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 copolymers, can solve the problems of time-consuming and energy-consuming, complicated purification process and high cost, and achieves good stability and simple and easy synthesis of raw materials. the effect

Active Publication Date: 2014-11-19
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] Embodiment 1, the synthesis of amphiphilic triblock copolymer 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...

Embodiment 2

[0134] Embodiment 2, the mensuration of block copolymer molecular weight

[0135] Adopt GPC method to measure the molecular weight of the polymer prepared in Example 1; Instrument: Agilent1260 type gel permeation chromatography, GPC column: 7.5 * 300mm, 10 μm gel chromatography column, solvent: tetrahydrofuran, flow rate: 1.0mL / min , column temperature: 35°C, standard sample: polystyrene. The GPC molecular weight distribution diagram of each polymer is as follows Figure 7 shown.

Embodiment 3

[0136] Embodiment 3, preparation and characterization of micelles (taking PEG5000-PLA5000-PEG5000 as an implementation 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 can be DMSO or THF), slowly drop the block copolymer DMF solution into 10 ml of stirred PBS buffer solution (also can be pure water or normal saline ) (10min / ml), stirred for 30min to form microemulsion balls, transferred to a dialysis bag, dialyzed with PBS buffer for 48 hours, changed the water once every 4h, and dialyzed 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 of DOX.HCI to dissolve in 2 mL of DMF (also DMSO or THF), add 20 μl of triethylamine and stir for 30 min. Or camptothecin; what adopted in the present embodiment is azithromycin) the synthesized block copolymer DMF solution slo...

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Abstract

Disclosed are an ABA-type triblock copolymer based on a molecular glue, synthesis therefor, and use thereof. The structural formula of the copolymer is selected from the Formula (I). The copolymer of the present invention can be used to prepare a self-assembled medicine-carrying micelle. The present invention is based on the hydrophilicity of polyethylene glycol and chitosan of a low molecular weight, and on the hydrophobicity of polylactic acid, polycaprolactone, lauric acid, and stearate. Single chains of molecular glue having hydrogen bond sequence-selectivity are separately introduced into known macro-molecular polymers, such that under certain conditions, two complimentary single chains can form a molecular glue. A series of amphiphilic triblock copolymers can thereby effectively synthesized. Additionally, the molecular glue introduced contains a disulfide bond, and the copolymer is therefore sensitive to oxidoreduction. The raw material agents for the synthesis of the present invention can be easily obtained, the conditions are temperate, and the synthesis process contains only conventional chemical reactions and is suitable for large-scale production.

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 its application. Background technique [0002] As a carrier material, amphiphilic block copolymers 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. , polyanhydride, etc. are hydrophobic segments. Polyethylene glycol (PEG) has the advantages of good hydrophilicity, non-toxicity, and easy elimination 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, which is non-toxic, sterile, good biocompatibility, biodegradability and tissue absorbability (Biomedical Science, Engineering and Te...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G81/00C08J3/07A61K47/34
CPCC08J3/07A61K9/1075A61K47/34C08G81/00C08J2353/00
Inventor 杨晴来龚兵沈玉梅
Owner SHANGHAI JIAO TONG UNIV
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