Amphiphilic polymer prodrug releasing original medicines through reduction response as well as preparation method and applications of amphiphilic polymer prodrug

An amphiphilic polymer and polymer technology, which can be used in drug combinations, pharmaceutical formulations, medical preparations with inactive ingredients, etc. The effect of high yield and product purity and mild reaction conditions

Active Publication Date: 2018-12-04
烟台药物研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ordinary nano-preparations cannot identify tumor sites and normal parts, nor can they distinguish between intracellular and extracellular environments. Therefore, how to selectively release the original drug from nano-preparations in vivo is still a big problem.

Method used

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  • Amphiphilic polymer prodrug releasing original medicines through reduction response as well as preparation method and applications of amphiphilic polymer prodrug
  • Amphiphilic polymer prodrug releasing original medicines through reduction response as well as preparation method and applications of amphiphilic polymer prodrug
  • Amphiphilic polymer prodrug releasing original medicines through reduction response as well as preparation method and applications of amphiphilic polymer prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] An amphiphilic polymer prodrug that releases the original drug in response to reduction has the following structural formula:

[0047]

[0048]The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0049] 1) Preparation of 2-(2-pyridyldithio)ethanol:

[0050] 2-Mercaptoethanol (0.87g, 11.1mmol) and 2,2'-dithiobipyridine (Py-SS-Py, 3.63g, 16.5mmol) were added into 100mL of methanol, and reacted at room temperature for 24 hours. Methanol was distilled off under reduced pressure, purified by silica gel column, concentrated and dried in vacuo to obtain 1.6 g of light yellow oily product with a yield of 82.8%. products tested 1 HNMR showed that 2-(2-pyridyldithio)ethanol represented by formula a was obtained.

[0051] 2) Preparation of 4-nitrophenyl-2-(2-pyridyldithio)ethyl carbonate:

[0052] 2-(2-Pyridyldithio)ethanol (1.6g, 9.19mmol) and triethylamine (1.85g, 18.3mmol) were dissolved in 100mL of dichloromethane, and phenyl p-nitrochl...

Embodiment 2

[0060] A nanomicelle containing the amphiphilic polymer prodrug obtained in Example 1 is made by the following method: 1.0 g of the polymer prodrug prepared in Example 1 is dissolved in 50 mL of water, ultrasonicated for 30 seconds, and passed through 0.22 μm filter the membrane, and add 3% (w / v) mannitol to freeze-dry to obtain the reduction-responsive polymer nanomicelle. The particle size and distribution of the nanomicelles were determined by dynamic light scattering (Dynamic Light Scattering, DLS), such as figure 2 shown; and observe the morphology of polymer nanomicelles with a transmission electron microscope (Transmission Electron Microscope, TEM), such as image 3 shown.

Embodiment 3

[0062] An amphiphilic polymer prodrug that releases the original drug in response to reduction has the following structural formula:

[0063]

[0064] The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0065] 1) Preparation of 3-(2-pyridyldithio)propanol:

[0066] 3-Mercaptopropanol (0.5 g, 5.43 mmol) and 2,2′-dithiobipyridine (Py-SS-Py, 2.4 g, 10.8 mmol) were added into 60 mL of methanol and reacted at room temperature for 24 hours. React at room temperature for 24 hours. The methanol was distilled off under reduced pressure, purified by silica gel column, concentrated, and dried in vacuo to obtain 0.87 g of a light yellow oily liquid product shown in formula e, with a yield of 79.7%.

[0067] 2) Preparation of 4-nitrophenyl-3-(2-pyridyldithio)propyl carbonate:

[0068] 3-(2-pyridyldithio)propanol (0.87g, 4.33mmol) and triethylamine (0.52g, 5.15mmol) were dissolved in 50mL of dichloromethane, and p-nitrochloroformic acid benzene was s...

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Abstract

The invention relates to amphiphilic polymer prodrug releasing original medicines through reduction response as well as a preparation method and applications of the amphiphilic polymer prodrug. The amphiphilic polymer prodrug has the molecular structural formula as shown in the formula I (the formula I is shown in the description), wherein X is NH or O; ROH is hydrophobic antitumor drug; n is 5-1000; m is 1 or 2. The prodrug provided by the invention can realize targeted drug delivery, the advantages of a nanometer drug delivery system are reserved, and meanwhile, the feature of specific degradation at the tumor site of the disulfide bond is also exerted. Compared with the conventional bonding arms including 2,2'-dithiodiglycolic acid and 3,3'-dithiodipropionic acid, the amphiphilic polymer prodrug provided by the invention has the advantage that the anti-cancer drug in the form of the original medicine molecule can be obtained without further hydrolysis.

Description

technical field [0001] The invention relates to a polymer drug prodrug and its preparation method and application, in particular to a PEGylated amphiphilic polymer drug prodrug applicable to tumor treatment as well as its preparation method and application. Background technique [0002] Chemotherapy is a basic tumor treatment method, which mainly uses anticancer drugs to kill tumor cells to achieve the purpose of treating tumors. Clinically commonly used anticancer drugs mainly include camptothecins, taxanes, vinblastine, and anthraquinones, etc., but these anticancer drugs have poor physical and chemical properties (such as insoluble in water, poor selectivity, etc.), and are not effective for normal The cells and tissues have serious toxic and side effects, resulting in poor tumor chemotherapy effect, so the clinical application is limited. [0003] Hydrophilic groups are introduced into the molecular structure of drugs through chemical modification to prepare water-solub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K45/00A61K31/337A61K31/475A61K31/4745A61K9/107A61P35/00C08G65/334
CPCA61K45/00A61K9/1075A61K31/337A61K31/4745A61K31/475C08G65/3348
Inventor 任春光李亚平李泽民孔德旭栾委静李暖暖李艺张丽刘奕彬
Owner 烟台药物研究所
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