A bortezomib-based small molecule nano-drug, its preparation method and application

Abstract

The present invention discloses a bortezomib-based small molecule nano-drug, its preparation method and application, belonging to the field of pharmaceutical technology. In the present invention, bortezomib and guanosine are added to an organic solvent, an alkali reagent and anhydrous sodium sulfate are added, and the mixture is reacted evenly. After completion, rotary evaporation is carried out to obtain a white solid product, the bortezomib-guanosine conjugate drug; the above-mentioned bortezomib-guanosine conjugate drug is dissolved in tetrahydrofuran, and then water is slowly added dropwise, stirred for a period of time, and transferred to continue stirring under a fume hood to obtain the bortezomib-guanosine nano-drug. The nano-drug of the present invention can achieve self-administration without the aid of a carrier. By avoiding the use of an additional carrier, the prepared small molecule nano-drug has the advantages of high drug loading (some can even reach 100%); precisely adjustable drug loading quantification; no long-term toxicity induced by the carrier, etc.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a bortezomib-based small molecule nano-drug, its preparation method and application. Background Art

[0002] Bortezomib (BTZ) is the first proteasome inhibitor approved for the treatment of cancer patients. Bortezomib is mainly used for the treatment of hematological tumors such as multiple myeloma (MM) and small cell lymphoma, and clinical studies have shown that it is also effective against the in vitro toxicity of various tumor cells. Guanosine (GUO) is an endogenous nucleoside involved in extracellular signal transduction, which has neuroprotective effects and also has the effect of inducing cancer cell differentiation. However, these drugs such as bortezomib have poor solubility on the one hand and high toxicity on the other hand. Therefore, how to effectively administer the drugs is an urgent problem to be solved. Summary of the Invention

[0003] To solve the above problems, the present invention provides a small molecule nano-drug with good solubility and capable of self-administering without the aid of a carrier.

[0004] A bortezomib-guanosine conjugate drug has the following structure:

[0005]

[0006] A preparation method of the above-mentioned bortezomib-guanosine conjugate drug includes:

[0007] Adding bortezomib and guanosine into an organic solvent, adding an alkali reagent and anhydrous sodium sulfate, mixing and reacting, and then rotary evaporating after completion to obtain a white solid product of bortezomib-guanosine conjugate drug.

[0008] In one embodiment of the present invention, the molar ratio of bortezomib to guanosine is 1:(0.8 - 2). Specifically, 1:1 is preferred.

[0009] In one embodiment of the present invention, the organic solvent is any one or a combination of two of tetrahydrofuran and N,N-dimethylformamide.

[0010] In one embodiment of the present invention, when the organic solvent is a combination of tetrahydrofuran and N,N-dimethylformamide, the volume ratio of tetrahydrofuran to N,N-dimethylformamide is 3:1.

[0011] In one embodiment of the present invention, the concentration of bortezomib relative to the organic solvent is 0.025 mmol / mL.

[0012] In one embodiment of the present invention, the reaction temperature is 30 - 60 °C and the time is 15 - 30 h. Specifically, it is optional to react at 40 °C for 24 h.

[0013] In one embodiment of the present invention, the base reagent is triethylamine.

[0014] In one embodiment of the present invention, the molar ratio of triethylamine to bortezomib is (2 - 4):1.

[0015] In one embodiment of the present invention, the amount of anhydrous sodium sulfate relative to the organic solvent is 25 mg / mL.

[0016] In one embodiment of the present invention, the synthetic route of the above preparation method is as follows:

[0017]

[0018] The present invention also provides a preparation method of bortezomib-guanosine nanomedicine, including:

[0019] Dissolve the above-mentioned bortezomib-guanosine conjugate drug in tetrahydrofuran, then slowly add water dropwise, stir for a period of time, and transfer to continue stirring under a fume hood to obtain a solution containing bortezomib-guanosine nanomedicine.

[0020] In one embodiment of the present invention, the concentration of the bortezomib-guanosine conjugate drug dissolved in tetrahydrofuran is 10 mg / mL.

[0021] In one embodiment of the present invention, the volume ratio of water to tetrahydrofuran is 5:1.

[0022] In one embodiment of the present invention, the concentration of the bortezomib-guanosine nanomedicine in the obtained solution containing bortezomib-guanosine nanomedicine is 2 mg / mL.

[0023] Based on the above preparation method, the present invention provides a bortezomib-guanosine nanomedicine.

[0024] The present invention also provides the application of the above-mentioned bortezomib-guanosine nanomedicine in the preparation of anticancer drugs.

[0025] In one embodiment of the present invention, the cancers include: multiple myeloma (MM), small cell lymphoma.

