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Environment-sensitive tumor-targeting polymer micelle and preparation method thereof

A polymer gel and tumor-targeting technology, which is applied in the preparation and preparation of tumor-targeted polymer micelles drug delivery system, and in the field of tumor-targeted polymer micelles, can solve the problems of complex peptide synthesis and achieve in vivo safety High, reduce drug leakage, good biocompatibility

Inactive Publication Date: 2015-01-14
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Studies have shown that most of the ligands are macromolecular polypeptides, which may be enzymatically hydrolyzed in vivo, and the synthesis of polypeptides is relatively complicated

Method used

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  • Environment-sensitive tumor-targeting polymer micelle and preparation method thereof
  • Environment-sensitive tumor-targeting polymer micelle and preparation method thereof
  • Environment-sensitive tumor-targeting polymer micelle and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] N 6 -Benzyloxycarbonyl-L-lysine (N 6 -Lys(Z)) and L-phenylalanine (L-Phe) NCA were carried out according to the Fuchs-Farthing method, according to synthetic route 1: Weigh N 6 -Lys(Z) 30g (107mmol), suspended in dry THF (300ml), under nitrogen protection, equilibrated in an oil bath at 50°C for 10min, added 10.58g (35.68mmol) of triphosgene solid, stirred at 50°C for 3h until solution To clarify, the reaction solution was poured into anhydrous n-hexane, and a white precipitate was precipitated, which was filtered and dried to obtain N 6 -Lys(Z)-NCA (compound a), recrystallized from anhydrous THF / n-hexane system to obtain white crystals with a yield of 98%. Similarly, weigh 5g of L-Phe (30.3mmol), suspend it in 50ml of anhydrous THF, operate as above, add 3g of triphosgene solid (12.1mmol), react for 3h, other operations are as above, use anhydrous THF / n-hexane system to weigh Crystallization afforded a white solid, Phe-NCA (compound b), in 96% yield. use 1 H NMR (...

Embodiment 2

[0069] synthetic N 3 - PEG-pLys-pPhe or MPEG-pLys-pPhe polymers, respectively, with N 3 -PEG-NH 2 (MW5000) and MPEG-NH 2 (MW5000) as the initiator, according to the synthetic route 2: weigh CH 3 O-PEG-NH 2 or N 3 -PEG-NH 2 (1g, 0.2mmol) was dissolved in anhydrous DMF (10ml), stirred constantly, weighed N 6 -Lys(Z)-NCA (compound a) 736mg (2.4mmol), was added to the PEG solution under nitrogen protection, and reacted at 50°C for 48h. Weigh 917mg (4.8mmol) of Phe-NCA (compound b), add it into the reaction solution, and react at 50°C for 48h. After the reaction, the reaction solution was poured into anhydrous ether, and a white precipitate was precipitated, which was filtered and dried to obtain a white solid with a yield of 92%. The white solid was added to TFA (10ml)-HBr / HOAc (0.5ml) and reacted for 3h to remove N 6 - benzyloxycarbonyl protecting group (Z). The product was transferred to a dialysis bag (MW1000), dialyzed in 1 L of pure water for 24 hours, and the water...

Embodiment 3

[0073] The propargylated DHA and N 3 -PEG-pLys-pPhe connection, according to synthetic route 3: Weigh polymer N 3 - 500 mg (0.1 mmol) of PEG-pLys-pPhe was dissolved in DMF, under nitrogen protection, and 43 mg (0.2 mmol, 2 eq.) of propargylated DHA was weighed and added to the polymer solution. CuI (0.5eq.) and DIPEA (1eq.) were freshly prepared, added to the reaction solution, and reacted at 30°C for 12h. The reaction solution was transferred to a dialysis bag (MW1000), dialyzed in 1L10mM EDTA-2Na pH7.0 for 24h, transferred to 1L pure water for dialysis for 24h, and freeze-dried to obtain purified DHA-PEG-pLys-pPhe; To characterize (such as figure 2 d).

[0074] Synthetic route 3:

[0075]

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Abstract

The invention belongs to the technical field of biology, relates to environment-sensitive tumor-targeting polymer micelle and a preparation method thereof, and especially relates to a cell microenvironment-sensitive oxidized ascorbic acid-modified tumor-targeting polymer micelle administration system and a preparation method thereof. An administration system realizes delivery in tumor by a glucose transporter mechanism, the polymer micelle of which the inner core has a disulfide bond crosslinked barrier is designed by use of the GSH characteristics of high density in the cell microenvironment, drug release characteristics trigged by the cell microenvironment are obtained, and the environment-sensitive tumor-targeting polymer micelle has a high transport capability, a fast transport rate and difficult saturation. Compared with polypeptide protein molecules, the environment-sensitive tumor-targeting polymer micelle has the characteristics of simple synthesis preparation, high stability and no immunogenicity. Through synergism of targeting and structure stabilization, drug delivery to a target position and a target cell is realized so that drug delivery efficiency is greatly improved and thus the environment-sensitive tumor-targeting polymer micelle has a good clinical application prospect.

Description

technical field [0001] The invention belongs to the field of biotechnology, relates to tumor-targeting polymer micelles, relates to an environment-sensitive tumor-targeting polymer micelles and a preparation method thereof, in particular to a tumor modified by oxidized ascorbic acid which is sensitive to the cell microenvironment Targeted polymer micelle drug delivery system and its preparation method. Background technique [0002] At present, the clinical treatment of malignant tumors adopts a combination of multiple methods (chemotherapy, radiotherapy or surgical treatment). Because malignant tumors have the characteristics of invasion and metastasis, some micrometastases are usually difficult to be detected. Therefore, chemotherapy is still one of the main ways to treat tumors clinically. However, most chemotherapeutic drugs have problems such as poor water solubility, no selectivity in vivo, high toxicity and side effects, fast metabolism, and low efficacy, which severe...

Claims

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Application Information

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IPC IPC(8): A61K47/34A61K9/107A61K31/337C08G69/48C08G69/40A61P35/00
Inventor 蒋晨邵堃匡宇阳
Owner FUDAN UNIV
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