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A kind of high drug-loaded podophyllin nano-prodrug and its preparation method and application

A podophyllotoxin and nano-sized technology, applied in the field of biomedicine, can solve problems such as undiscovered, achieve simple operation, simple preparation method, and improve the effect of pharmaceutical effects

Inactive Publication Date: 2016-06-01
CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(VetvickaD., HrubyM., HovorkaO., etal., BioconjugateChem., 2009, 20, 2090-2097.) As we all know, imine bonds are also a kind of covalent bonds that are sensitive to pH, which are more sensitive than hydrazone bonds under acidic conditions. It has better responsiveness, but so far, there has been no report on the use of imine bonds as covalent bonds connected by hydrophilic and hydrophobic segments for nanoparticle construction and drug release.

Method used

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  • A kind of high drug-loaded podophyllin nano-prodrug and its preparation method and application
  • A kind of high drug-loaded podophyllin nano-prodrug and its preparation method and application
  • A kind of high drug-loaded podophyllin nano-prodrug and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Synthesis of a PEG followed by an aminopodophyllo (NPOD) self-assembled prodrug (PEG-NPOD).

[0042] (1) Synthesis of PEG-CHO

[0043] 4.01g (5.45mmol) polyethylene glycol monomethyl ether (PEG, MW=750), 0.82g (5.46mmol) p-formylbenzoic acid and 0.33g (2.59mmol) 4- (dimethylamino) pyridine ( DMAP) was dissolved in 30ml of dichloromethane, and then 1.34g (6.54mmol) of dicyclohexylcarbodiimide (DCC) was added under ice-cooling, and the reaction solution was reacted at room temperature for 24h. After the reaction, the insoluble by-products were removed by filtration, and the filtrate was concentrated and then separated by a silica gel column. The eluent was dichloromethane / methanol 5:1, and 4.34 g of the desired product was obtained with a yield of 90.3%. The reaction formula of PEG-CHO is as follows (n=16):

[0044]

[0045] (2) Synthesis of PEG-NPOD

[0046] 1.05g (1.21mmol) of PEG-CHO was dissolved in 30ml of absolute ethanol, and then 0.59g (1.43mmol) of aminopod...

Embodiment 2

[0049] Synthesis of a self-assembled prodrug (PEG-NPOD) of one PEG followed by two aminopodophyllos (NPOD).

[0050] (1) Protection of 2,2-dimethylolpropionic acid

[0051] Dissolve 5.05g (37.28mmol) of 2,2-dimethylolpropionic acid, 7.0ml (55.91mmol) of 2,2-dimethoxypropionate and 0.355g (1.87mmol) of p-toluenesulfonic acid in 30ml of acetone , and then stirred at room temperature for 12 h. After the reaction, 0.5ml of ammonia water and ethanol solution (volume ratio 1:1) was added, and the reaction solvent was removed by rotary evaporation. The obtained solid was dissolved in 80ml of dichloromethane, and extracted twice with water (10ml each time), and separated to obtain The organic phase was dried with anhydrous sodium sulfate, and finally the solvent was removed to obtain 8.21 g of the product with a yield of 72.5%. The reaction formula is as follows:

[0052]

[0053] (2) Reaction of the protected product of 2,2-dimethylolpropionic acid with PEG:

[0054] 5.00g (6....

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Abstract

The invention discloses a prodrug of a podophyllotoxin (POD) derivative. The prodrug is formed by acid-sensitive imine bond covalent combination of a medicine molecule and hydrophilic short-chain polyethylene glycol (PEG), wherein the medicine molecule is the podophyllotoxin derivative namely amino podophyllotoxin (NPOD), and the drug loading capacity can reach over 35%. The prodrug can form a micelle with a nano structure through a self-assembly manner in a water solution. The invention further discloses application of a self-assembled prodrug micelle as a novel medicine carrier to loading hydrophobic drugs such as taxol to realize the co-therapeutic effect of the medicine. The prodrug disclosed by the invention has the advantages of simple preparation method, environmental friendliness and economical benefit, and has greater application value in the biomedical field.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and relates to a preparation method and application of a nanometer prodrug of podophyllotoxin and its derivatives. Background technique [0002] Podophyllotoxin (POD for short) and its derivatives are a class of natural substances with significant cytotoxic activity, mainly distributed in East Asia, North America and other places. This kind of substance can act on topoisomerase and is a class of potential anticancer drugs. At present, Etoposide (VP-16 for short) and Teniposide (VM-26 for short) have passed the FDA certification, and clinical tests have broad-spectrum anticancer activity. , Acute monocytic leukemia, myelomonocytic leukemia, breast cancer, bladder cancer, testicular cancer and other cancers have special curative effects, and were promoted and marketed in European and American countries in the 1970s and 1980s. Although drugs such as VP-16 and VM-26 are widely used clinically, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K31/365A61K9/51A61P35/00
Inventor 李帮经康洋哈伟张晟丁立生
Owner CHENGDU INST OF BIOLOGY CHINESE ACAD OF S
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