Tumor-targeting pH- and redox-response macromolecule nano prodrug and preparation method and application thereof

A tumor-targeting, dual-response technology, applied in anti-tumor drugs, pharmaceutical formulations, medical preparations with inactive ingredients, etc., can solve problems such as unrealistic, insufficient cumulative concentration to kill tumor cells, and increased injection dose, etc. achieve high drug loading

Inactive Publication Date: 2019-07-05
GUANGZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally, the process of loading drug molecules on polymer carriers mainly relies on the physical interaction of "hydrophilic-hydrophobic", which leads to extremely low efficiency of carrier loading drugs
Therefore, when the drug-loaded micelles enter the tumor cells, the accumulated concentration of the drug in the cells is not enough to kill the tumor cells, unless the injection dose is greatly increased, which is obviously clinically unrealistic (NatureReviews Materials 2016, 1, 16014)

Method used

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  • Tumor-targeting pH- and redox-response macromolecule nano prodrug and preparation method and application thereof
  • Tumor-targeting pH- and redox-response macromolecule nano prodrug and preparation method and application thereof
  • Tumor-targeting pH- and redox-response macromolecule nano prodrug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1: Synthesis of the terminal azide hyaluronic acid in formula (1)

[0078] Dissolve hyaluronic acid (4.8 parts by mass) in 145 parts by volume of acetic acid-sodium acetate buffer solution (pH5.6), then add azidopropylamine (4.9 parts by mass) and (2.8 parts by mass) cyano Sodium borohydride, stirred at room temperature for 7 days. After the mixture was concentrated, it was dialyzed with a dialysis bag (3.5 kDa), acidified with hydrochloric acid, stirred for 30 min, dialyzed again, and a white solid product was obtained after freeze-drying.

Embodiment 2

[0079] Embodiment 2: the synthesis of the glutamic acid esterification product containing furan ring in formula (two)

[0080] Copper acetate monohydrate (41.2 parts by mass) and glutamic acid (29.4 parts by mass) were dissolved in 750 parts by volume of water, respectively. Under the condition of 70°C, the copper acetate aqueous solution was added dropwise to the glutamic acid aqueous solution, and reacted at room temperature for 48 hours after the dropwise addition was completed. The precipitate was filtered out with suction and washed with appropriate amount of water and ethanol respectively. Vacuum drying at 70°C for 24 hours yielded chelated copper glutamic acid with a yield of 90%.

[0081] Glutamic acid (5.5 parts by mass) and copper glutamate chelated copper (3.38 parts by mass) were suspended in a mixed solution of DMF (2 parts by volume) and 4 parts by volume of water, and then added dropwise in 1,1,3 , 3-Tetramethylguanidine (5.8 parts by volume). Stirring of the m...

Embodiment 3

[0082] Embodiment 3: the synthesis of acid anhydride monomer in the N-carboxyl ring in formula (three)

[0083] Suspend 0.05 mole parts of the glutamic acid esterification product with dry ethyl acetate. When the temperature rises to 70 °C, add 0.020 mole parts of triphosgene in batches. N 2 bubbling. After the reaction, the reaction solution was cooled to room temperature, and extracted once with ice water, 0.5% sodium bicarbonate and ice water respectively. The organic phase was dried with anhydrous sodium sulfate, and the solvent was rotary evaporated to dryness after filtering off the sodium sulfate. The product was pale yellow flocculent crystals, and the yield was 45%.

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Abstract

The invention belongs to the technical field of biological medical polymer materials and discloses a pH- and redox-response macromolecule nano prodrug based on CD44 receptor tumor targeting and preparation method and application thereof. The molecular structure of the macromolecule nano prodrug is as shown in general formula (1), wherein R is one of the structures as shown in the specifications; mand n are respectively side chain polymerization degree and peptide chain polymerization degree, and x is the repetitive unit number; when R1 is phenyl, R2 is acetyl; when R1 is tert-butoxy, R2 is hydrogen. The macromolecule nano prodrug is applicable to the precise delivery of antitumor drugs and the preparation of drugs for inhibiting tumor cell proliferation; after the macromolecule nano prodrug forms nano-micelles in water through self-assembling, tumor tissue is actively identified, the nano-micelles are devoured by cancer cells, the low-pH and high-concentration GSH environments in thecancer cells allow the acylhydrazone bond and disulfide bond in the structure of the nano-micelles to break, the nano-micelles disassemble to accelerate the release of chemotherapy drugs, and the cancer cells are finally killed.

Description

technical field [0001] The invention belongs to the technical field of biomedical polymer materials, and in particular relates to a macromolecular nano-prodrug based on CD44 receptor tumor-targeting pH and redox dual response and its preparation method and application. Background technique [0002] At present, chemotherapy is still the main means of treating tumors, but the toxic and side effects of chemotherapy often lead to unsatisfactory chemotherapy effects (Advanced Drug Delivery Reviews.2011, 63, 136-151). Using polymer nano-drug delivery system to precisely deliver drugs to tumor tissue can effectively reduce the toxic and side effects of chemical drugs and improve the effect of chemotherapy. To achieve precise drug delivery, tumor-targeting molecules can be bonded to the surface of drug-loaded polymer nanoparticles, which can specifically recognize and penetrate into tumor tissues in an "active targeting" manner (Chemical Reviews .2018, 118, 6844-6892). When this "...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/61A61K47/64A61K47/69A61K31/704A61K31/4745A61K31/337A61P35/00
CPCA61K31/337A61K31/4745A61K31/704A61K47/61A61K47/64A61K47/6907A61P35/00
Inventor 黄玉刚刘厚赫叶国东
Owner GUANGZHOU MEDICAL UNIV
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