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Preparation of pH-response doxorubicin-dopamine conjugate and prodrug nano particle thereof

A nanoparticle and doxorubicin technology, which is applied in the preparation of sugar derivatives, medical preparations of non-active ingredients, wave energy or particle radiation treatment materials, etc., can solve the problem of difficult application without doxorubicin-dopamine conjugates , Uncontrollable drug burst release and other issues

Active Publication Date: 2017-06-13
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is currently no research on the preparation of doxorubicin-dopamine conjugates and their polymeric prodrugs
Moreover, the above-mentioned drug-loaded nano-drug system has problems such as uncontrollable drug burst release, which is difficult to apply in clinical practice.

Method used

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  • Preparation of pH-response doxorubicin-dopamine conjugate and prodrug nano particle thereof
  • Preparation of pH-response doxorubicin-dopamine conjugate and prodrug nano particle thereof
  • Preparation of pH-response doxorubicin-dopamine conjugate and prodrug nano particle thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1 Preparation of doxorubicin-dopamine conjugate molecule

[0039] Step 1, 455.5 mg of 3,4-dihydroxyphenylpropionic acid, 405.36 mg of 1-hydroxybenzotriazole, and 619.2 mg of dicyclohexylcarbodiimide were dissolved in 20 mL of anhydrous dimethylformamide, After reacting at 25° C. for 4 hours, a dimethylformamide solution of 396.5 mg tert-butyl carbazate was added dropwise into the reaction flask. After reacting at 25°C for 20 hours, centrifuge to remove dicyclohexylurea, and then evaporate with an oil pump at 60°C. The column was loaded with petroleum ether, and the eluent was a mixed solvent of ethyl acetate:petroleum ether (3:1), Rf=0.35. Vacuum oven dry. The product is white powdery solid tert-butyl-2-(3-(3,4-dihydroxyphenyl)propionyl)hydrazinecarboxylate. The yield is 47.3-61.0%.

[0040]Step 2: Dissolve tert-butyl-2-(3-(3,4-dihydroxyphenyl) propionyl) hydrazine carboxylate in 5 mL of dichloromethane, slowly add 2 mL of trifluoroacetic acid, and stir a...

Embodiment 2p

[0045] Example 2 Preparation of pH-responsive doxorubicin-polydopamine prodrug nanoparticles

[0046] Add 410mg of tris, 20mL of distilled water to a 50mL round bottom flask, stir at 30°C for 30 minutes, dissolve 12.5mg of dopamine hydrochloride and 2.74mg of the doxorubicin-dopamine conjugate molecules obtained in Example 1 in 1mL of distilled water was quickly injected into the above solution, and the reaction time was 24 hours, and the nanoparticle solution was black. Distilled water dialysis (dialysis bag molecular weight cut-off 3500) for two days, 1000mL distilled water × 8. Freeze dry for 48 hours. The yield is 38%~45%.

[0047] The dynamic light scattering pattern of the doxorubicin-polydopamine prodrug nanoparticles prepared in this embodiment is as follows: Figure 4 As shown, its number average particle diameter is 90±8nm, and PDI is 0.65±0.02.

Embodiment 3p

[0048] Example 3 Preparation of pH-responsive doxorubicin-polydopamine prodrug nanoparticles

[0049] The difference between this example and Example 2 is that the molecular weights of dopamine hydrochloride and doxorubicin-dopamine conjugate are 12.5 mg and 5 mg, respectively. The yield of the product obtained in this example is 34%-39%.

[0050] The dynamic light scattering pattern of the doxorubicin-polydopamine prodrug nanoparticles prepared in this embodiment is as follows: Figure 5 As shown, the number average particle diameter is 88±8nm, and the PDI is 0.46±0.08.

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Abstract

The invention discloses a synthetic method of a pH-response doxorubicin-dopamine conjugate and a prodrug nano particle thereof. The synthetic method comprises the steps of synthesizing a tertiary butyl-2-(3-(3,4-dihydroxyphenyl) propionyl) diamine carboxylic ester through 3,4-dihydroxyphenyl propionic acid; removing t-butyloxycarboryl through the tertiary butyl-2-(3-(3,4-dihydroxyphenyl) propionyl) diamine carboxylic ester for synthesizing 3-(3,4-dihydroxyphenyl) propanohydrazide; reacting the 3-(3,4-dihydroxyphenyl) propanohydrazide with doxorubicin hydrochloride for synthesizing a doxorubicin-dopamine conjugate molecule; synthesizing the doxorubicin-dopamine conjugate molecule and dopamine hydrochloride to obtain the doxorubicin-dopamine prodrug nano particle. Compared with the prior art, the invention provides a simple and effective way for preparing the doxorubicin-dopamine conjugate molecule and the doxorubicin-dopamine prodrug nano particle, and provides an experiment platform for obtaining a molecular drug carrier with integration of pH responsiveness, photothermal therapy and chemotherapy.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, and in particular relates to the preparation of a pH-responsive doxorubicin-dopamine conjugate and its prodrug nanoparticles. Background technique [0002] Recently, the integration of photothermal therapy and chemotherapy has attracted widespread attention in cancer treatment and has broad application prospects in clinic. Conjugated polymers (such as polypyrrole, polyaniline) and polydopamine have strong absorption in the near-infrared region, which can effectively convert near-infrared light with a wavelength of 650nm to 1000nm into heat to kill cancer cells. Polydopamine has good biocompatibility and biodegradability, and has become a new generation of efficient organic polymer photothermal therapeutic agent. At the same time, polymer prodrugs and their nano-drug systems have been extensively studied in tumor chemotherapy, and related products have entered the clinical trial stage....

Claims

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Application Information

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IPC IPC(8): C07H15/252C07H1/00C08G73/06A61K47/59A61K9/51A61K31/704A61K41/00A61P35/00
Inventor 杜畅董常明
Owner SHANGHAI JIAO TONG UNIV
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