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In situ thermosensitive gel medicine delivery system for immunochemotherapy combination therapy

A temperature-sensitive gel and combined therapy technology, applied in drug delivery, drug combination, liquid delivery, etc., can solve systemic side effects, barriers and other problems, achieve the effects of reducing systemic side effects, overcoming systemic toxicity, and improving curative effect

Inactive Publication Date: 2018-04-20
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The intravenous injection method used in traditional chemotherapy faces many challenges, such as the drug delivery system is hindered by mucosal barriers and non-specific uptake before reaching the target, and it has serious systemic toxic side effects, etc.

Method used

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  • In situ thermosensitive gel medicine delivery system for immunochemotherapy combination therapy
  • In situ thermosensitive gel medicine delivery system for immunochemotherapy combination therapy
  • In situ thermosensitive gel medicine delivery system for immunochemotherapy combination therapy

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Embodiment 1

[0042] The following specific examples are further descriptions of the present invention, but the following are only used to illustrate the present invention rather than limit the scope of the present invention. Embodiment 1: Preparation of PLGA-PEG-PLGA temperature-sensitive material

[0043] 20.06g of PEG with Mn~1000Da was dehydrated under vacuum at 120°C for 4h. After the temperature dropped to 80°C, 4.21gGA and 37.18g LA were added and dehydrated for 30min under the protection of argon. Then 0.15% stannous octoate (w / w) of LA and GA feedstock was added as a catalyst. After reacting at 150°C for 12 hours, the product was washed with hot water at 80°C three times to purify the product.

[0044] for PLGA-PEG-PLGA 1 H-NMR analysis (attached figure 1 ), the ratio of lactide (LA) to glycolide (GA) is 1.7 / 1, the molecular weight is 1250-1000-1250, and the gel permeation chromatography (GPC) obtains Mw / Mn=1.4.

Embodiment 2

[0045] Embodiment 2: Preparation of peptide dendrimers:

[0046] 1. H-Lys-OMe (699.4mg, 3mmol), Boc-L-Lys(Boc)-OH (2.18g, 6.3mmol), hexafluorophosphate (HBTU, 2.39g, 6.3mmol) were mixed under nitrogen protection and 1-hydroxybenzotriazole (HOBt, 851.1 mg, 6.3 mmol) were dissolved in anhydrous dimethylformamide (DMF, 50 mL). Diisopropylethylamine (DIPEA, 1.63 g, 12.6 mmol) was added and stirred in an ice bath for 5 minutes, then tris(2-aminoethyl)amine (220 mg, 1.5 mmol) was added. Stir in an ice bath under nitrogen for 30 minutes, then at room temperature for 8 hours. After the reaction was completed, the solvent was removed, the residue was dissolved in ether (150 mL), and saturated NaHCO 3 Aqueous solution, NaHSO 4 Aqueous solution (1M), saturated NaHCO 3 Aqueous solution and water wash. use Na 2 SO 4 The solution was dried and the solvent was removed by rotary evaporation to give a white solid.

[0047] 2. The compound obtained in the previous step (2.26 g, 2 mmol) ...

Embodiment 3

[0050] Example 3: Preparation of drug-loaded peptide dendrimers

[0051] Dissolve 10 mg of peptide dendrimers in 1.5 ml of water, 15 mol equivalent DOX·HCL in 300 μL of methanol, add 5 μL of triethylamine to alkalinize, then add the DOX solution into the peptide dendrimer solution, and stir overnight Afterwards, the mixed solution was centrifuged (8000 rpm for 5 min), and the supernatant was freeze-dried to obtain the drug-loaded peptide dendrimers.

[0052] The drug loading capacity of the peptide dendrimers was determined to be 17 μg / mg by ultraviolet light. And the ultraviolet absorption spectrum scanning of the drug-loaded peptide dendrimers was carried out (attached Figure 4 ), the maximum absorption peak of the drug-loaded peptide dendrimers has a slight red shift.

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Abstract

The invention belongs to the field of pharmaceutical preparations, and in particular relates to an in-situ temperature-sensitive gel drug delivery system for combined chemotherapy and immune therapy. The delivery system consists of drug carrier peptide dendrimers (G4‑arg), antineoplastic drugs and thermosensitive gel matrix material PLGA‑PEG‑PLGA, and the antineoplastic drugs are entrapped in the cavity of peptide dendrimers to form The drug-loaded peptide dendrimers wrap the drug-loaded peptide dendrimers in a temperature-sensitive gel matrix through the swelling process to form an in-situ drug delivery system that is an injectable sol at room temperature and turns into a gel at body temperature. The in situ delivery system of the present invention can form a gel near the tumor, slowly release the drug-loaded peptide dendrimer molecules to act on the tumor tissue, and the peptide dendrimer molecules act on the macrophages in the tumor tissue to generate NO , together with anti-tumor drugs to act on tumors, forming a chemotherapy-immune combination therapy to inhibit the development of tumors.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to an in-situ temperature-sensitive gel drug delivery system for combined chemotherapy and immune therapy. Background technique [0002] Chemotherapy, surgical resection or radiation therapy are the most commonly used cancer treatment strategies. Among them, chemotherapy is currently the most widely used treatment method, but it often faces many challenges in clinical application, such as the dose-dependence between anti-tumor effect and drug dose. However, high doses of drugs often induce severe toxic side effects. How to construct a new type of drug delivery system with high efficiency, low toxicity and controllable production is the key to current research. [0003] In the treatment of tumors, chemotherapy is one of the important methods to inhibit the rapid proliferation of cancer cells at the primary site. Cytotoxic chemotherapy drugs are used to kill tu...

Claims

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Application Information

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IPC IPC(8): A61K9/06A61K31/704A61K31/785A61K47/34C08G83/00A61P35/00
CPCA61K9/06A61K9/0024A61K31/704A61K31/785A61K47/34C08G83/003C08G83/004A61K2300/00
Inventor 姜雷宗莉薛夏琳蒋锡群
Owner CHINA PHARM UNIV
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