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Drug carrier with tumor cell and tumor-associated fibroblast dual-targeting function, preparation method and application

A fibroblast and tumor-related technology, applied in the field of drug carriers with dual-targeting functions of tumor cells and tumor-related fibroblasts, can solve the problems of low cell selectivity, poor drug effect for patients, and low curative effect, etc. Suitable for industrial promotion, promoting rapid migration, and the effect of simple and easy methods

Active Publication Date: 2021-06-25
潍坊中医药产业技术研究院 +1
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  • Description
  • Claims
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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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  • Drug carrier with tumor cell and tumor-associated fibroblast dual-targeting function, preparation method and application
  • Drug carrier with tumor cell and tumor-associated fibroblast dual-targeting function, preparation method and application
  • Drug carrier with tumor cell and tumor-associated fibroblast dual-targeting function, 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 medicines, in particular to a drug carrier with a tumor cell and tumor-related fibroblast dual-targeting function, a preparation method and application. The drug carrier with the tumor cell and tumor-associated fibroblast dual-targeting function contains hyaluronic acid and Z-glycine-proline which are connected through an acyl group, the hyaluronic acid can target a CD44 receptor on the surface of a tumor cell, and when the drug carrier is loaded with an anti-tumor component, the rapid migration of the anti-tumor component to the tumor center can be promoted; the dipeptide Z-glycine-proline can target FAPalpha receptors on the surfaces of tumor-associated fibroblasts, so that after tumor tissue fibrosis, when tumor cells are hindered by fibroblasts, 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 Applications(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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