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Preparation and application of mixed structure PLGA-PLL-PEG targeting polymer carrier

A technology of polymers and intermediates, applied in the preparation of targeted nanoparticles, in the field of synthesis of poly(lactic-co-glycolic acid-polylysine-polyethylene glycol) polymers, can solve the problem of reducing body circulation time, reaction Reduced yield, many reaction steps, etc., to achieve the effects of increased in vivo stability, convenient product purification, and mild reaction conditions

Inactive Publication Date: 2013-04-17
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still two main disadvantages in simply using PLGA as a carrier material: (1) PLGA is easily absorbed by organs rich in reticuloendothelial system such as liver and spleen in the systemic circulation, resulting in a decrease in the amount of drugs in the systemic circulation
(2) PLGA is easy to degrade, which often leads to problems such as early drug release and accelerated drug degradation in the later stage, which affects the safety of drug use in vivo
This patent mainly has the following deficiencies: ① There are many steps in the carrier synthesis reaction, which will lead to a decrease in the reaction yield and increase the difficulty of product purification
②The content of PEG in each segment of polymer carrier is less, which may weaken the in vivo stability of nanoparticles prepared later and reduce the time of systemic circulation; ③In general carrier design, the targeting ligand connected to increase targeting is usually connected to At the end of PEG, and in this invention, only the carboxyl group at the end of the PLL polymer can be connected to the protein ligand, and there are relatively few binding sites, resulting in a narrow range of application of the target body and a low cross-linking rate with the ligand.

Method used

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  • Preparation and application of mixed structure PLGA-PLL-PEG targeting polymer carrier

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Experimental program
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Effect test

Embodiment 1

[0036] (1) Preparation of polylysine (PLL-CBZ):

[0037] Take 4g of Nε-benzyloxycarbonyl-L-lysine-N-carboxylic acid anhydride (Lys(z)-NCA) into a three-necked flask, stir and dissolve with 30ml of anhydrous DMF, protect with nitrogen, and use a micro-injector according to the molar ratio Add anhydrous ethylenediamine at a ratio of 36:1, stir at room temperature for 72 hours, add 8 times the volume of anhydrous ether to precipitate, filter with suction, and dry in vacuo overnight.

[0038] 1 H-NMR: δ=1.18-1.66(m; -(CH 2 ) 3 -CH 2 -NH-Z), δ=3.04(m; ε-CH 2 ), δ=3.78(s; α-CH), δ=4.31(s; -CO-CH-NH-), δ=5.05(s; C 6 h 5 CH 2 ; 2H), δ=6.85(s; -NH-Z; 1H), δ=7.33(m; C 6 h 5 CH 2 ; 5H), δ=7.95 (α-NH 2 ; 2H). 1 α-NH appears at δ=7.95 in the H-NMR spectrum 2 A hydrogen peak, indicating the occurrence of polymerization.

[0039] (2) Activated polyethylene glycol:

[0040] Dissolve 4g of PEG4000 in dioxane, dissolve and keep warm at 37°C, add excess CDI (molar ratio 1:8), N 2...

Embodiment 2

[0051] (1) Synthesis of polylysine (PLL-CBZ):

[0052] Take 3g of Nε-benzyloxycarbonyl-L-lysine N-carboxylic acid anhydride (Lys(z)-NCA) into a three-necked flask, stir and dissolve with 20ml of anhydrous DMF, protect with nitrogen, and use a micro-injector according to the molar ratio Add anhydrous triethylamine at a ratio of 60:1, stir for 72 hours, add 5 times the volume of anhydrous ether to precipitate, filter with suction, and dry in vacuo overnight.

[0053] (2) Synthesis of polylactic acid glycolic acid-polylysine:

[0054] Weigh quantitative PLGA-COOH and the synthesized PLL-CBZ above in a molar ratio of 1:1 and dissolve them in anhydrous DMF, add 5 times PLGA molar equivalent of DCC and 1 molar equivalent of DMAP under ice bath, N 2 Protection, reaction 36h. Trichloromethane and methanol were used to remove unreacted raw materials and by-products generated by the reaction, and the final product was vacuum-dried at room temperature for 24 hours. Take 3g of PLGA-PLL...

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Abstract

The invention relates to the technical field of polymer materials, and particularly relates to preparation and application of a mixed structure PLGA-PLL-PEG (Polylactide Acid Glycolic Acid-Polylysine-Polyethylene Glycol) targeting polymer carrier. The preparation is characterized in that polylactide acid glycolic acid and side chain protected polylysine are acted by a dehydrating agent and then connected in the block way to form a midbody; the midbody is deprotected and then connected with activated polyethylene glycol in the grafting manner, so that the polylactide acid glycolic acid-polylysine-polyethylene glycol polymer having the molecular weight of 4*10 <4> to the power of 4 to 5*10<5> is obtained. The polymer is used for carrying various medicines and also capable of being coupled with various ligands to realize targeted medicine delivery. The preparation of the polymer carrier provided by the invention is few in synthesis steps, mild in reaction conditions, available in materials and convenient for product purification.

Description

technical field [0001] The invention relates to the technical field of polymer materials, in particular to a synthesis method of poly(lactic-co-glycolic acid-polylysine-polyethylene glycol) polymer and its application in the preparation of targeted nanoparticles. Background technique [0002] Traditional chemotherapy is still the main means of cancer treatment at the present stage. Chemotherapy drugs themselves have a strong killing effect on tumor cells, but most of them are non-selective drugs, widely distributed in the body, and conventional therapeutic doses can produce significant toxicity to normal tissues and organs. Therefore, improving the targeting of drugs to tumor tissues and reducing their accumulation in non-targeted sites are the keys to improving the efficacy of anti-tumor drugs. [0003] The problem encountered in tumor treatment is not the lack of drugs that can kill cancer cells, but the lack of targeting carriers that can accurately deliver anti-tumor dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G81/00A61K47/34A61K47/48
Inventor 李学明陈宝安王永禄陈卫刘苒殷海祥郭莉婷程坚张孝平鲍文
Owner NANJING UNIV OF TECH
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