Hydrazone bond-containing block copolymer having targeting antitumor activity and preparation thereof, and applications of block copolymer as antitumor drug carrier
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An anti-tumor activity, block copolymer technology, applied in the field of polymer chemistry, can solve the problems of strong cardiotoxicity and limitation of doxorubicin
Inactive Publication Date: 2015-11-18
NORTHWEST NORMAL UNIVERSITY
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[0004] Doxorubicin has strong cardiotoxic
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Embodiment 1
[0071] Embodiment 1, the preparation of two-block polymer copolymer A
[0072] Preparation of 4-nitrophenyl methacrylate: 4-nitrophenol (0.5g, 3.6mmol) and triethylamine (0.437g, 4.32mmol) were dissolved in 15ml of THF, cooled to 0°C in an ice-water bath, Methacryloyl chloride (0.417ml, 4.32mmol) was dissolved in 10ml of THF and slowly added dropwise to the above solution. Reaction 12~15h. After the reaction, the precipitate produced in the filter solution was washed once with a small amount of distilled water, anhydrous MgSO 4 Dry and serve. Yield 95%.
[0073] 1 HNMR (400MHz, CDCl 3 ,δ,ppm):8.29(d, J =7.2Hz,2H,–OC 6 h 2 H 2 NO 2 ),7.43(d, J =7.2Hz,2H,–OC 6 H 2 h 2 NO 2 ),6.39(s,1H,CH H =C(CH 3 )CO–),5.84(s,1H,C H H=C(CH 3 )CO–),2.07(s,3H,CHH=C(C H 3 )CO–).
[0080] Embodiment 2, the preparation of triblock macromolecule copolymer B
[0081] compound , The preparation: with embodiment 1.
[0082] compound Preparation: Weigh folic acid (441.4mg, 1.0mmol), cyclohexylcarbodiimide (247.6mg, 1.2mmol) and N-hydroxysuccinimide (138.1mg, 1.2mmol), dissolve in 30mL di In methyl sulfoxide, react in the dark at 45~55°C for 6~8 hours. After all the folic acid is converted into folic acid activated ester, add allylamine (571mg10mmol) to the reaction solution, and react in the dark at -5~5°C for 12~ 15h. Add acetone to precipitate, filter with suction, and dry in a vacuum oven to obtain (321.2 mg, yield 65%).
[0083] 1 HNMR(400MHz,DMSO-d6,δ,ppm):8.62(s,1H,–CH–ofheterocyclic),7.61(d, J =8.6Hz,2H,–CH 2 NHC 6 H 2 h 2 CONHCH(COOH)CH 2 CH 2 CO–), 6.64 (d, J =8.6Hz,2H,–CH 2 NHC 6 h 2 H 2 CONHCH(COOH)CH 2 CH 2 CO–),5.88(m,1H,–NHCH 2 C H =CH 2 ),5.28(dd, J =27.0,13.9Hz,2H,–NHCH 2 CH=C H 2 ),4.46(s,2H,–C H 2 NHC 6 h 4...
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Abstract
The present invention provides a hydrazone bond-containing block copolymer having targeting antitumor activity. The preparation method comprises that: 4-nitrophenol methacrylate is subjected to RAFT polymerization to form a hydrophobic block, a good-biocompatibility hydrophilic polymer N-(2-hydroxypropyl)methacrylamide is introduced as a hydrophilic block, a double bond-containing folic acid targeting monomer is subjected to initiation polymerization to obtain a block polymer, and finally hydrazinolysis and a series of modification reactions are performed to introduce a pH sensitive group hydrazone bond. According to the present invention, with the doxorubicin-supporting block copolymer drug micelles, the toxicity of the small molecule drug in the body is reduced, and the residence time of the anticancer drug in the tumor cells is substantially prolonged; and the tumor cell growth inhibition experiment results prove that the copolymer provides a strong inhibition effect on HELA cells, the acidic pH-sensitive smart release bond (hydrazone bond) can identify the tumor cell micro-acidic environment, and the drug can break after reaching the tumor site so as to achieve the targeting antitumor activity of the drug, such that the copolymer is the antitumor activity substance having application prospects.
Description
technical field [0001] The invention belongs to the field of polymer chemistry, and relates to a block copolymer with targeted anti-tumor activity, in particular to a block copolymer containing hydrazone bonds with targeted anti-tumor activity; the invention also relates to the block copolymer Preparation method of segment copolymer and application as antitumor drug carrier. Background technique [0002] Doxorubicin has a strong anti-tumor effect, because its structure contains both fat-soluble anthracycline and water-soluble daunosamine; it also has acidic phenolic hydroxyl groups and basic amino groups. As a cycle non-specific anti-cancer chemotherapy drug, this product has effects on cells in all phases, but it is most sensitive to the early stage of S phase, followed by M phase, and has a delaying effect on G1, S and G2 phases. Its mechanism of action is that it can directly act on DNA, insert into the double helix strand of DNA, untie the latter, change the template pr...
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