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Amphiphilic polymeric prodrugs for reducing and releasing original drug and preparation method thereof

An amphiphilic polymer and drug technology, applied in the field of medicine and chemical industry, can solve the problems of inability to distinguish cells, inability to identify tumor sites, etc., and achieve the effects of easy availability of raw materials, mass production, and mild reaction conditions.

Active Publication Date: 2018-05-25
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 polymeric prodrugs for reducing and releasing original drug and preparation method thereof
  • Amphiphilic polymeric prodrugs for reducing and releasing original drug and preparation method thereof
  • Amphiphilic polymeric prodrugs for reducing and releasing original drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1, the synthesis of polyethylene glycol-disulfide bond-SN38

[0048] (1) Preparation of 4-mercaptobutyric acid:

[0049] Add 4-bromobutyric acid (10 g, 59.9 mmol) and thiourea (6.37 g, 83.8 mmol) into 250 mL of ethanol, and reflux for 4 hours. After dissolving NaOH (24 g, 600 mmol) in 250 mL of ethanol, it was added into the reaction system, and the reflux was continued for 16 hours. Cool to room temperature, filter to obtain a white solid, add water to dissolve. The aqueous phase was washed with ether, separated, adjusted to pH 1 with 2M HCl, extracted with ether, dried over anhydrous sodium sulfate, and dried in vacuo to obtain 4.9 g of light yellow oil with a yield of 68%. products tested 1 H NMR shows that the 4-mercaptobutyric acid of structure shown in formula a is obtained, such as figure 1 .

[0050] (2) Preparation of 4-(2-pyridyldithio)butanoic acid:

[0051] 4-mercaptobutyric acid (4.9 g, 40.8 mmol) and dithiobipyridine (Py-SS-Py, 18 g, 81.7 ...

Embodiment 2

[0059] Embodiment 2, the synthesis of different molecular weight polyethylene glycol-disulfide bond-SN38

[0060] Synthetic method is the same as embodiment 1, wherein with mPEG 1000 -SH or mPEG 5000 -SH replaces mPEG 2000 -SH, to obtain polyethylene glycol-disulfide bond-SN38 conjugates of different molecular weights.

Embodiment 3

[0061] Embodiment 3, the synthesis of polyethylene glycol-disulfide bond-cabazitaxel

[0062] (1) Preparation of 5-(2-pyridyldithio)pentanoic acid:

[0063] Add 5-bromobutyric acid (2 g, 11 mmol) and thiourea (1.18 g, 15.5 mmol) into 60 mL of ethanol, and reflux for 4 hours. After dissolving NaOH (4.4g, 110mmol) in 60mL of ethanol, it was added into the reaction system, and the reflux was continued for 16 hours. Cool to room temperature, filter to obtain a white solid, add water to dissolve. The aqueous phase was washed with ether, separated, adjusted to pH 1 with 2M HCl, extracted with ether, dried over anhydrous sodium sulfate, and dried in vacuo to obtain 0.88 g of a light yellow oil.

[0064] (2) The light yellow oil and dithiobipyridine (Py-SS-Py, 2.9 g, 13.1 mmol) were dissolved in 30 mL of methanol, and reacted at room temperature for 3 hours. The methanol was distilled off under reduced pressure, separated through a neutral alumina column, concentrated, and dried in...

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Abstract

The invention relates to an amphiphilic polymeric prodrug for reducing and releasing an original drug and a preparation method thereof. The method has the advantages of a wide range of applicable medicines, easy availability of raw materials, high yield, high purity and the like. A hydrophilic polymer and a hydrophobic drug in the amphipathic polymeric prodrug are linked through a connecting arm containing a self-disrupting disulfide bond, and the disulfide bond breaks and undergoes molecular rearrangement in a tumor cell reducing environment. An original drug molecule is released to ensure activity of the drugs, and can self-assemble into nanomicelles in an aqueous medium, and is expected to achieve long-term circulation in vivo and increase accumulation in tumor tissues, thereby achieving purposes of improving drug efficacy and reducing toxic and side effects.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a reduction-response-releasing amphiphilic drug precursor formed of a hydrophilic polymer and a hydrophobic drug and a preparation method thereof. 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. And tissue have serious toxic and side effects, resulting in poor tumor chemotherapy effect, so the clinical application is limited. [0003] The introduction of hydrophilic groups through chemical modification to prepare water-soluble prodrugs can effectively solve the problem of water solubility of drugs. Among water-soluble high molecular polymers, polyethylene glycol has received extensive attention. Polyethyl...

Claims

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Application Information

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IPC IPC(8): A61K47/60A61K47/69A61K47/54A61K31/337A61K31/475A61K31/4745A61P35/00C08G65/334
CPCA61K31/337A61K31/4745A61K31/475C08G65/3348
Inventor 任春光李亚平孔德旭李暖暖李艺
Owner 烟台药物研究所
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