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ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same

A copolymer and amphiphilic technology, which is applied in the field of ABA type amphiphilic triblock copolymer, can solve the problems of complicated purification process, time-consuming and energy-consuming conditions, and high cost, and achieve simple and easy-to-obtain synthetic raw materials with high stability good effect

Active Publication Date: 2013-04-24
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The current methods of synthesizing PLA-PEG-PLA block copolymers mainly focus on the direct melt condensation of lactic acid and PEG and the melt polymerization of lactide and PEG. They have their own advantages and disadvantages, but the direct melt condensation method generally adopts High temperature and high pressure synthesis, the conditions are time-consuming and energy-consuming, the ring-opening polymerization of lactide is generally used ZnCl 2 Heavy metal catalysis introduces toxic heavy metals into synthetic materials, and requires polymerization-grade purity lactide. The purification process is complicated and the cost is high.

Method used

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  • ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same
  • ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same
  • ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1. Synthesis of amphiphilic triblock copolymers PEG-PLA-PEG and PLA-PEG-PLA

[0052] 1. Synthesis of Hydrophilic Fragment PEG-A4

[0053] (1) When n=2 of PEG, Mn=163;

[0054] Its synthetic route is as follows figure 1 Shown: Under alkaline conditions, compound A4 is subjected to amidation reaction with PEG163 whose terminal is an amino group to obtain compound PEG163-A4;

[0055] The steps are specifically: weigh A4 (0.841g, 1mmol) and dissolve 15ml DMF in a 25ml single-necked flask, add NMM (N-methylmorpholine) (112 μL, 1.0mmol) under stirring in an ice-water bath, HATU (2 -(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate) (0.57g, 1.5mmol) after activation for 30min (TLC monitors that the activation reaction is complete), Add PEG163 (0.163g, 1mmol) with an amino group at the end, stir for 1h, then warm up to room temperature and react for 10h, stop the reaction (TLC monitors the end of the reaction), add an appropriate amount of wa...

Embodiment 2

[0134] Example 2. Determination of molecular weight of block copolymer

[0135] The molecular weight of the polymer prepared in Example 1 was determined by GPC method; instrument: Agilent 1260 gel permeation chromatograph, GPC column: 7.5×300 mm, 10 μm gel chromatographic column, solvent: tetrahydrofuran, flow rate: 1.0 mL / min , column temperature: 35 ℃, standard sample: polystyrene. The GPC molecular weight distribution of each polymer is as follows Figure 7 shown.

Embodiment 3

[0136] Example 3. Preparation and characterization of micelles (taking PEG5000-PLA5000-PEG5000 as an example)

[0137] 1. Preparation of blank micelles

[0138] Accurately weigh 10 mg of the synthesized block copolymer, dissolve it in 2 mL of DMF (also DMSO or THF), and slowly drop the block copolymer DMF solution into 10 ml of agitated PBS buffer solution (or pure water or normal saline). ) (10min / ml), stirred for 30min to form microemulsion spheres, transferred into a dialysis bag, dialyzed with PBS buffer for 48 hours, changed water once in 4h, and dialyzed out DMF to obtain self-assembled micelles.

[0139] 2. Preparation of drug-loaded micelles

[0140] Accurately weigh 10 mg of the synthesized block copolymer and 1 mg DOX.HCI and dissolve them in 2 mL of DMF (also DMSO or THF), add 20 μl of triethylamine and stir for 30 min, and then dissolve the mixture containing drugs (which can be azithromycin, paclitaxel, elemene). Or camptothecin; in the present embodiment, the...

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Abstract

The invention discloses an ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same. The copolymer structure is as follows: the copolymer can be used for preparing a self-assembled loading drug micelle. The ABA type amphiphilic triblock copolymer based on molecular glue and uses of the same utilize a method of organic synthesis to modify polymer polyethylene glycol (PEG) and poly lactic acid (PLA) for the first time, introduce a molecular glue single chain with a hydrogen bond sequence selectivity into a polymer macromolecule, and enable the molecular glue single chain to form a molecular glue under certain conditions so as to selectively efficient synthesize the series amphiphilic triblock copolymer. The synthetic raw material of the compound is simple and easy to prepare, each synthesizing process is a conventional reaction, and suitable for mass production. The prepared block copolymer micelle has good stability, a blank micelle does no harm to normal cells, and the drug-loading micelle can effectively release encapsulated drugs under the reductants of dithiothreitol or reductible glutathione.

Description

technical field [0001] The invention relates to the fields of chemical synthesis, biochemistry and pharmacy, in particular to an ABA-type amphiphilic triblock copolymer based on molecular glue and use thereof. Background technique [0002] Amphiphilic block copolymers as carrier materials have broad development potential in the field of pharmaceutical research and have strong self-assembly ability. Usually polyethylene glycol (PEG) is used as the hydrophilic segment, polyester, polycaprolactone, etc. , polyanhydrides, etc. are hydrophobic segments. Polyethylene glycol (PEG) has the advantages of good hydrophilicity, non-toxicity, and easy removal of residues, and has been approved by the US Federal Drug Administration for use in humans (Macromol Biosci, 2006, 6: 846-854). Polylactic acid (PLA) is an important biodegradable material with non-toxic sterility, good biocompatibility, biodegradability and tissue absorbability (Biomedical Science, Engineering and Technology, 2012...

Claims

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Application Information

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IPC IPC(8): C08G81/00C08J3/07A61K47/34
CPCA61K47/34A61K9/1075C08J3/07C08J2353/00
Inventor 杨晴来龚兵沈玉梅
Owner SHANGHAI JIAO TONG UNIV
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