Water-soluble cyclodextrin drug carrier with cell targeting and preparation method thereof

Abstract

The invention discloses a water-soluble cyclodextrin drug carrier with cell targeting. The water-soluble cyclodextrin drug carrier comprises beta-cyclodextrin as an entrapment drug body, and the beta-cyclodextrin is linked with at least one choline phosphate at a fixed point. The preparation method comprises the following steps: (1) taking methanol and 2-chloro-2-oxo-1, 3, 2-dioxaphospholane as raw materials to synthesize 2-methoxy-2-oxo-1, 3, 2-dioxaphospholane; (2) synthesizing choline phosphate by taking 2-methoxy-2-oxo-1, 3, 2-dioxaphospholane and 1-dimethylamino-2-propyne as raw materials; and (3) finally, through a click reaction, enabling the mono (6-azide-6-deoxy)-beta-cyclodextrin, choline phosphate and a ligand N, N, N', N, N''-pentamethyldiethylenetriamine to react to generate the mono-substituted choline phosphate cyclodextrin. The drug carrier can improve the hydrophilicity of beta-cyclodextrin and endow the beta-cyclodextrin with cell adhesiveness by utilizing the chargeeffect between choline phosphate and a cell membrane, so that the high efficiency of drug absorption in cells is realized.

Description

technical field

[0001] The invention relates to the technical field of targeting drug carriers, in particular to a water-soluble cyclodextrin drug carrier with cell targeting and a preparation method thereof. Background technique

[0002] The special frustum-shaped cavity and inclusion effect of cyclodextrin make it widely used in drug delivery. On the one hand, cyclodextrin, as a natural macromolecular structure, has low toxicity and low immunogenicity. On the other hand, the formation of clathrates complexed with drugs can increase the solubility of the drug while also reducing the systemic toxicity of the drug and controlling the release of the drug. Among them, β-cyclodextrin is the most commonly used, but the water solubility of β-cyclodextrin is not satisfactory under the influence of crystal structure, so researchers chemically modify cyclodextrin to improve its water solubility. Common cyclodextrin derivatives include methyl-β-cyclodextrin, sulfobutyl ether-β-cyclod...

Examples

Embodiment 1

[0042] This embodiment provides a water-soluble cyclodextrin drug carrier with cell targeting, which mainly uses β-cyclodextrin (β-CD) as the main body, and introduces at least one phosphorylcholine on it through a click reaction The reverse order structure molecule - phosphorylcholine (CP).

[0043] This example mainly focuses on the single-substituted phosphocholine cyclodextrin with only one phosphorylcholine (CP) introduced into β-cyclodextrin (β-CD). There are multiple fixed-point links on other β-cyclodextrins. The compounds of phosphorylcholine can be obtained based on the preparation process of monosubstituted phosphorylcholine cyclodextrin.

[0044] The specific preparation process of monosubstituted phosphocholine cyclodextrin as a water-soluble cyclodextrin drug carrier with cell targeting comprises the following steps:

[0045] (1) Synthesis of 2-methoxy-2-oxo-1,3,2-dioxophospholane (MDP)

[0046] Glass instruments need to be dried with a flame gun and protected ...

Embodiment 2

[0055] In this example, the drug carrier (monosubstituted phosphorylcholine cyclodextrin) prepared in the above example was characterized by using nuclear magnetic resonance (400Hz) to characterize the synthetic product, tetramethylsiloxane (TMS) was used as a reference, and the solution was selected DMSO-d 6 or D 2 O, respectively detect the synthesis product 1 HNMR, 31 PNMR.

[0056] The prepared phosphocholine-modified cyclodextrin solid is mixed with KBr, ground, pressed into tablets, and scanned in a transmission mode with a wavelength range of 500-4000nm.

[0057] A gas chromatograph is used in conjunction with methanol as a solvent.

[0058] Structural characterization of phosphorylcholine-modified cyclodextrins, as figure 1 As shown in the figure, it can be seen that δ=7.98ppm corresponds to the corresponding hydrogen atoms on the triazole ring, and the characteristic absorption peaks of 14 hydrogen atoms corresponding to cyclodextrin 2 and 3-OH can be seen near 5...

Embodiment 3

[0061] In this example, for the drug carrier (monosubstituted phosphorylcholine cyclodextrin) prepared in the above examples, apatinib was used as a model drug to conduct research on the inclusion capacity of the phosphorylcholine modified cyclodextrin carrier (phase solubility study ).