[0026] The beneficial effects of the present invention:

[0027] The small molecule nano-drug of the present invention can achieve self-administration without the aid of a carrier. By avoiding the use of additional carriers, the prepared small molecule nano-drug has the advantages of high drug loading (some can even reach 100%); precisely adjustable drug loading quantification; and no long-term toxicity induced by the carrier. Description of the Drawings

[0028] Figure 1 It is the mass spectrometry data of the bortezomib-guanosine conjugate drug obtained in Example 1.

[0029] Figure 2 It is the 1H NMR data of the bortezomib-guanosine conjugate drug in Example 1.

[0030] Figure 3 It is the particle size data of the bortezomib-guanosine nano-drug in Example 2.

[0031] Figure 4 It is the electron microscopy data of the bortezomib-guanosine nano-drug in Example 2. Detailed Description of the Invention

[0032] To make the above objects, features and advantages of the present invention more obvious and understandable, the following specific embodiments are used to make a detailed description of the specific implementation manners of the present invention.

[0033] Example 1

[0034] 38.4 mg of bortezomib (0.1 mmol) and 28.3 mg of guanosine (0.1 mmol) were added to a 50 mL reaction flask in an equimolar ratio, 3 mL of tetrahydrofuran and 1 mL of N,N-dimethylformamide were added, 30 μL (0.2 mmol) of triethylamine and 100 mg of anhydrous sodium sulfate were added to remove water, and the reaction was carried out at 40 °C for 24 h. After the reaction, the white solid product bortezomib-guanosine conjugate drug was obtained by rotary evaporation.

[0035] Example 2

[0036] 6 mg of the prepared bortezomib-guanosine conjugate drug was weighed and dissolved in 600 μL of tetrahydrofuran, and slowly added dropwise to 3 mL of deionized water while stirring continuously. After stirring for 30 minutes, it was transferred to a fume hood and continuously stirred at 40 °C for 2 h to obtain a bortezomib-guanosine nano-drug with a concentration of 2 mg / mL.

[0037] The bortezomib-guanosine nano-drug obtained in the above example has good solubility and can achieve self-administration without the aid of a carrier. Moreover, the bortezomib-guanosine nano-drug obtained in the above example, by avoiding the use of additional carriers, the prepared small molecule nano-drug has high drug loading (some can even reach 100%); precisely adjustable drug loading quantification; and no long-term toxicity induced by the carrier.

[0038] The embodiments provided above are not intended to limit the scope covered by the present invention, nor are the described steps intended to limit the order of their execution. Obvious improvements made by those skilled in the art to the present invention in combination with the existing well-known general knowledge also fall within the protection scope defined by the claims of the present invention.

Claims

1. A bortezomib-guanosine conjugate drug, characterized in that, Its structure is as follows:

2. A method for preparing the bortezomib-guanosine conjugate drug according to claim 1, characterized in that, Including: Bortezomib and guanosine are added to an organic solvent, an alkali reagent and anhydrous sodium sulfate are added, mixed and reacted, and after completion, rotary evaporation is carried out to obtain a white solid product, bortezomib-guanosine conjugate drug.

3. The method according to claim 2, wherein The molar ratio of bortezomib to guanosine is 1:(0.8 - 2).

4. The method according to claim 2, wherein The molar ratio of bortezomib to guanosine is 1:

1.

5. The method according to claim 2, wherein The organic solvent is any one or a combination of two of tetrahydrofuran and N,N-dimethylformamide; when the organic solvent is a combination of tetrahydrofuran and N,N-dimethylformamide, the volume ratio of tetrahydrofuran to N,N-dimethylformamide is 3:

1.

6. The method according to claim 2, wherein The concentration of bortezomib relative to the organic solvent is 0.025 mmol / mL.

7. The method according to claim 2, characterized in that, The alkali reagent is triethylamine.

8. A preparation method of bortezomib-guanosine nano-drug, characterized in that, Including: The bortezomib-guanosine conjugate drug described in claim 1 is dissolved in tetrahydrofuran, then water is slowly added dropwise, stirred for a period of time, and transferred to continue stirring under a fume hood to obtain a solution containing bortezomib-guanosine nano-drug.

9. The method according to claim 8, characterized in that, The concentration of the bortezomib-guanosine conjugate drug dissolved in tetrahydrofuran is 10 mg / mL; the volume ratio of water to tetrahydrofuran is 5:

1.

10. A bortezomib-guanosine nano-drug prepared by the preparation method described in claim 8 or 9.

11. Use of the bortezomib-guanosine nano-drug described in claim 10 in the preparation of an anticancer drug.

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