighted images and relaxation time pseudo-color images of dispersions of different concentrations (measured in terms of the molar concentration of manganese element contained); B is the longitudinal relaxation rate; C is the transverse relaxation rate, indicating that the product exhibits T1-T2 weighted double-enhanced MR imaging effect, and the longitudinal relaxation rate is 1.005mM-1s-1, and the transverse relaxation rate is 11.84mM-1s-1.

[0058] Example 6

[0059] The cytotoxicity of the CMO nanoparticles obtained in Example 1 was measured.

[0060] First, human epithelial keratinocytes HaCaT were inoculated and cultured in 96-well plates. Then, different concentrations of CMO nanoparticles (0-100ug / mL) were added and cultured for 24h. The in vitro compatibility of HaCaT cells was evaluated using a standard CCK-8 detection kit, and CCK-8 readings were obtained using an ELISA reader at 450nm to calculate cell survival rate. The results are shown in Figure 2. Figure 5As shown, within the concentration range of 0-100 μg / mL, the survival rate of normal epithelial cells HaCaT was as high as over 90%, indicating that the cytotoxicity of the material was almost negligible.

[0061] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing cobalt manganese oxide nanoparticles, characterized in that: The following steps are involved: (1) dispersing cobalt salt and manganese salt in ethylene glycol, stirring until dissolved, heating to 180° C. and reflux for 1 to 2 hours, centrifuging, washing, and drying to obtain a brown cobalt manganese oxide precursor; (2) heat treating the cobalt manganese oxide precursor in step (1) at 150 to 250° C. for 8.0 to 24 hours to obtain black cobalt manganese oxide; (3) dispersing the cobalt manganese oxide obtained in step (2) into deionized water and subjecting it to ultrasonic grinding with an ultrasonic power of 50 to 300 W and an ultrasonic time of 10 to 60 min to obtain the product.

2. The method for preparing cobalt manganese oxide nanoparticles according to claim 1, characterized in that: In step (1), the cobalt salt and the manganese salt are both selected from one or more of nitrates, acetates or chlorides.

3. The method for preparing cobalt manganese oxide nanoparticles according to claim 1, characterized in that: In step (1), the molar ratio of the cobalt salt to the manganese salt is x:3-x, 0≤x≤3; And / or the molar volume ratio of the cobalt salt, the manganese salt and the ethylene glycol is x:3-x:30-120 mL.

4. The method for preparing cobalt manganese oxide nanoparticles according to claim 1, characterized in that: In step (2), the atmosphere for heat treatment of the cobalt manganese oxide precursor is selected from one or more of air, nitrogen or argon.

5. The method for preparing cobalt manganese oxide nanoparticles according to claim 1, characterized in that: In step (3), the ultrasonic pulverization is carried out in an ice bath; And / or the concentration of the cobalt manganese oxide dispersed in deionized water is 0.5-20 mg / mL.

6. A cobalt manganese oxide nanoparticle, characterized in that: The cobalt manganese oxide nanoparticles are prepared by the preparation method of any one of claims 1 to 5, and have an average particle size of 10 to 300 nm.

7. The cobalt manganese oxide nanoparticles according to claim 6, characterized in that: The cobalt manganese oxide nanoparticles have no effect on cell survival rate within a concentration range of 0 to 100 ug / mL.

8. Use of the cobalt manganese oxide nanoparticles according to claim 6 or 7 in the preparation of T1-T2 dual-weighted enhanced magnetic resonance nanocontrast agents.

9. A T1-T2 dual-weighted enhanced magnetic resonance nanocontrast agent, characterized in that: The method is obtained by adding hyaluronic acid to the dispersion of the cobalt manganese oxide nanoparticles for surface modification.

10. The T1-T2 dual-weighted enhanced magnetic resonance nanocontrast agent according to claim 9, characterized in that: The T1-T2 dual-weighted enhanced magnetic resonance nanocontrast agent exhibits concentration-dependent longitudinal and transverse relaxation rates; and / or the dispersion concentration of the cobalt manganese oxide nanoparticles is 0.5 to 20 mg / mL; And / or the mass ratio of the cobalt manganese oxide nanoparticles to hyaluronic acid is 1:5-200.

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