Preparation method of redox-sensitive reversible crosslinked nano micelle with reversible charges

A technology of nano-micelle and nano-micelle solution, which is applied in the field of preparation of reduction-sensitive reversible cross-linked nano-micelle, which can solve the problems of cumbersome reactions, reducing the feasibility of the application of such materials, and the inability of materials to meet biodegradability, etc. Achieve the effect of mild and efficient reaction, excellent anti-protein adsorption performance, and increase the difficulty of reaction

Active Publication Date: 2017-05-31
JIANGNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are few reports on drug carriers with reversible nuclear crosslinking with charge reversal, and the reactions required to endow charge reversal properties and crosslinked structures are cumbersome, and most of the formed materials cannot meet the requirements of biodegradability, which reduces the biodegradability of such materials. Application Feasibility

Method used

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  • Preparation method of redox-sensitive reversible crosslinked nano micelle with reversible charges
  • Preparation method of redox-sensitive reversible crosslinked nano micelle with reversible charges
  • Preparation method of redox-sensitive reversible crosslinked nano micelle with reversible charges

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1) Synthesis of lipoyl ethylenediamine:

[0047] Weigh 3.00g (1.45×10 -2 mol) lipoic acid and 2.59g (1.60×10 -2 mol) N,N'-carbonyldiimidazole, dissolved in 30mL of chloroform, reacted for 1 hour at 25°C under nitrogen protection, then transferred the mixture to the dropping funnel, and added dropwise evenly stirred ethylenediamine (8mL , 0.12mol) in chloroform (30mL) solution, reacted for 12 hours at 25°C under nitrogen protection. After the reaction was completed, the reaction mixture was transferred to a separatory funnel, extracted with 10% NaCl (100mL) and 1M NaOH (100mL) respectively, and the organic phase was collected, and the organic solvent was removed by rotary evaporation to obtain a yellow gel-like compound Thioct Ethylenediamide (2.2 g, 61%).

[0048] 2) Synthesis of poly(lysine-co-polyethylene glycol diglycidyl ether-co-lipoyl ethylenediamine):

[0049] Weigh 315mg (1mmol) polyethylene glycol diglycidyl ether, 102mg (0.7mmol) lysine, and 75mg (0.3mmol)...

Embodiment 2

[0055] Measurement of charge-reversible reduction-sensitive reversibly cross-linked nanomicelles (CMC):

[0056] Dilute the charge-reversible reduction-sensitive reversible cross-linked nanomicelle solution obtained in Example 1 into a series of different concentrations, take 4 mL of the micellar solution of each concentration, and add 30 μL of it to a concentration of 1.622×10 -5 g / mL pyrene solution in acetone, protected from light, placed in a constant temperature shaking box under a nitrogen atmosphere, and incubated at 30°C for 24 hours. Measure the emission spectrum with a fluorescence spectrophotometer, set the fluorescence excitation wavelength λ=333nm, the scanning range λ=350-500nm, the excitation and emission slit widths are both 5nm, and the sample cell thickness is 1cm. By measuring a series of nanomicelle solutions with different concentrations at 373nm (I 1 ) and 384nm (I 3 ) fluorescence intensity, with the concentration logarithm as the X-axis, I 1 / I 3 Dr...

Embodiment 3

[0058] pH sensitivity of charge-reversible reduction-sensitive reversibly crosslinked nanomicelles:

[0059] The charge-reversible reduction-sensitive reversibly cross-linked nanomicelles obtained in Example 1 were adjusted to different pH values ​​with 0.1 mol / L sodium hydroxide solution and hydrochloric acid solution, and the Zeta potential was measured with a Zeta potential analyzer. Results from Figure 4 It can be seen from the figure that when no lysine is added to the composition of the carrier material (that is, N 1 ), at pH 7.4, the nanomicelles were almost uncharged; and as the pH decreased, the positive charges on the surface of the nanomicelles increased. After adding the lysine component, the carboxyl group can be deprotonated under alkaline conditions, making the nano-micelle negatively charged; adjusting the distribution ratio of the three components can adjust the isoelectric point of the carrier. Glyceryl ether: lipoyl ethylenediamine: lysine molar ratio is ...

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Abstract

The invention relates to the technical field of biomedical materials. The method comprises the steps of firstly synthesizing a yellow gelatinous compound thiocinamide from lipoic acid and ethylenediamine under an N,N'-carbonyl diimidazole catalyst; carrying out polymerization by using thiocinamide, ethylene glycol diglycidyl ether and lysine through a nucleophilic addition mechanism to prepare a poly(lysine-co-ethylene glycol diglycidyl ether-co-thiocinamide) terpolymer, and then forming a zwitter-ion nano micelle in a selective solvent through self-assembly. The micelle can be endowed with excellent anti-protein nonspecific adsorption and enhanced cell uptake property through protonation / deprotonation action under different pH conditions; a disulfide bond in lipoyl can form a linear polydisulfide structure under the action of 1,4-dithiothreitol, so that a micelle core is crosslinked and a cross-linked structure is destroyed in the cell, and controlled release of a drug can be achieved. The nano micelle is expected to be a drug carrier for treating cancers.

Description

technical field [0001] The invention relates to the technical field of biomedical materials, in particular to a method for preparing charge-reversible reduction-sensitive reversible cross-linked nano-micelles. Background technique [0002] In the past few decades, in order to improve the therapeutic effect of chemotherapy drugs, polymer carriers such as nanomicelles, vesicles, and microspheres have been vigorously developed. The polymer drug carrier physically encapsulates the drug or covalently binds the drug through the hydrophilic-hydrophobic interaction between the segment and the drug, so as to improve the circulation stability of the drug in the body, improve the targeting of the treatment site and effectively reduce the side effects on the body. However, the current development of nano-drug carriers still faces some challenges, such as the interaction between carriers and blood components, poor stability of antibody dilution, and low cellular uptake rate, etc. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08J3/07C08J3/24C08G73/02A61K9/107A61K47/34
CPCA61K9/1075A61K47/34C08G73/028C08J3/07C08J3/24C08J2379/02
Inventor 丁媛媛倪才华张丽萍石刚桑欣欣
Owner JIANGNAN UNIV
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