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

A nanomicelle, mercaptopurine technology, applied in the fields of nanomedicine, new materials, and biomedical technology, can solve problems such as unfavorable long-acting circulation, lack of biocompatibility, unable to achieve stable release, etc. Effect

Inactive Publication Date: 2013-01-23
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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] The first step, the synthesis of mPEG-NPC

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

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

[0047] 1.3) Concentrate the reaction solution and reprecipitate three times in diethyl ether, 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 drop into the first step product mPEG-NPC (3.8 g, 1.84 mmol) in DMSO solution, continued stirring for 24 hours;

[0050] 2.2) Use a dialysis bag with a molecular weight cut-off of 1000 to dial...

Embodiment 2

[0068] Assembly of targeted mercaptopurine nanomicelle prodrugs

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

Embodiment 3

[0071] Targeting the degradation of mercaptopurine nanomicelle prodrugs

[0072] A sufficient amount of dithiothreitol (DTT) was added to the above-mentioned micelles to carry out reductive degradation of the micelles, and 1 mL of samples were taken at intervals, and the change in particle size was measured by DLS. like Figure 7 As shown, with the increase of time, the particle size of the micelles gradually increased, indicating that under the reduction of DTT, the disulfide bonds were broken, and the micelles were 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, nanometer medicine and new materials, and specifically relates to a mercaptopurine nano-micelle prodrug with controllable reduction and degradation and its application. Background technique [0002] Mercaptopurine (6-MP) is an antimetabolite antineoplastic drug. It not only inhibits the synthesis of cellular DNA, but also slightly inhibits the synthesis of cellular RNA. It is mainly used clinically for the treatment of leukemia. However, the low water solubility of mercaptopurine, severe gastrointestinal reactions, and especially easy to cause liver damage and bone marrow suppression in patients limit the further improvement of its clinical efficacy. [0003] Marina Zacchigna et al. 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 and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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 UNIV
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