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A kind of preparation method of charge-reversible reduction-sensitive reversible cross-linked nanomicelles

A nanomicelle and charge technology, applied in the field of preparation of reduction-sensitive reversible cross-linked nanomicelles, can solve the problems of reducing the application feasibility of such materials, cumbersome reactions, and the inability of materials to meet biodegradability, and achieve excellent resistance. Protein adsorption performance, mild and efficient reaction, and the effect of increasing the difficulty of the reaction

Active Publication Date: 2018-09-28
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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  • A kind of preparation method of charge-reversible reduction-sensitive reversible cross-linked nanomicelles
  • A kind of preparation method of charge-reversible reduction-sensitive reversible cross-linked nanomicelles
  • A kind of preparation method of charge-reversible reduction-sensitive reversible cross-linked nanomicelles

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

Disclosed is a preparation method for charge reversal and reversibly crosslinked redox-sensitive nanomicelles, falling within the technical field of biomedical materials. The method comprises: synthesizing thiocinamide from lipoic acid and ethylenediamine under an N,N′-carbonyl diimidazole catalyst; and polymerizing thiocinamide, polyethylene glycol diglycidyl ether and lysine through a nucleophilic addition mechanism to prepare a poly(lysine-co-polyethylene glycol diglycidyl ether-co-thiocinamide) terpolymer. The micelle is endowed with excellent anti-protein nonspecific adsorption and enhanced cell uptake property through a self-assembly and protonation / deprotonation action; and a disulfide bond in lipoyl may form a linear polydisulfide structure under the action of 1,4-dithiothreitol, so that a micelle core is crosslinked, and a crosslinked structure is destroyed in the cell under a redox condition, and controlled release of a drug can be achieved. The Nanomicelle of the present invention is expected to be a carrier of drugs 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 Patents(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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