Tumor targeted prodrug having endosome escaping function as well as nano preparation and preparation method of tumor targeted prodrug

An escape function and endosome technology, which is applied in the field of tumor-targeted prodrugs, can solve the problems of lack of endosome escape ability and inability to fully exert the drug effect

Inactive Publication Date: 2015-12-23
SHANGHAI PUTUO DISTRICT CENT HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, drugs need to escape from endosomes/lysosomes to play an anti-tumor effect; and the existing nano-drug systems usually do not have good end

Method used

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  • Tumor targeted prodrug having endosome escaping function as well as nano preparation and preparation method of tumor targeted prodrug
  • Tumor targeted prodrug having endosome escaping function as well as nano preparation and preparation method of tumor targeted prodrug
  • Tumor targeted prodrug having endosome escaping function as well as nano preparation and preparation method of tumor targeted prodrug

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preparation example Construction

[0052] In the second aspect, the present invention provides a method for preparing the above-mentioned tumor-targeting prodrug with endosome escape function, and its synthesis route is shown in the attached figure 1 , including the following steps:

[0053] (1) Preparation of intermediate product P(OEGMA-co-BSMA-co-BEMA):

[0054] A certain amount of reversible addition-fragmentation chain transfer initiator BPTPA, oligoethylene glycol methacrylate OEGMA, monomer BSMA containing β-thiocarboxyl group, monomer BEMA containing atom transfer radical initiator, solvent and free Add the base initiator into the glass tube, freeze and thaw three times in vacuum and then seal the tube; then, react at 20-80°C for 0.5-40 hours to obtain the crude product P(OEGMA-co-BSMA-co-BEMA), and finally the The crude product P(OEGMA-co-BSMA-co-BEMA) was purified to obtain the P(OEGMA-co-BSMA-co-BEMA).

[0055] (2) Preparation of intermediate product P(OEGMA-co-BSMA)-g-P(DEA-co-BMA):

[0056]Add a...

Embodiment 1

[0083] cRGD-modified poly(oligoethylene glycol methacrylate-co-bufalin-co-RGD)-g-poly(N,N-diethylaminoethyl methacrylate- co-n-butyl methacrylate) tumor targeting prodrug, namely the preparation of P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA):

[0084] (1) Preparation of P(OEGMA-co-BSMA-co-BEMA): BPTPA (33mg0.1mmol), OEGMA (3.0g, 6mmol), BSMA (686mg, 2.5mmol), BEMA (140mg, 0.5mmol) and AIBN (1.6 mg) was added to a glass tube, and 10 mL of dioxane was added, and the tube was sealed after vacuum freezing and thawing three times. Thereafter, the reaction was carried out at 70° C. for 5 hours. The crude product obtained from the reaction was dialyzed in water for 24 hours to remove impurities, and after freeze-drying, the P(OEGMA-co-BSMA-co-BEMA) was obtained. The molecular weight M of the obtained P (OEGMA-co-BSMA-co-BEMA) determined by GPC n =30,300, molecular weight distribution M w / M n = 1.07.

[0085](2) Preparation of P(OEGMA-co-BSMA)-g-P(DEA-co-BMA): P(OEGMA-co-BSMA-co-BEM...

Embodiment 2

[0089] Preparation of P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA) nanoparticle solution:

[0090] Dissolve 10 mg of P(OEGMA-co-BUF-co-RGD)-g-P(DEA-co-BMA) in 1 mL of DMSO, drop the solution into 9 mL of stirring water, and then put the solution into a dialysis bag (molecular weight cut-off of 7,000 Da ) in dialysis for 24 hours to remove the organic solvent to obtain a nanoparticle solution. Its particle size is about 148.4nm (±0.65) (see Figure 4 ), potential -7.6mV (±0.37). Cytotoxicity experiments show that its killing effect on various cancer cells is significantly better than that of free bufolin. Such as Figure 5 As shown, the killing effect of targeted nano-drugs on colorectal cancer cell line LoVo, its IC50 is much lower than that of free bufalin.

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Abstract

The invention provides a tumor targeted prodrug having an endosome escaping function; the tumor targeted prodrug is P (OEGMA-co-BUF-co-RGD)-g-P (DEA-co-BMA), wherein POEGMA is a water-soluble polymer having a long circulation function, BUF is chemotherapeutic bufalin having an antineoplastic activity, cRGD is polypeptide capable of targeting tumor tissues actively and P (DEA-co-BMA) is a polymer having an endosome escaping function. The invention also provides a method for preparing the tumor targeted prodrug, as well as a nano preparation and a preparation method of the tumor targeted prodrug having the endosome escaping function. The nano preparation can be used for effectively killing cancer cells with a relatively low dosage; and an effect of killing various cancer cells is obviously better than that of a free bufalin medicine.

Description

technical field [0001] The invention relates to the technical field of tumor-targeted delivery and sustained-release drug delivery system, in particular to a tumor-targeted prodrug with endosome escape function, a preparation method of the prodrug, a nano-preparation of the prodrug and the nano-preparation method of preparation. Background technique [0002] The incidence of cancer is increasing year by year, and it has become one of the most serious diseases threatening human health (Siegel R.L. etal, 2015, CA Cancer J Clin, 2015, 65:5-29). Chemotherapy, as an important treatment method besides surgery and radiotherapy, has been widely used all over the world. However, most chemotherapeutic drugs (such as doxorubicin, paclitaxel, camptothecin, etc.) have serious disadvantages such as poor water solubility, uncontrollable release, low bioavailability, and large toxic and side effects. However, the development of a new type of anticancer drug often has unfavorable factors s...

Claims

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Application Information

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IPC IPC(8): A61K31/585A61K47/48A61P35/00
Inventor 刘涛殷佩浩袁易彭文袁夏贾婷婷邱艳艳邹瑜石晓静于卉
Owner SHANGHAI PUTUO DISTRICT CENT HOSPITAL
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