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Amphiphilic camptothecin polymer prodrug taking phenylboronic acid ester as connecting unit, as well as preparation method and application thereof

A linking unit and phenylboronic acid ester technology, which is applied in the field of biomedical technology, nanomedicine and new materials, can solve the problems of lack of targeting, no function of fixed-point release of drugs, and reduced activity.

Inactive Publication Date: 2018-11-02
EAST CHINA NORMAL UNIV
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  • Abstract
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Problems solved by technology

The closed lactone ring form in its molecular structure is an effective form with tumor suppressor activity, but in a physiological environment, the 20-position hydroxyl of the camptothecin lactone ring can form an intramolecular hydrogen bond with the adjacent ester carbonyl, so that Hydrolysis of the lactone ring opens, resulting in reduced activity
In addition, the poor water solubility of camptothecin hinders its application in clinical treatment
[0003] In the prior art, most construct camptothecin prodrugs by improving the solubility of camptothecin. A.V.Yurkovetskiy et al. reported that the nano drug delivery system of cyclodextrin polymer form wrapped camptothecin was discovered in 1998, 2003 On the basis of the linear cyclodextrin copolymer published in 2009, the polymer is modified by carboxylation to bond camptothecin to it (Advance DrugDelivery Review, 2009, 61, 1193-1202) to improve the dissolution of camptothecin However, this polymer prodrug lacks targeting, has poor biodegradability, and does not have the function of intracellular site-specific release of drugs
[0004] In the clinical treatment of cancer, single chemotherapy has great limitations, such as easy to produce drug resistance, increase the dose of drugs, and correspondingly increase the side effects
Inspired by the "cocktail" therapy of AIDS, a "cocktail" therapy for the treatment of cancer has been clinically developed, but the drugs cannot be distributed synergistically in the body, which has greatly limited the clinical application of this therapy
The nano-drug co-delivery system can realize the synergistic distribution of drugs in the body. Gu et al. (Biomaterials, 2014, 35, 7194-7203) used NHS-PEG 5000 -NHS constructs a camptothecin prodrug and co-delivers it with the fat-soluble drug doxorubicin to realize the synergistic distribution of the drug in the body, but the micelles constructed by it can only rely on endocytosis after passive targeting and aggregation in the tumor tissue Enter the cell to release the drug, which has certain restrictions on the concentration of the drug in the cell and its effect

Method used

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  • Amphiphilic camptothecin polymer prodrug taking phenylboronic acid ester as connecting unit, as well as preparation method and application thereof
  • Amphiphilic camptothecin polymer prodrug taking phenylboronic acid ester as connecting unit, as well as preparation method and application thereof
  • Amphiphilic camptothecin polymer prodrug taking phenylboronic acid ester as connecting unit, as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Embodiment 1, the synthesis of mPEG-3,4-DA

[0120] Weigh 3,4-dihydroxyphenylacetic acid (0.126g, 0.750mmol) and dissolve it in 25mL of anhydrous dichloromethane, disperse it by ultrasonic to form a suspension, add 1-ethyl-(3-dimethylamino Propyl)carbodiimide hydrochloride (0.154g, 0.800mmol), 1-hydroxybenzotriazole (0.108g, 0.800mmol), N,N-diisopropylethylamine (0.260mL, 1.500mmol ), after 0.5h, add mPEG-NH under nitrogen protection 2 (1.000g, 0.500mmol), the reaction device was protected from light, reacted overnight at room temperature, concentrated, added pure water to dissolve, extracted several times with dichloromethane, dried the organic phase with anhydrous sodium sulfate, concentrated the filtrate and mixed the sample and purified it through a silica gel column. The mobile phase was mixed with dichloromethane and methanol in a certain volume ratio (30:1). After the purified product was concentrated, it was added to glacial ether to precipitate, and the white...

