Degradable acid-sensitive amphipathic segmented copolymer and preparation method and application thereof

An amphiphilic block and copolymer technology, applied in the fields of polymer chemistry, pharmacy and biomedical engineering, can solve problems such as not being able to promote the decomposition of self-assembly systems well, achieve excellent biodegradability, and realize fixed-point targets release, excellent biocompatibility

Inactive Publication Date: 2010-09-15
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the folding of hydrophilic polyamino acids does not promote the disassembly of the self-assembled system very well, so it is necessary to further modify it to achieve the transformation of hydrophilicity and hydrophobicity under the action of protonation.

Method used

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  • Degradable acid-sensitive amphipathic segmented copolymer and preparation method and application thereof
  • Degradable acid-sensitive amphipathic segmented copolymer and preparation method and application thereof
  • Degradable acid-sensitive amphipathic segmented copolymer and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Biodegradable Acid Sensitive Amphiphilic Block Copolymer

[0039] Preparation of N-carboxylic acid anhydride of 1.1L type amino acid benzyl ester:

[0040] After drying 10 g (67 mmol) of L-lysine benzyl ester in vacuo for at least 2 hours, it was dissolved in 100 ml of dry tetrahydrofuran at 45°C. Another 5 g of trimeric phosgene solid was weighed and dissolved in 50 ml of dry tetrahydrofuran, and then the solution was slowly added dropwise to the L-lysine solution, and fully stirred until clear. All operations were performed under the protection of dry argon. Stop heating and turn on argon gas bubbles for at least 2 hours to remove hydrogen chloride and excess phosgene generated by the reaction. The reaction solution was poured into excess anhydrous petroleum ether, shaken fully until crystals were precipitated, then frozen at low temperature for two days, and filtered and washed several times to obtain white needle-like crystals. The obtained product...

Embodiment 2

[0058] Determination of Proton Responsiveness of Acid Sensitive Amphiphilic Block Copolymer

[0059] 2.1 Determination of proton responsiveness of PEG-poly(L-lysine acid sensitive derivative)

[0060] Weigh about 400mg of PEG-P(LL-DIP)A and dissolve it in 35ml of deionized water, adjust the solution to about pH9, carry out acid-base titration with 0.1M HCl solution and record the change of pH value of the solution, the test results are shown in figure 1 .

[0061] 2.2 Determination of proton responsiveness of PEG-poly(L-glutamic acid sensitive derivative)

[0062] Weigh 16mg of PEG-P (LGA-DIP) A, B and C and dissolve them in 20ml of deionized water, adjust the solution to pH11, carry out acid-base titration with 0.1M HCl solution and record the change of pH value of the solution. solution as a reference, test results see figure 2 .

Embodiment 3

[0064] Preparation of Polymer Nano-Drug Carriers

[0065] 3.1 Preparation of PEG-poly(L-lysine acid-sensitive derivative) nano-loaded micelles

[0066] 25mg PEG-P(LL-DIP)A and 5mgDOX were dissolved in 10ml deionized water, and the pH value of the solution was adjusted to 4 with 1M HCl solution. After the polymer and the drug are completely dissolved, a small amount of triethylamine is added dropwise to quickly adjust the pH value to about 10. The resulting solution was dialyzed in water for two days through a 3500 Da dialysis bag, and then freeze-dried to obtain red drug-loaded micelles.

[0067] 3.2 Preparation of PEG-poly(L-glutamic acid-sensitive derivative) nano drug-loaded micelles

[0068] 10mg of copolymer and 2mg of DOX were co-dissolved in 2ml of DMSO / THF 1:1 mixed solution, and 1ml of triethylamine was added to ensure the hydrophobicization of DOX. Then it was added dropwise into 7ml of water in an ice bath under the action of ultrasound, and then the mixture was ...

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Abstract

The invention discloses a degradable acid-sensitive amphipathic segmented copolymer and a preparation method and application thereof. The hydrophilic and hydrophobic sections of the amphipathic segmented copolymer consist of polyethylene glycol of which the molecular weight is more than 1,000 and acid-sensitive radicals respectively, wherein the corresponding segmentation ratio is 5:1-75. The degradable acid-sensitive amphipathic segmented copolymer is prepared by initiating ring-opening polymerization on N-dicarboxylic acid ahhydride of L-alanine benzyl ester with an active side group by single amine-terminated poly(ethylene glycol), and reacting the product with activated diisopropyl aminoethanol after debenzylation protection so as to perform acid-sensitivity modification. The copolymer of the invention has good acid sensitivity, biocompatibility and biodegradability, can self-assemble in aqueous solution and form a nano-grade medicament carrier, and has important research value and application prospect in the fields of targeted therapy and diagnosis.

Description

technical field [0001] The invention relates to the fields of polymer chemistry, pharmacy and biomedical engineering, in particular to a degradable acid-sensitive amphiphilic block copolymer and its preparation method and application. Background technique [0002] Medical research has shown that many pH gradients exist in both normal and pathological situations. For example, both tumor and inflamed tissue have a slightly lower pH (about 6.8) than blood and normal tissue (about 7.4). Moreover, although the endocytosis channel of the cell is close to the physiological environment of 7.4 at the beginning, the pH drops to 5.5~6.0 when it reaches the endosome, and the pH will drop even lower when it reaches the lysosome, only 4.5~5.0. Therefore, pH-responsive systems have begun to be widely used in drug delivery vehicles. It has been verified that encapsulating or loading anticancer drugs on suitable high molecular weight polymers can effectively improve the solubility, half-li...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48C08G69/48C08G69/40C08G69/08A61K47/34A61K47/10
Inventor 帅心涛李皓李芬
Owner SUN YAT SEN UNIV
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