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A drug carrier with dual targeting function of tumor cells and tumor-related fibroblasts, preparation method and application

A technology related to fibroblasts and tumors, applied in the field of drug carriers with dual targeting functions of tumor cells and tumor-associated fibroblasts, can solve the problems of poor drug effect, low curative effect, and low cell selectivity for patients, and achieve Promote rapid migration, the method is simple and easy to implement, and is suitable for industrial promotion

Active Publication Date: 2021-08-06
潍坊中医药产业技术研究院 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Chemotherapy is currently one of the main methods for clinical treatment of tumors. However, many chemical drugs and gene drugs with great therapeutic potential have low selectivity for tumor tissues and cells, low curative effect, high toxicity, many adverse reactions, and difficulty in controlling metastases. Many problems lead to poor drug effect in some patients. Although it will kill some pericancerous tissues, it is difficult to prevent tumor recurrence from the root cause

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  • A drug carrier with dual targeting function of tumor cells and tumor-related fibroblasts, preparation method and application
  • A drug carrier with dual targeting function of tumor cells and tumor-related fibroblasts, preparation method and application
  • A drug carrier with dual targeting function of tumor cells and tumor-related fibroblasts, preparation method and application

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preparation example Construction

[0055] In a second aspect, the present invention provides a method for preparing a drug carrier with dual targeting functions for tumor cells and tumor-associated fibroblasts, the preparation method comprising linking Z-glycine-proline to hyaluronic acid through an acylation reaction acid side chain;

[0056] The temperature of the acylation reaction is 30°C;

[0057] After the acylation reaction, a step of removing impurities of the acylation product is also included;

[0058] The impurity removal step includes a dialysis step of the acylated product and a freeze-drying step of the acylated product in sequence;

[0059] The dialysis step of the acylated product adopts a dialysis bag with a molecular weight cut-off of 2000-3000Da.

[0060] In an optional embodiment, before the acylation reaction, hyaluronic acid is connected with the condensate sulfur ketal-ginger ketal through the first esterification reaction in the EDC / DMAP catalyzed esterification reaction system;

[00...

Embodiment 1

[0077] This example takes FAPα receptor and CD44 receptor as the main targets to construct a drug carrier with dual targeting of tumor cells and tumor-associated fibroblasts (CAFs) to improve the targeting of the carrier, and at the same time introduce a thioketal bond and ketal bonds, making the carrier both ROS responsive and pH sensitive, the synthetic route is as follows figure 1 shown. Concrete synthetic steps are as follows:

[0078] 1.1 Synthesis of hyaluronic acid-thioketal-gingerketal (HSO) material

[0079] (1) Refer to the method for preparing ginger ketal in Chinese patent CN110054608A to prepare ginger ketal. The specific steps are: select gingerone (ZZ) to react with triglycerol to synthesize ginger ketal (ZO) with a pH-sensitive ketal structure.

[0080] (2) Preparation of condensate sulfur ketal-ginger ketal (SO), the specific steps are:

[0081] The thioketal (TKL) is esterified with the ginger ketal (ZO) synthesized in the above step (1) under the catalysi...

Embodiment 2

[0087] In this example, the drug carrier (GHSO) obtained in Example 1 was used to load paclitaxel (PTX) to prepare drug-loaded micelles (GHSO@PTX), and the specific steps were as follows:

[0088] Accurately weigh 10 mg of the drug carrier (GHSO), dissolve it completely in 3 mL of formamide, dissolve 1 mg of paclitaxel (PTX) in 1 mL of formamide, mix the GHSO solution and the PTX solution completely, and put them in a 2000 Da dialysis bag. The dialysis bag was placed in 800 mL of deionized water for dialysis, and the water was changed every 2 h to completely permeate the organic solvent. The obtained drug-loaded micelles were scanned by a field emission scanning electron microscope, and the results were as follows: Figure 4 As shown, it can be seen that the size of the drug-loaded micelles obtained in this embodiment is uniform, and then the particle diameter of the drug-loaded micelles in the scanning results is counted, and the statistical results are as follows Figure 5 ...

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Abstract

The invention relates to the technical field of medicine, in particular to a drug carrier with dual targeting functions of tumor cells and tumor-associated fibroblasts, a preparation method and application. The drug carrier with dual targeting function of tumor cells and tumor-associated fibroblasts provided by the present invention contains hyaluronic acid and Z-glycine-proline linked by acyl groups, wherein hyaluronic acid can target the CD44 receptor on the surface of tumor cells. When the drug carrier is loaded with anti-tumor components, it can promote the rapid migration of anti-tumor components to the center of the tumor; and the dipeptide Z-glycine-proline can target the FAPα receptor on the surface of tumor-associated fibroblasts , so that when tumor cells are blocked by fibroblasts after tumor tissue fibrosis, the drug carrier can still accurately target the tumor center.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a drug carrier with dual targeting functions of tumor cells and tumor-associated fibroblasts, a preparation method and application. Background technique [0002] The tumor microenvironment (TEM), which mainly includes extracellular matrix (ECM), tumor-associated fibroblasts (CAFs), tumor-associated immune cells, tumor vasculature, and a hypoxic and acidic environment, creates a physical barrier that hinders drug Delivery to the tumor center. Chemotherapy is currently one of the main methods for clinical treatment of tumors. However, many chemical drugs and gene drugs with great therapeutic potential have low selectivity for tumor tissues and cells, low curative effect, high toxicity, many adverse reactions, and difficulty in controlling metastases. Many problems have led to poor drug effects in some patients. Although some pericancerous tissues will be killed, it is difficult t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/42A61K47/36A61K31/337A61K9/107A61P35/00C08B37/08
CPCA61K9/1075A61K31/337A61K47/36A61K47/42A61P35/00C08B37/0072
Inventor 郭春静
Owner 潍坊中医药产业技术研究院
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