Embodiment 2

[0124] The synthesis of embodiment 2, mPEG-BC

[0125]Weigh 3-aminophenylboronic acid (0.191g, 1.390mmol) and 200mL redistilled toluene into a 500mL single-necked flask, ultrasonically promote its dissolution, add mPEG-3,4-DA (0.300g, 0.139mmol) under nitrogen protection , react at 120°C for 5 hours, concentrate the reaction solution, add 30 mL of anhydrous tetrahydrofuran to dissolve, transfer the tetrahydrofuran solution to a dialysis bag with a molecular weight cut-off of 1000, dialyze the anhydrous tetrahydrofuran for 5 hours, add it dropwise to 100 mL of ice ether, wash and filter After three times, 0.360 g of light yellow powder mPEG-BC was obtained with a yield of 87%.

[0126] The structural formula of the mPEG-BC is shown in formula (2);

[0127]

[0128] Among them, m=44.

Embodiment 3

[0129] Embodiment 3, the synthesis of Boc-Glu(CPT)-OtBu

[0130] Weigh Boc-L-glutamate-1-tert-butyl ester (1.7416g, 5.74mmol), 4-dimethylaminopyridine (0.1754g, 1.44mmol), 1-hydroxybenzotriazole (0.4654g, 3.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.6604g, 3.44mmol), triethylamine (0.48mL, 3.44mmol), and 110mL of anhydrous di Chloromethane was placed in the reaction flask. After 0.5h, camptothecin (1.000g, 2.87mmol) was added under nitrogen protection. After reacting at room temperature for 5h, the reaction solution became clear. Add the aqueous hydrochloric acid solution of pH 1 to terminate the reaction, extract three times with saturated NaCl aqueous solution, anhydrous NaSO Dry the organic phase, after filtering, the filtrate is concentrated and mixed and purified by a silica gel column, and the mobile phase is dichloromethane and methanol by a certain volume ratio (300: 1) Mixing, the purified product is 1.54g of light yellow powder Boc-Glu...

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Abstract

The invention discloses an amphiphilic camptothecin polymer prodrug taking phenylboronic acid ester as a connecting unit and a co-delivery micelle system thereof. A polyethylene glycol-polyglutamate camptothecin two-block polymer (mPEG-BC-PGluCPT) is synthesized by taking catechol phenylborate (BC) as a connecting unit, and then a doxorubicin loaded micelle (mPEG-BC@PGluCPT.Dox) of the polymer isconstructed. Aiming at the poor water solubility of camptothecin, a polymer prodrug using camptothecin as a hydrophobic end by modifying 20 sites of hydroxyl groups of camptothecin is synthesized, which can effectively promote the assembly of the two-block polymer into a micelle. The solubility of camptothecin is improved, the stability of a camptothecin lactone ring is increased, and the curativeeffect and bioavailability are improved in order to overcome limitations of clinical treatment of camptothecin. The amphiphilic camptothecin polymer prodrug prepared by the method provided by the invention can be used for constructing a nano drug common delivery system, and has good drug release property, strong cell inhibition rate and good cell phagocytosis.

Description

technical field [0001] The invention relates to the technical fields of biomedicine technology, nanomedicine and new materials, in particular to the synthesis of an amphiphilic camptothecin polymer prodrug with phenylboronate as a linking unit and the construction and construction of a co-delivery micelle system. application. Background technique [0002] Traditional chemotherapy drugs have achieved great success in the treatment of tumors, but there are many limitations that limit the further improvement of their clinical efficacy, such as serious side effects, poor selectivity, and tumor cells are prone to drug resistance, etc. . Camptothecin (CPT) is a tryptophan-terpene alkaloid anticancer drug, which has a significant effect on the treatment of various malignant tumors. Replication, transcription and mitosis. The closed lactone ring form in its molecular structure is an effective form with tumor suppressor activity, but in a physiological environment, the 20-position...

Claims

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Application Information

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IPC IPC(8): C08G65/333C08G65/332C08G65/337A61K31/4745A61K31/704A61K9/107A61P35/00
CPCA61K9/1075A61K31/4745A61K31/704C08G65/3326C08G65/33306C08G65/33396C08G65/337C08G2650/02A61K2300/00
Inventor 余家会高雅黄钰淑张晗
Owner EAST CHINA NORMAL UNIV
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