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Reduction trigger type polypeptide modified hyaluronic acid conjugate carrier and preparation method thereof

A technology of hyaluronic acid and polypeptide modification, applied in drug combinations, microcapsules, inactive components of polymer compounds, etc., can solve the lack of targeting of small molecule chemotherapy drugs, limit the clinical use of antitumor drugs, damage organs and tissues and other problems, to achieve a good application prospect, avoid long-term accumulation, and reduce the effects of toxic and side effects

Inactive Publication Date: 2015-05-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the treatment of cancer, chemotherapy plays an extremely important role in the treatment of most tumors, especially advanced tumors. However, the current small-molecule chemotherapy drugs are seriously lacking in targeting, and they will also damage health while treating cancer. organs and tissues, causing local or systemic side effects
In addition, many chemotherapeutic drugs also have problems such as low solubility, poor stability, and easy multidrug resistance.
These reasons severely limit the clinical use of anticancer drugs

Method used

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  • Reduction trigger type polypeptide modified hyaluronic acid conjugate carrier and preparation method thereof
  • Reduction trigger type polypeptide modified hyaluronic acid conjugate carrier and preparation method thereof
  • Reduction trigger type polypeptide modified hyaluronic acid conjugate carrier and preparation method thereof

Examples

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Embodiment 1

[0049] Example 1 Synthesis of reduction-triggered T7 peptide-modified hyaluronic acid carrier (PEPHSSC)

[0050] Hyaluronic acid with a molecular weight of 10000Da was selected as the hydrophilic end of the carrier. The specific preparation method is four steps:

[0051] 1) Preparation of the hydrophobic group-bonded reduction-sensitive linker: 10 mmol cystamine and 0.5 mmol pyridine were dissolved in 30 mL dichloromethane, and a dichloromethane solution of 0.5 mmol cholesterol chloroformate was slowly added dropwise. After overnight reaction at 25°C, the organic solvent was removed by rotary evaporation.

[0052] 2) Preparation of hydrophobically modified hyaluronic acid: Dissolve 0.1mmol hyaluronic acid, 0.3mmol EDC and 0.3mmol HOBT in formamide, stir for 15min, add 0.002mmol of hydrophobic groups containing reduction-sensitive linking arms to react for 24h , precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, dialyze with...

Embodiment 2

[0055] Example 2 Synthesis of reduction-triggered octreotide-modified hyaluronic acid carrier (PEPHSSC)

[0056] Hyaluronic acid with a molecular weight of 20000Da was selected as the hydrophilic end of the carrier. The specific preparation method is four steps:

[0057] 1) Preparation of the hydrophobic group-bonded reduction-sensitive linker: 10 mmol cystamine and 0.5 mmol triethylamine were dissolved in 30 mL dichloromethane, and a dichloromethane solution of 0.5 mmol cholesterol chloroformate was slowly added dropwise. After overnight reaction at 25°C, the organic solvent was removed by rotary evaporation.

[0058] 2) Preparation of hydrophobically modified hyaluronic acid: Dissolve 0.1mmol hyaluronic acid, 0.3mmol EDC and 0.3mmol HOBT in formamide, stir for 15min, add 0.006mmol of hydrophobic groups containing reduction-sensitive linkers to react for 24h , precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, dialyze with...

Embodiment 3

[0061] Example 3 Synthesis of reduction-triggered GE11 peptide-modified hyaluronic acid carrier (PEPHSSC)

[0062] Hyaluronic acid with a molecular weight of 40000Da was selected as the hydrophilic end of the carrier. The specific preparation method is four steps:

[0063] 1) Preparation of the hydrophobic group-bonded reduction-sensitive linker: 10 mmol cystamine and 0.5 mmol pyridine were dissolved in 30 mL dichloromethane, and a dichloromethane solution of 0.5 mmol cholesterol chloroformate was slowly added dropwise. After overnight reaction at 25°C, the organic solvent was removed by rotary evaporation.

[0064] 2) Preparation of hydrophobically modified hyaluronic acid: dissolve 0.1mmol hyaluronic acid, 0.3mmol EDC and 0.3mmol HOBT in formamide, stir for 15min, add 0.010mmol of hydrophobic groups containing reduction-sensitive linking arms to react for 24h , precipitated with excess acetone, and filtered with suction. Add water to redissolve the precipitate, dialyze wi...

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Abstract

The invention discloses a reduction trigger type polypeptide modified hyaluronic acid conjugate carrier and a preparation method thereof. The carrier is a nanoparticle mainly consisting of hyaluronic acid, hydrophobic groups, tumor targeted hydrophilic groups and a medicament, wherein the hydrophobic groups are bonded with hyaluronic acid through reduction sensitive bonds. The conjugate carrier can be self-assembled into the nanoparticle in an aqueous medium and is capable of supporting anti-tumor active medicine molecules. The reduction trigger type polypeptide modified hyaluronic acid conjugate carrier has the main advantages that (1) the carrier has a dual targeting capacity, so that the transfer efficiency of drugs in tumors is improved, and the untoward effect is reduced; (2) a disulfide bond linking arm is intruded into the conjugate and can be specifically degraded by high-concentration reduced glutathione in the tumor cells, so that the drugs are rapidly released, and the bioavailability of the drugs is improved; and (3) the anti-tumor drugs are loaded by virtue of a physical embedding action, so that the water solubility of the anti-tumor drugs is improved. The preparation method is simple, a process is mature, and the carrier has a good application prospect.

Description

technical field [0001] The invention belongs to the field of pharmacy, and discloses a hyaluronic acid conjugate carrier with reduction-triggered polypeptide modification and a preparation method thereof. Background technique [0002] Malignant tumor is one of the major diseases that seriously endanger human life and health. It has been listed as the "second killer" (second only to cardiovascular disease) facing human beings, resulting in about 13% of global mortality. According to the statistics of the World Health Organization (WHO), the number of cancer patients is increasing year by year. Nearly 1 million people are diagnosed with cancer every year in the world. It is predicted that more than 80 million people will die of cancer between 2005 and 2015. . [0003] In the treatment of cancer, chemotherapy plays an extremely important role in the treatment of most tumors, especially advanced tumors. However, the current small-molecule chemotherapy drugs are seriously lackin...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K47/36A61K47/42A61K31/704A61P35/00
Inventor 柯学胡丹蓉奥马尔张蕾
Owner CHINA PHARM UNIV
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