Novel orthoester crosslinking agent monomer and method using same to prepare acid-sensitive nano drug carrier

A nano-drug carrier and cross-linking agent technology, which can be used in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve the problems of reducing drug efficacy, achieve good biocompatibility, prolong internal delivery time, and enhance tumor targeting. tropism effect

Active Publication Date: 2016-11-09
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional acid sensitivity is mainly based on the change of the pKa value of the ionic group. This acid sensitivity is easily removed by protein adsorption in the body and reduces the efficacy of the drug.

Method used

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  • Novel orthoester crosslinking agent monomer and method using same to prepare acid-sensitive nano drug carrier
  • Novel orthoester crosslinking agent monomer and method using same to prepare acid-sensitive nano drug carrier
  • Novel orthoester crosslinking agent monomer and method using same to prepare acid-sensitive nano drug carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of N'N-{2-[2-methoxy-[1,3]dioxolane-4-methyleneoxy)]-ethyl}-2-methacrylamide

[0033] Under nitrogen atmosphere, add orthoester diamine monomer 5.59g (18.1mmol) triethylamine 5.49g (54mmol) and 100ml dichloromethane in the three-necked flask of 250ml, after stirring and dissolving, methacrylic anhydride 5.58g (36.2 mmol) was added dropwise to the above mixture, and after overnight reaction at room temperature, the crude product was separated by silica gel column chromatography to obtain 5.06 g of a yellow oily product with a yield of 53%. 1 H NMR (400MHz, CDC1 3 ): δ(ppm)1.97(s,6H,C-CH 3 ),3.32-3.33(m,3H,O-CH 3 ),3.48-3.75(m,8H,CHZ-O-CH 2 ,O-CH 2 -CH 2 -NH),3.77-4.2(m,4H,CH-O-CH 2 ),4.28-4.51(m,2H,O-CH-CH 2 ),5.34-5.36(m,2H,C=CH 2 ),5.71-5.76(m,2H,CH-(O) 3 ),5.84-5.86(m,2H,C=CH 2 ). 3 CNMR (400MHz, CDC1 3 ,8):18.49,39.33,42.37,61.53,65.64,66.02,71.62,72.5574.05,75.02,115.40,115.89,119.81,139.70,168.49. 20 h 32 N 2 o 9 ),444.21,found m / z,443.2...

Embodiment 2

[0035] Preparation of polyethylene glycol monomethyl ether acrylamide

[0036]Under a nitrogen atmosphere, dissolve 5.28g (9.6mmol) of polyethylene glycol monomethyl ether and 2.9g (28.8mmol) of triethylamine into a 250ml three-necked flask. After stirring and dissolving, add 2.6g (28.8mmol) of acryloyl chloride dropwise Added to the above solution, after overnight reaction at room temperature. Remove a small amount of triethylamine hydrochloride by filtration, add dichloromethane to dilute the reaction solution, use 0.5M HCl, 5% NaCHO 3 Wash the organic phase with saturated NaCl solution, dry the organic phase with anhydrous magnesium sulfate, filter, and remove the organic solvent under reduced pressure to obtain 5.53 g of viscous liquid with a yield of 86.2%. 1 H NMR (400MHz, CDC1 3 )δ(ppm): 3.24(s,3H,PEG-OCH 3 ), 3.51(s, MPEG), 5.76(s, 1H, C=CH 2 ),6.05(s,1H,CH),6.30(s,1H,C=CH 2 ).

Embodiment 3

[0038] Preparation of Acid Sensitive Nano Drug Carriers

[0039] N'N-{2-[2-methoxy-[1,3]dioxolane-4-methyleneoxy)]-ethyl}-2-methacrylamide, polyethylene glycol mono Methyl ether acrylamide, sodium lauryl sulfate and ultrapure water were added into a one-necked flask, and stirring was started to dissolve completely. Nitrogen gas was introduced under the liquid surface to exclude air, the temperature of the oil bath was raised to 70°C and nitrogen gas was continuously introduced, and potassium persulfate was added to initiate polymerization, the stirring speed was adjusted, and the reaction was terminated after 5 hours of reaction. After the reaction solution is cooled, it is loaded into a dialysis bag and dialyzed in ultrapure water, and then freeze-dried to obtain a nano drug carrier. Nano-drug carriers with controllable particle size can be prepared by changing the amount of cross-linking agent, the results are shown in the attached Figure 4 .

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Abstract

The invention discloses novel orthoester crosslinking agent monomer and a method using the same to prepare an acid-sensitive nano drug carrier. The novel orthoester crosslinking agent monomer is good in acid sensitivity, and the acid-sensitive nano drug carrier built by using the novel orthoester crosslinking agent monomer is good in biocompatibility and biodegradability and promising in application prospect in the field of tumor treatment.

Description

technical field [0001] The invention relates to a novel acid-sensitive cross-linking agent monomer containing orthoester groups and a nano drug carrier prepared therefrom, belonging to the technical field of drug carrier and drug controlled release. Background technique [0002] In recent years, cancer has become the number one killer threatening human health. According to the survey, the number of people who died of cancer worldwide in 2008 was 7.6 million, and this figure reached 8.2 million in 2012. There are about 3.12 million new cancer cases in my country every year, an average of 8,550 people per day, and 6 people are diagnosed with cancer every minute in the country. Currently, chemotherapy is the most commonly used and most effective treatment to suppress malignant tumors. However, traditional chemotherapeutic drugs have many shortcomings, such as: poor solubility, no target tissue selectivity, high toxicity, and irreversible damage to normal tissues. In order to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K9/19A61P35/00A61K31/704
CPCA61K9/19A61K31/704A61K47/34
Inventor 唐汝培杨冠青
Owner ANHUI UNIVERSITY
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