Cross-linked acid-responsive natural polysaccharide polymer prodrug, preparation method and use
A natural polysaccharide and cross-linking technology, which can be used in pharmaceutical formulations, drug combinations, anti-tumor drugs, etc., can solve the problems of toxic side effects in healthy tissues, poor drug targeting, and fast blood clearance, and achieve less toxic side effects and easy synthesis , Synthetic steps are simple and controllable
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Embodiment 1
[0050] The synthesis of embodiment 1 DEX-VEA-DTX
[0051] (1) Synthesis of small molecule prodrug docetaxel-vinyl ether acrylate complex
[0052] The synthetic route of docetaxel-vinyl ether acrylate complex (DTX-VEA) is shown below:
[0053]
[0054] Take vinyl ether acrylate (2mL, 14mmol) in a reaction bottle, and dry it in vacuum for 0.5h; take another docetaxel (500 mg, 0.62mmol) and dissolve it in 10mL tetrahydrofuran (THF), and weigh the 15 mg of p-toluenesulfonic acid (PTSA) was added to the reaction system under nitrogen protection, and the reaction was stirred at room temperature for 2 hours. The reaction process was monitored by high performance liquid chromatography or thin layer chromatography. After the reaction was complete, 50 μL of triethylamine was added to terminate the reaction. The reaction solution was concentrated under reduced pressure, and added dropwise to n-hexane for precipitation. After the precipitate was washed repeatedly, it was vacuum-dri...
Embodiment 2
[0059] The synthesis of embodiment 2 HA-VEA-PTX
[0060] (1) Synthesis of small molecule prodrug paclitaxel-vinyl ether acrylate complex
[0061] The synthetic route of paclitaxel-vinyl ether acrylate complex (PTX-VEA) is as follows:
[0062]
[0063] Take vinyl ether acrylate (0.2mL, 1.4mmol) in a reaction flask, and dry it in vacuum for 0.5h; separately take paclitaxel (100mg, 0.12mmol) and dissolve it in 5mL tetrahydrofuran (THF), and weigh the pair that was dried under reduced pressure in advance. 4mg of toluenesulfonic acid (PTSA) was added into the reaction system under the protection of nitrogen, and the reaction was stirred at room temperature for 2 hours. The reaction process was monitored by high performance liquid chromatography or thin layer chromatography. After the reaction was complete, 5 μL of triethylamine was added to terminate the reaction. The reaction solution was concentrated under reduced pressure, and added dropwise to a mixed solvent of diethyl e...
Embodiment 3
[0068] The preparation of embodiment 3 polymer prodrug nanogels (HA-VEA-PTX)
[0069] Polymer prodrug nanogel (HA-VEA-PTX) was prepared by solvent exchange method. Under ultrasonic conditions, 0.1 mL polymer prodrug HA-VEA-PTX DMSO solution (10 mg / mL) was slowly added to 1 mL high-purity water, and dialyzed in high-purity water for 2 h to remove the organic solvent. The cross-linked nanogel was prepared by cross-linking the polymer prodrug (HA-VEA-PTX) with a peptide sensitive to MMP-9, and 100 μL of the DMSO solution of the polymer prodrug HA-VEA-PTX was taken under nitrogen protection (20mg / mL) mixed with 20μL of DMSO solution (10mg / mL) of the polypeptide, added 0.1μL triethylamine, stirred and reacted for 1h under nitrogen protection, then added dropwise to 1mL high-purity water under ultrasonic conditions, and dialyzed for 2h to remove the organic solvent . Figure 4 is the particle size characterization diagram of polymer prodrug nanogel (HA-VEA-PTX) before and after cr...
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