[0062] Drawing of the standard curve of apatinib aqueous solution: Weigh 5 mg of apatinib and dissolve it in 10 mL of ultrapure water, sonicate for 10 min and transfer it to a 25 mL volumetric flask after it is completely dissolved. Take 1, 3, 5, 7, and 10 mL of apatinib solution respectively, and dilute to volume in a 10 mL volumetric flask to prepare concentrations of 0.02, 0.06, 0.10, 0.14, and 0.20 mg / mL, respectively. Transfer 3.5mL of the prepared solution to the sample cell, and test its UV absorbance at a wavelength of 254nm, with blank ultrapure water as a reference.

[0063] according to image 3 It can be seen that the standard curve of apatinib: according to the absorbance corre...

technical field

[0001] The invention relates to the technical field of targeting drug carriers, in particular to a water-soluble cyclodextrin drug carrier with cell targeting and a preparation method thereof. Background technique

[0002] The special frustum-shaped cavity and inclusion effect of cyclodextrin make it widely used in drug delivery. On the one hand, cyclodextrin, as a natural macromolecular structure, has low toxicity and low immunogenicity. On the other hand, the formation of clathrates complexed with drugs can increase the solubility of the drug while also reducing the systemic toxicity of the drug and controlling the release of the drug. Among them, β-cyclodextrin is the most commonly used, but the water solubility of β-cyclodextrin is not satisfactory under the influence of crystal structure, so researchers chemically modify cyclodextrin to improve its water solubility. Common cyclodextrin derivatives include methyl-β-cyclodextrin, sulfobutyl ether-β-cyclod...

Examples

Embodiment 1

[0042] This embodiment provides a water-soluble cyclodextrin drug carrier with cell targeting, which mainly uses β-cyclodextrin (β-CD) as the main body, and introduces at least one phosphorylcholine on it through a click reaction The reverse order structure molecule - phosphorylcholine (CP).

[0043] This example mainly focuses on the single-substituted phosphocholine cyclodextrin with only one phosphorylcholine (CP) introduced into β-cyclodextrin (β-CD). There are multiple fixed-point links on other β-cyclodextrins. The compounds of phosphorylcholine can be obtained based on the preparation process of monosubstituted phosphorylcholine cyclodextrin.

[0044] The specific preparation process of monosubstituted phosphocholine cyclodextrin as a water-soluble cyclodextrin drug carrier with cell targeting comprises the following steps:

[0045] (1) Synthesis of 2-methoxy-2-oxo-1,3,2-dioxophospholane (MDP)

[0046] Glass instruments need to be dried with a flame gun and protected ...

Embodiment 2

[0055] In this example, the drug carrier (monosubstituted phosphorylcholine cyclodextrin) prepared in the above example was characterized by using nuclear magnetic resonance (400Hz) to characterize the synthetic product, tetramethylsiloxane (TMS) was used as a reference, and the solution was selected DMSO-d 6 or D 2 O, respectively detect the synthesis product 1 HNMR, 31 PNMR.

[0056] The prepared phosphocholine-modified cyclodextrin solid is mixed with KBr, ground, pressed into tablets, and scanned in a transmission mode with a wavelength range of 500-4000nm.

[0057] A gas chromatograph is used in conjunction with methanol as a solvent.

[0058] Structural characterization of phosphorylcholine-modified cyclodextrins, as figure 1 As shown in the figure, it can be seen that δ=7.98ppm corresponds to the corresponding hydrogen atoms on the triazole ring, and the characteristic absorption peaks of 14 hydrogen atoms corresponding to cyclodextrin 2 and 3-OH can be seen near 5...

Embodiment 3

[0061] In this example, for the drug carrier (monosubstituted phosphorylcholine cyclodextrin) prepared in the above examples, apatinib was used as a model drug to conduct research on the inclusion capacity of the phosphorylcholine modified cyclodextrin carrier (phase solubility study ).

[0062] Drawing of the standard curve of apatinib aqueous solution: Weigh 5 mg of apatinib and dissolve it in 10 mL of ultrapure water, sonicate for 10 min and transfer it to a 25 mL volumetric flask after it is completely dissolved. Take 1, 3, 5, 7, and 10 mL of apatinib solution respectively, and dilute to volume in a 10 mL volumetric flask to prepare concentrations of 0.02, 0.06, 0.10, 0.14, and 0.20 mg / mL, respectively. Transfer 3.5mL of the prepared solution to the sample cell, and test its UV absorbance at a wavelength of 254nm, with blank ultrapure water as a reference.

[0063] according to image 3 It can be seen that the standard curve of apatinib: according to the absorbance corre...

Images