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Biologically responsive nitric oxide donor type polymer prodrug and preparation method thereof

A body-shaped polymer and nitric oxide technology, applied in drug combinations, pharmaceutical formulations, medical preparations of non-active ingredients, etc., can solve the problems of limiting the application of small molecule chemotherapy drugs, large toxic and side effects in healthy tissues, and poor drug targeting, etc. problem, to achieve the effect of improving the tumor microenvironment, less toxic and side effects, and good stability

Pending Publication Date: 2021-05-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, most chemotherapy drugs have multiple aromatic ring structures, which have problems such as poor water solubility, fast blood clearance, poor drug targeting, and large toxic and side effects on healthy tissues, which limits the application of these small molecule chemotherapy drugs.

Method used

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  • Biologically responsive nitric oxide donor type polymer prodrug and preparation method thereof
  • Biologically responsive nitric oxide donor type polymer prodrug and preparation method thereof
  • Biologically responsive nitric oxide donor type polymer prodrug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1) Synthesis of small molecule 2-azaethyl vinyl ether (AzVE)

[0045] The synthetic route of small molecule AzVE is as follows:

[0046]

[0047] Weigh 2-chloroethyl vinyl ether (29.5mL, 0.290mol) and dissolve it in 175mL of anhydrous N, N-dimethylformamide, in N 2 Under protective conditions, sodium azide (21.2 g, 0.326 mol) was slowly added, reacted at 80°C for 5 h, and then distilled under reduced pressure to obtain 2-azaethyl vinyl ether (AzVE) as a colorless transparent liquid, producing Rate 72%, H NMR spectrum such as figure 1 shown.

[0048] (2) Synthesis of small molecule prodrug estradiol-2-azaethyl vinyl ether complex (Estradiol-AzVE)

[0049] The synthetic route of the small molecule Estradiol-AzVE is as follows:

[0050]

[0051] Take 2-azaethyl vinyl ether (0.5g, 4.4mmol) and estradiol (120mg, 0.44mmol) respectively in a reaction flask, add an appropriate amount of dichloromethane solvent, and add p-toluenesulfonic acid under nitrogen protection...

Embodiment 2

[0056] Example 2 Preparation of bioresponsive nitric oxide donor polymer estradiol prodrug micelles (PEG-PNTC-co-Estradiol)

[0057] Polymer prodrug micelles (PEG-PNTC-co-Estradiol) were prepared by solvent exchange method. Slowly add 0.1 mL of N,N-dimethylformamide solution (20 mg / mL) of polymer prodrug PEG-PNTC-co-Estradiol to 1 mL of high-purity water under ultrasonic conditions, and continue to sonicate the resulting mixed solution for half an hour , and finally dialyzed in high-purity water for 2 h. Figure 4 is the particle size characterization diagram of polymer prodrug micelles (PEG-PNTC-co-Estradiol). The results showed that the average particle size of the prodrug micelles was 103nm, and the PDI was 0.21.

Embodiment 3

[0058] Example 3 In vitro degradation experiment of bioresponsive polymer estradiol prodrug micelles (PEG-PNTC-co-Estradiol)

[0059] Prepare two parts of polymer prodrug micelles (PEG-PNTC-co-Estradiol, 1mL, 1mg / mL) and add them to the glass sample cell, add a certain amount of hydrochloric acid solution to one of the sample cells to make the final pH of the micellar solution 5.0, add an equal amount of pH 7.4 phosphate buffer solution to another sample cell to make the final pH of the micellar solution 7.4, then seal the glass sample cell with a rubber stopper, shake it evenly, and place it in a constant temperature shaker (200rpm) at 37°C. At selected times at 37°C, the particle size change of the particles was tracked by dynamic laser light scattering (DLS). Figure 5 It is the particle size diagram of the polymer prodrug micelle (PEG-PNTC-co-Estradiol) placed under different pH conditions for different times. The results showed that at pH 7.4, the particle size of the pr...

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Abstract

The invention discloses a biologically responsive nitric oxide donor type polymer prodrug and a preparation method thereof, wherein the polymer prodrug is obtained by connecting a hydroxyl-containing chemotherapeutic drug and a nitric oxide donor type polycarbonate macromolecule through a tumor microenvironment acid responsive acetal bond, and then the polymer prodrug nano-drug is obtained through self-assembly. According to the invention, chemotherapeutic drugs are modified, and a nitric oxide donor is introduced to a polymer carrier material, so that the nitric oxide donor type polymer prodrug with high drug loading capacity, high stability and biological response is prepared, drug sensitization and synergistic treatment effects are realized, and the prodrug has a wide application prospect in the aspect of efficient anti-tumor.

Description

technical field [0001] The invention relates to biomedical polymer materials and pharmaceutical preparations and a preparation method thereof, in particular to a bioresponsive nitric oxide donor polymer prodrug and a preparation method thereof. Background technique [0002] Nitric oxide (nitric oxide) is a multifunctional, dose-dependent cell signaling molecule, known as the "star molecule" in the world, it can be produced in mammals by nitric oxide synthase (nitric oxide synthase, NOS) Catalyzes the oxidation of L-arginine. Due to the good fat-soluble characteristics of NO, it is easy to pass through the phospholipid bilayer and act on the inside of the cell, thereby exerting the functions of blood vessel expansion, nerve delivery, wound healing, and tumor killing. NO is a "double-edged sword". The research results show that when the concentration of NO is lower than 50nM, NO will increase the permeability of blood vessels through vasodilator effect, which is more conduciv...

Claims

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Application Information

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IPC IPC(8): A61K47/59A61K47/60A61K9/107A61K31/565A61K31/704A61K33/00A61P35/00C08G64/42
CPCA61K47/59A61K47/60A61K9/1075A61K33/00A61K31/565A61K31/704A61P35/00C08G64/42A61K2300/00Y02P20/55
Inventor 陈维赵兵兵钟伊南黄德春
Owner CHINA PHARM UNIV
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