Zwitterionic fluorinated cross-linking agent, nanogel and application of nanogel

A technology of fluorinated cross-linking agent and zwitterion, which is applied in the application field of zwitterionic fluorinated nanogel as a 19FMRI nano-contrast agent, which can solve the problems of inappropriate targeted molecular imaging research, poor stability of nanoemulsion, and long imaging time

Pending Publication Date: 2020-10-23
INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still many problems with PFCs nanoemulsion contrast agents: perfluorinated molecules are superhydrophobic, and surfactants are needed to form nanoemulsions, but nanoemulsions are poor in stability and prone to flocculation, aggregation, phase separation, and Ostwald ripening; The relaxation rate of fluoride is significantly affected by tissue oxygen content, and it is difficult to establish a unified quantitative calculation method; the longitudinal relaxation time of perfluoride nanoemulsions (T 1 ) long, resulting in too long imaging time; especially, after intravenous injection of perfluorinated nanoemulsion contrast agent, it quickly accumulates in the liver and spleen, which is not only not suitable for targeted molecular imaging research, but also can stay for several months or even longer , there are potential security issues
Limited by this, even if the fluorine content in the molecular structure is further increased, not only will it not enhance, but it will aggravate the signal attenuation caused by hydrophobic aggregation.

Method used

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  • Zwitterionic fluorinated cross-linking agent, nanogel and application of nanogel
  • Zwitterionic fluorinated cross-linking agent, nanogel and application of nanogel
  • Zwitterionic fluorinated cross-linking agent, nanogel and application of nanogel

Examples

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Effect test

example 2

[0198] A representative zwitterionic fluorinated nanogel PCBMAF is described in Example 2 3 / PCBMAF 3 Preparation and characterization of X.

[0199] PCBMAF 3 / PCBMAF 3 The synthetic route and characterization of X zwitterionic fluorinated nanogels are shown in Figure 3.

[0200] Figure 3A shows PCBMAF 3 / PCBMAF 3 Synthetic route of X zwitterionic fluorinated nanogels. PCBMAF was synthesized by microemulsion radical polymerization 3 / PCBMAF 3 X Zwitterionic Fluorinated Nanogels.

[0201] Thanks to PCBMAF 3 / PCBMAF 3 Potential application of zwitterionic fluorinated nanogels as therapeutic and diagnostic agent loading and delivery vehicles involving temperature-sensitive bioactive compounds such as proteins, DNA or RNA, thus initiating polymerization at 40°C using low-temperature free radical initiators .

[0202] Figure 3B are shown with different PCBMAF 3 and PCBMAF 3 X molar ratio of PCBMAF 3 / PCBMAF 3X Particle size distribution of zwitterionic fluorinat...

Embodiment 1

[0278] Example 1: Preparation and characterization of zwitterionic fluorinated crosslinkers.

[0279] In this example, a representative zwitterionic fluorinated crosslinker of the invention, CBMAF, is described 3 The preparation of X, synthetic route such as figure 2 shown.

[0280] 2,2'-((3,3,3-trifluoropropyl) azepine) bis(ethane-1-ol) (1). Under the protection of argon, to the diethanolamine dissolved in acetonitrile ( 5mmol) solution was added 3-bromo-1,1,1-trifluoropropane (7.5mmol). Then, after reacting at 50° C. for 24 hours, it was cooled to room temperature, and the mixture was purified by column chromatography using 90% DCM / 10% methanol as the eluent to obtain the target product as a light yellow oil (yield 83%). 1 H NMR (400MHz, Chloroform-d) δ4.16(s, 2H), 3.42(t, J=5.8Hz, 3H), 2.57(t, J=5.8Hz, 4H), 2.46(t, J=5.8Hz ,2H),1.91(m,2H). 13 C NMR (100MHz, CDCl 3 )δ126.56(q, J=274.7Hz), 60.1, 59.3, 50.31(q, J=3.4Hz), 40.21(q, J=27.3Hz), 39.05. 19 F NMR (376MHz, Chl...

Embodiment 2

[0284] Example 2: Representative PCBMAF 3 / PCBMAF 3 X. Preparation and Characterization of Zwitterionic Fluorinated Nanogels.

[0285] PCBMAF 3 / PCBMAF 3 X. Method for the preparation of zwitterionic fluorinated nanogels. at PCBMAF 3 In the monomer solution, add sodium dodecyl sulfate (SDS) as a surfactant, and the molar ratio is a crosslinking agent PCBMAF with a certain proportion of the total moles of monomers 3 X: Continuously feed argon into the reaction system, heat the oil bath to control the reaction temperature (40° C.), and add 0.05 wt % ammonium persulfate (APS) under the protection of argon to initiate the polymerization reaction. By adjusting the shear rate, reaction temperature, monomer concentration, molar ratio of cross-linking agent to monomer, etc., the nano-hydrogel particle size, shape and cross-linking degree can be regulated. After the reaction, the nanogel is dialyzed in ultrapure water to remove residual monomers, cross-linking agents, surfactants...

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Abstract

The invention provides zwitterionic fluorinated nanogel prepared by copolymerization of a zwitterionic fluorinated monomer and a zwitterionic fluorinated cross-linking agent, and relates to a preparation method of the zwitterionic fluorinated cross-linking agent and the nanogel, and application of the zwitterionic fluorinated nanogel as a nanometer contrast agent for fluorine-19 magnetic resonanceimaging (<19>F MRI).

Description

technical field [0001] The invention relates to a zwitterionic fluorinated nanogel prepared by copolymerization of a zwitterionic fluorinated monomer and a zwitterionic fluorinated cross-linking agent, especially the zwitterionic fluorinated nanogel as 19 Application of F MRI nanocontrast agents. Background technique [0002] Early monitoring of many diseases, requiring the development of non-invasive diagnostic tools to implement targeted treatments, is one of the major challenges in current medicine, where imaging plays a key role, and Magnetic Resonance Imaging (MRI) does not require the use of radioactive Nuclides, in the absence of ionizing radiation, have great potential for clinical imaging applications. [0003] In the early 1970s, Lauterbur et al. laid the foundation for nuclear magnetic resonance imaging, which relied on hydrogen atoms ( 1 H) Alignment and precession under the action of an external magnetic field. For many years, clinical 1 H MRI utilizes a lar...

Claims

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Application Information

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IPC IPC(8): C07C229/12C07C227/08C07C227/18C07C213/08C07C215/12C07C213/06C07C219/08C08F220/36C08F222/22A61K49/18A61K49/12
CPCC07C229/12C07C227/08C07C227/18C07C213/08C07C213/06C08F220/365A61K49/1803A61K49/124C07C215/12C07C219/08C08F222/102
Inventor 黄平升王伟伟李青华时圣彬
Owner INST OF BIOMEDICAL ENG CHINESE ACAD OF MEDICAL SCI
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