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Preparation method and application of EPR effect enhanced combined pharmacy system

A combined drug and enhanced technology, which is applied in the direction of medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, can solve the problems that anti-vascular drugs cannot achieve the desired effect and affect practical applications. Achieve the effects of strong tumor tissue diffusion, increased vascular permeability, and simple preparation process

Active Publication Date: 2018-12-14
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Antivascular drugs alone often cannot achieve the desired effect, which greatly affects its practical application

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation method of a kind of EPR effect-enhanced combined drug system of the present invention is:

[0028] (1) Synthesis of blood vessel targeting nanoparticles (Alg-CA4):

[0029] Add 50mg of sodium alginate (Alg) to 4ml of formamide, stir magnetically at 50°C and 450rpm for 2.5h to swell, then magnetically stir at room temperature and 450rpm for 15h to obtain solution A; ), 22mg 4-dimethylaminopyridine (DMAP), 28µl 2,4,6-trichlorobenzoyl chloride, 25µl triethylamine, dissolved in 3ml formamide, magnetically stirred at room temperature for 25min and mixed uniformly to obtain solution B; B was added to solution A, and magnetically stirred at room temperature for 20 hours, so that compretin was grafted onto sodium alginate through the Yamaguchi reaction to obtain the product; 20ml of ether was added to the product, and it was left to settle at 4°C for 2h, Centrifuge at 10000r for 35min, collect the precipitate, redissolve the precipitate in 1.5ml formamide, tran...

Embodiment 2

[0035] The preparation method of a kind of EPR effect-enhanced combined drug system of the present invention is:

[0036] (1) Synthesis of blood vessel targeting nanoparticles (Alg-CA4):

[0037] Add 50mg of sodium alginate (Alg) to 4ml of formamide, stir magnetically at 55°C and 480rpm for 2h to swell, then magnetically stir at room temperature at 480rpm for 12h to obtain solution A; , 44mg 4-dimethylaminopyridine (DMAP), 56µl 2,4,6-trichlorobenzoyl chloride, 50µl triethylamine, dissolved in 4ml formamide, magnetically stirred at room temperature for 30min to obtain solution B; Add it into solution A, stir magnetically at room temperature for 24 hours, and graft compretin (CA4) onto sodium alginate through the Yamaguchi reaction to obtain the product; add 25ml of ether to the product, and stand at 4°C to precipitate 3, Centrifuge at 12000r for 30min at 4°C, collect the precipitate, redissolve the precipitate in 2ml formamide, transfer to a dialysis bag with MWCO=3500, dialyz...

Embodiment 3

[0043] The preparation method of a kind of EPR effect-enhanced combined drug system of the present invention is:

[0044] (1) Synthesis of blood vessel targeting nanoparticles (Alg-CA4):

[0045] Add 120mg of sodium alginate (Alg) to 6ml of formamide, stir magnetically at 55°C and 470rpm for 2h to swell, then magnetically stir at room temperature and 470rpm for 13h to obtain solution A; , 30mg 4-dimethylaminopyridine (DMAP), 40µl 2,4,6-trichlorobenzoyl chloride, 35µl triethylamine, dissolved in 4ml formamide, magnetically stirred at room temperature for 30min to obtain solution B; Add it into solution A, stir magnetically at room temperature for 25 hours, and graft compretidine (CA4) onto sodium alginate through the Yamaguchi reaction to obtain the product; add 25ml of ether to the product, and let it stand for precipitation at 4°C for 3 hours. Centrifuge at 13,000r for 28min at 4°C, collect the precipitate, redissolve the precipitate in 1.5-2.5ml formamide, transfer to a dia...

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Abstract

The invention relates to a preparation method and application of an EPR effect enhanced combined pharmacy system, and can effectively solve the problem of preparation of anti-tumor drugs. The technical proposal comprises that a pharmaceutical adjuvant sodium alginate with good biocompatibility and easy gelation is used as a base material, Fe<3+> is used as a crosslinking agent and a door controlled switch, hydroxychloroquine and combretastatin are used as model drugs, combretastatin is used as a vascular target molecule, and a nano gel as an anti-tumor deliquite system is built. The preparation process is simple, stable and reliable, and has the advantages of energy saving and environmental protection. The prepared EPR effect enhanced combined pharmacy system can be efficiently accumulatedat a tumor target site and achieves long-term controlled release effect; under the stimulation of tumor microenvironment, the particle size can be transformed from big to small, and deep penetrationof tumors can be achieved; endogenous H2O2->.OH transformation can be activated and is used for local high-efficiency treatment of tumors. Anti-vascular and anti-autophagy combined pharmacy can play asynergistic and significant treatment effect and a new strategy is provided for improving the efficiency of tumor treatment.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a preparation method and application of an EPR effect-enhanced combined drug system. Background technique [0002] Compared with normal tissue, due to the rapid proliferation of tumor cells, the blood vessels and lymphatic vessels in the tumor tissue are incomplete, which makes it easy for nano-medicine to leak from the blood vessels into the tumor tissue, and it is difficult to return from the lymphatic vessels, resulting in enhanced tumor viability. Penetration and retention effect (enhanced permeability and retention effect, EPR effect). The EPR effect is known as the cornerstone of nano-drug delivery, however, the EPR effect is weak, and nano-drugs only increase delivery by 20-30% compared with normal organs. It has been reported that the EPR effect can be improved by affecting several parameters: (1) modulating tumor blood flow (2) modulating tumor vasculature and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/06A61K47/36A61K31/4706A61K31/09A61P35/00
CPCA61K9/06A61K31/09A61K31/4706A61K47/36A61P35/00A61K2300/00
Inventor 张红岭张慧娟任延平张振中侯琳
Owner ZHENGZHOU UNIV
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