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Reductively degradable mercaptopurine nanometer micellar prodrug with controllable drug release and application thereof

A technology of nano-micelle and mercaptopurine, which is applied in the field of nano-medicine and new materials, and biomedical technology, can solve the problems of unfavorable long-term circulation, lack of biocompatibility, and inability to achieve stable release, and achieve the goal of reducing drug toxicity and side effects Effect

Inactive Publication Date: 2012-02-01
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cytotoxicity experiments have proved that the modified mercaptopurine has reduced toxicity to cells, but its high hydrophobicity is not conducive to long-term circulation in the body, lacks biocompatibility, and cannot achieve stable release. Addressing deficiencies of original small molecule mercaptopurine drugs (T. Miron, F. Arditti, L. Konstantinovski, A. Rabinkov, D. Mirelman A. Berrebi, M. Wilchek, European Journal of Medicinal Chemistry 44 (2009) 541-550)

Method used

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  • Reductively degradable mercaptopurine nanometer micellar prodrug with controllable drug release and application thereof
  • Reductively degradable mercaptopurine nanometer micellar prodrug with controllable drug release and application thereof
  • Reductively degradable mercaptopurine nanometer micellar prodrug with controllable drug release and application thereof

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Embodiment 1

[0043] Preparation of mercaptopurine nanomicelle prodrug of the present invention

[0044] Step 1: Synthesis of mPEG-NPC

[0045] 1.1) Take mPEG (Mw= 1900, 7.6 g, 4 mmol) and p-nitrophenyl chloroformate (NPC, 3.21 g, 16 mmol) and dissolve them in 30 mL of dichloromethane (DCM);

[0046] 1.2) Add 0.81 mL (10 mmol) of pyridine to the mPEG solution in DCM, drop NPC into the mPEG solution drop by drop under the protection of nitrogen at room temperature, and stir for 24 h;

[0047] 1.3) Concentrate the reaction solution and re-precipitate in ether 3 times, and then vacuum dry to obtain mPEG-NPC.

[0048] The second step, mPEG-SS-NH 2 Synthesis

[0049] 2.1) Dissolve cystamine dihydrochloride (2.89 g, 12.88 mmol) and triethylamine (4.21 mL, 30 mmol) in dimethyl sulfoxide (DMSO), and gradually drip into the first product mPEG-NPC (3.8 g, 1.84 mmol) in DMSO solution, keep stirring for 24 hours;

[0050] 2.2) Dialysis the mixed solution with a dialysis bag with a molecular weight cut-off of 1000...

Embodiment 2

[0068] Assembly of targeted mercaptopurine nanomicelle prodrugs

[0069] Weigh 20 mg of lyophilized mPEG-SS-NH-g-PAsp-MP and dissolve it in 10 mL of deionized water. After ultrasonic vibration, amphiphilic nanomicelles are formed. The particle size measured by dynamic light scattering is 160 nm. ( Image 6 ), belongs to the nanometer level.

Embodiment 3

[0071] Degradation of targeted mercaptopurine nanomicelle prodrugs

[0072] Sufficient dithiothreitol (DTT) was added to the aforementioned micelles to reduce the degradation of the micelles, and 1 mL was sampled at regular intervals, and the change in particle size was measured by DLS. Such as Figure 7 It is shown that with the increase of time, the particle size of the micelles gradually increases, indicating that under the reducing action of DTT, the disulfide bonds are broken, and the micelles are degraded and agglomerated to increase the particle size.

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Abstract

The invention discloses a reduction-sensitive mercaptopurine nanometer micellar prodrug with controllable drug release and application thereof. According to the invention, considering deficiency of small molecular mercaptopurine drugs, mercaptopurine and polyethylene glycol derivatives are grafted on main chains of imide polyasparate through a ring-opening reaction and a mercaptan-disullfide exchange reaction so as to synthesize the high-molecular micellar prodrug which is capable of molecular self-assembly at nanometer scale in human bodies, has a particle size of about 160 nm, a narrow distribution scope and long-acting cycles in blood, is targeted to cancer tissue, and has a controllable drug release rate. The objectives of the invention are to improve water-solubility of original mercaptopurine, to minimize toxic and side effects of original mercaptopurine and enhance curative effects and bioavailability simultaneously so as to overcome the bottleneck of undesirable clinical therapeutic effects on acute lymphocytic leukemia at present.

Description

Technical field [0001] The invention belongs to the fields of biomedicine technology, nano medicine and new materials, and specifically relates to a mercaptopurine nanomicelle prodrug with controllable reduction and lowering interpretive drugs and its application. Background technique [0002] Mercaptopurine (6-MP) is an anti-metabolic anti-tumor drug. In addition to inhibiting the synthesis of cellular DNA, it also has a mild inhibitory effect on the synthesis of cellular RNA. It is mainly used in the clinical treatment of leukemia. However, the low water solubility of mercaptopurine, severe gastrointestinal reactions, especially easy to cause liver damage and bone marrow suppression, limit the further improvement of its clinical efficacy. [0003] Marina Zacchigna and others introduced the hydrophilic unit polyethylene glycol (PEG) to modify mercaptopurine and synthesized the polymer prodrug PEG-MP-PEG, which improved the water solubility of mercaptopurine and reduced its toxic a...

Claims

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Application Information

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IPC IPC(8): A61K31/795A61P35/02
Inventor 余家会张许柱郭倩吴庆娥骆萍黄进
Owner EAST CHINA NORMAL UNIVERSITY
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