Nano medicine system with bacterium pore-forming toxin adsorption capability and application of nano medicine system

A nano-drug and toxin adsorption technology, which is applied in the direction of medical preparations of non-active ingredients, antibacterial drugs, pharmaceutical formulas, etc., can solve the problems of weakening the detoxification effect of nano-sponge, weak detoxification ability, and high requirements for the core of nano-particles

Active Publication Date: 2020-06-02
FUDAN UNIV
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Problems solved by technology

According to the mechanism of action of pore-forming toxins, researchers in this technical field synthesized various types of erythrocyte-like nanoparticles to adsorb pore-forming toxins for the treatment of bacterial infections. For example, Zhang Liangfang et al. prepared PLGA nanoparticles coated with erythrocyte membranes (Nanosponge) for removing bacterial pore-forming toxins (Hu CM, Fang RH, Copp J, Luk BT, Zhang L.A biomimetic nanosponge that absorbs pore-forming toxins. Nat Nanotechnol. 2013; 8: 336-40.); Preparation of liposomes containing sphingomyelin and cholesterol for adsorption of pore-forming toxins (Henry BD, Neill DR, Becker KA, Gore S, Bricio-Moreno L, Ziobro R, et al. Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice.NatBiotechnol.2015; 33:81-8.); studies have shown that the specific adsorption of pore-forming toxins on the cell membrane is closely related to a variety of receptors (including sugars, lipids, proteins) on the cell membrane surface, simple It is difficult for artificial lipid membranes to completely simulate the composition, structure and function of cell membranes, their detoxification spectrum is narrow, and their stability in vivo is poor, so their applications are greatly limited.
Studies have shown that although the red blood cell membrane-coated nanoparticles have a wide detoxification spectrum, their detoxification ability is weak, and the coating process is complicated, which requires high requirements for the nanoparticle core, poor stability, and difficult to mass-produce; in addition, the cell membrane The protein component is easy to be inactivated in the process of coating nanoparticles, which is easy to further weaken the detoxification effect of the nano-sponge, and further reduces the resource utilization efficiency of the red cell membrane; therefore, it is necessary to construct a new type of The erythrocyte-mimicking nanoparticles are particularly important for detoxification of pore-forming toxins and antibacterial infection treatment

Method used

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  • Nano medicine system with bacterium pore-forming toxin adsorption capability and application of nano medicine system
  • Nano medicine system with bacterium pore-forming toxin adsorption capability and application of nano medicine system
  • Nano medicine system with bacterium pore-forming toxin adsorption capability and application of nano medicine system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: Construction of erythrocyte membrane hybrid liposome

[0043] In this example, erythrocytes were first isolated from the whole blood of mice, and then the erythrocyte membrane was extracted by hypotonicity and centrifugation. The specific operation was as follows: the eyeballs of ICR male mice were removed to take blood, and 1ml of whole blood was anticoagulated with heparin sodium, 700g, Collect erythrocytes by centrifugation at 4°C, add 10 mL of PBS solution containing 1 mM EDTA to resuspend erythrocytes, repeat the above steps to wash erythrocytes 3 times, and collect erythrocytes at the bottom. Then use PBS to make red blood cell suspension, and divide each 0.25ml into 1.5mL EP tube, add 950μL 0.2mM EDTA aqueous solution, mix well and vortex to break the red blood cells, then add 50μL 20×PBS to adjust to isotonicity, 4℃ Centrifuge at 20,000 g for 10 min, and discard the supernatant. Then add 950 μL of 0.2 mM EDTA aqueous solution, and repeat the above...

Embodiment 2

[0049] Example 2: Experimental verification of fusion between erythrocyte membrane and lipid membrane

[0050] Using fluorescence resonance energy transfer (FRET) technology to investigate membrane fusion, the specific operation: first use FRET fluorescent dyes to mark lipid membranes (C6-NBD and RhB-DHPE), and then add different amounts of red blood cell membranes to squeeze through the micropores Membrane, prepare the erythrocyte membrane hybrid liposome, and record the spectrogram with a fluorescence spectrometer (such as figure 2 shown in A). The results showed that with the increase of the amount of red blood cell membrane, the fluorescence intensity of RM-PLs at 534nm (C6-NBD) gradually increased, and the fluorescence intensity at 583nm (RhB-DHPE) gradually decreased, indicating that the red blood cell membrane was successfully fused into the lipid membrane. Increasing the gap of the FRET dye leads to the weakening of the FRET phenomenon;

[0051] The erythrocyte memb...

Embodiment 4

[0059] Embodiment 4: Physicochemical property characterization of erythrocyte membrane hybrid liposome

[0060] Observation under the transmission electron microscope after negative staining with uranyl acetate showed that the hybrid liposomes were regular spherical and uniform in size ( Figure 4 A), potential / laser particle size analyzer measurement result shows that hybrid liposome average particle diameter is 117.4 ± 2.3nm ( Figure 4 B&C), the potential is -36.0±0.2mv ( Figure 4 D).

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Abstract

The invention belongs to the technical field of biologics, relates to bacterial anti-toxin treatment medicines and in particular relates to a nano medicine system with a bacterial pore-forming toxin adsorption capability and application of the nano medicine system. According to the nano medicine system, an erythrocyte membrane and a phospholipid membrane are fused to prepare an erythrocyte membrane heterozygosis lipidosome by using an extrusion membrane-through method, a high-pressure homogenization method or a microjet method, and an anti-bacterial antibiotic is further prepared; and by adsorbing pore-forming toxins of bacteria to the surface of a nano medicine, the nano medicine neutralizes toxicity of the toxins to achieve anti-toxin treatment of the bacteria, and thus the effect of anti-bacterium infection treatment, particularly drug-resistant bacterium infection treatment, can be improved. The invention provides a novel interference strategy for anti-bacterium infection for clinical practice.

Description

technical field [0001] The invention belongs to the field of biological technology, and relates to a drug for treating bacterial antitoxins, in particular to a nanomedicine system with the adsorption performance of bacterial pore-forming toxins and its application. Toxicity enables bacterial antitoxin therapy, thereby improving the efficacy of antibacterial infection treatment, especially drug-resistant bacterial infection. Background technique [0002] At present, bacterial infection is still a disease with high morbidity and mortality worldwide. Bacterial drug resistance has brought more challenges to the treatment of antibacterial infection. Therefore, the industry urgently needs to design new strategies to improve the treatment effect of bacterial infection . Studies have reported that pore-forming toxins (PFTs) are the main virulence factor components of bacterial infection, which mainly kill target cells by forming pores on the cell membrane and changing the permeabil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/46A61K47/24A61K47/28A61P31/04
CPCA61K9/127A61K47/46A61K47/24A61K47/28A61P31/04Y02A50/30
Inventor 庞志清王建新何雨薇李瑞翔
Owner FUDAN UNIV
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