Ph-responsive polypeptide polymer based on cholesterol modification, preparation method and application

A technology of peptide polymers and cholesterol, which is applied in the direction of non-active ingredients of high molecular compounds, drug combinations, emulsion delivery, etc., can solve the problem of decreased white blood cells, red blood cell platelets, reduced drug availability and therapeutic effect, normal tissue cell damage, etc. problem, to achieve the effect of accelerating drug release rate, improving pH response sensitivity and release efficiency, and increasing drug loading

Active Publication Date: 2017-06-06
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But there are the following problems: (1) Poor drug solubility: most anticancer drugs, such as paclitaxel, camptothecin, doxorubicin, etc., are hydrophobic, and precipitation and aggregation will occur in blood circulation, which greatly affects the Reduced drug availability and therapeutic effect; (2) high toxicity and side effects: because drugs in the blood circulation non-selectively enter cells in the body including malignant tumor cells and normal tissue cells, and most drugs have strong toxicity, such as a Mycin has cardiotoxicity, which can damage normal tissue cells and cause serious side effects on the body, resulting in a decrease in the number of white blood cells, red blood cells and platelets, nausea, vomiting and hair loss, etc., and even life-threatening; (3) Tumor (cancer cells) Drug resistance: In the early stage of chemotherapy, cancer cells in the patient's body respond to anticancer drugs, and there are relief phenomena such as tumor volume reduction. However, with the enhancement of the drug resistance mechanism of the tumor, it often leads to the failure of chemotherapy and the patient's result of death
The usual micellar drug-loading system is divided into an outer protective layer and an inner drug-loaded core, so that the drug-loaded core also plays a role in pH response, so that the pH response of micelles, micellar inflation, and drug release are in an almost simultaneous process. , the drug release rate is too fast, the burst release effect is obvious, and the drug loading capacity will be reduced, making the drug effect of the entire drug loading system unsatisfactory

Method used

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  • Ph-responsive polypeptide polymer based on cholesterol modification, preparation method and application
  • Ph-responsive polypeptide polymer based on cholesterol modification, preparation method and application
  • Ph-responsive polypeptide polymer based on cholesterol modification, preparation method and application

Examples

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Embodiment 1

[0070] Example 1: Preparation of pH-responsive polypeptide polymer based on cholesterol modification

[0071] The reaction formula for the preparation of pH-responsive polypeptide polymers based on cholesterol modification is shown in figure 1 .

[0072] (1) The preparation of the polypeptide having the structure shown in formula (2) can be prepared by conventional solid-phase synthesis polypeptide preparation method, which can be prepared by the following method: put 2-chlorotrityl chloride resin (2-Chlorotrityl Chloride Resin) into Into the reaction tube, add dichloromethane (15mL / g), shake for 30min. Remove the solvent by suction filtration, add a 3-fold molar excess of Fmoc-Cys(Trt)-OH amino acid, add N,N-dimethylformamide to dissolve, and then add a 10-fold molar excess of N,N-diisopropylethylamine , shake for 60min, seal with methanol, add 20% piperidine N,N-dimethylformamide solution (15mL / g), mix for 15min, and use N,N-dimethylformamide solution and dichloromethane s...

Embodiment 2

[0076] Example 2: Preparation of pH-responsive polypeptide polymer based on cholesterol modification

[0077] (1) The preparation of the polypeptide shown in formula (3) adopts the conventional solid-phase synthesis polypeptide preparation method, which can be prepared by the following method: 2-Chlorotrityl Chloride Resin (2-Chlorotrityl Chloride Resin) is put into the reaction Add dichloromethane (15mL / g) to the tube and shake for 30min. Filter out the solvent through a sand core, add 3-fold molar excess of Fmoc-Cys(Trt)-OH amino acid, add N,N-dimethylformamide to dissolve, and then add 10-fold molar excess of N,N-diisopropyl ethylamine, shaken for 60min. Block with methanol. Add 20% piperidine N,N-dimethylformamide solution (15mL / g), mix for 15min, rinse with N,N-dimethylformamide solution and dichloromethane solution twice. Add three times the molar amount of amino acid and O-benzotriazole-tetramethyluronium hexafluorophosphate, and ten times the molar amount of N,N-dii...

Embodiment 3

[0080] Example 3: Preparation of pH-responsive polypeptide polymer based on cholesterol modification

[0081] (1) The preparation of the polypeptide shown in formula (4) adopts the conventional solid-phase synthesis polypeptide preparation method, which can be prepared by the following method: 2-Chlorotrityl Chloride Resin (2-Chlorotrityl Chloride Resin) is put into the reaction Add dichloromethane (15mL / g) to the tube and shake for 30min. Filter out the solvent through a sand core, add 3-fold molar excess of Fmoc-Cys(Trt)-OH amino acid, add N,N-dimethylformamide to dissolve, and then add 10-fold molar excess of N,N-diisopropyl ethylamine, shaken for 60min. Block with methanol. Add 20% piperidine N,N-dimethylformamide solution (15mL / g), mix for 15min, rinse with N,N-dimethylformamide solution and dichloromethane solution twice. Put in a three-fold molar excess of the special raw material Fmoc-Lys(Fmoc)-OH, a three-fold molar excess of O-benzotriazole-tetramethyluronium hexa...

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Abstract

The invention belongs to the technical field of high-molecular polymer materials for biological medicines, and discloses a cholesterol modification based pH response polypeptide polymer as well as a preparation method and application thereof. The polypeptide polymer has a structure shown in a formula (1): mPEG-R-Chol (1). The polypeptide polymer disclosed by the invention is a polypeptide pH response amphiphilic tri-block polymer material which is hydrophilically modified by methoxy polyethylene glycol and is hydrophobically modified by cholesterol, can be self-assembled to be nano-micelles in an aqueous solution, can be used for effectively encapsulating water-insoluble medicines, can be applied to the field of medicines, and is particularly suitable for preparing a targeted medicine delivery system of water-insoluble anti-cancer medicines. Moreover, the polypeptide polymer is adjustable and controllable in topological structure and simple in synthesis process, and can be used for adjusting and controlling the release rate of the medicines by adjusting the content of polypeptide with pH response so as to ensure that the release requirements of different medicines can be met. The polypeptide polymer disclosed by the invention has relatively low critical aggregation concentration, and the critical aggregation concentration is only 1.8-4.8mg / L, so that high stability of the medicine delivery micelles can be achieved.

Description

technical field [0001] The invention belongs to the technical field of high-molecular polymer materials for biomedicine, and in particular relates to a pH-responsive polypeptide polymer based on cholesterol modification, a preparation method and an application. Background technique [0002] Cancer (cancer) or malignant tumor (malignant neoplasm) is a disease caused by the abnormality of the control mechanism of cell growth and proliferation. The World Health Organization pointed out that cancer kills more than 7 million people every year in the world, and this number will increase rapidly. By 2030, it may exceed 13.1 million. , There are about 3.12 million new cancer cases, an average of 8,550 people per day, and 6 people are diagnosed with cancer every minute across the country. Cancer has been listed as the "No. 2 killer" facing human beings, and cancer has increasingly become the main killer that endangers human life and health. At present, the treatment of cancer is ma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G81/00A61K9/10A61K47/42A61P35/00
Inventor 章莉娟张灿阳陈全吴文胜姚娜
Owner SOUTH CHINA UNIV OF TECH
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