Iron-abstracting agent compound with therapeutic effect and preparation method thereof
阅读说明：本技术 一种具有治疗作用的夺铁剂复合物及其制备方法 (Iron-abstracting agent compound with therapeutic effect and preparation method thereof ) 是由 陈清良 于 2020-05-08 设计创作，主要内容包括：本发明公开了一种具有治疗作用的夺铁剂复合物及其制备方法,利用离子性凝胶法形成纳米复合材料,纳米复合材料由[Fe<Sup>III</Sup>(CN)<Sub>6</Sub>]<Sup>3-</Sup>和[Fe<Sup>II</Sup>(CN)<Sub>6</Sub>]<Sup>4-</Sup>作为双重夺铁剂,交联壳聚糖作为高分子药物传递载体。本发明采用上述一种具有治疗作用的夺铁剂复合物及其制备方法,可以实现广谱抗菌,抗菌和抗真菌效果好,持续性强。(The invention discloses an iron-capturing agent compound with therapeutic action and a preparation method thereof, wherein an ionic gel method is utilized to form a nano composite material, and the nano composite material is made of [ Fe ] III (CN) 6 ] 3‑ And [ Fe ] II (CN) 6 ] 4‑ As a double iron-extracting agent, and cross-linked chitosan as a macromolecular drug delivery carrier. The iron-abstracting agent compound with the treatment effect and the preparation method thereof can realize broad-spectrum antibiosis, and have good antibacterial and antifungal effects and strong persistence.)
1. An iron-abstracting agent complex having a therapeutic effect, characterized in that: the iron-abstracting agent compound is a bionic iron-abstracting nano compound and comprises an iron-abstracting agent and chitosan.
2. A therapeutically effective iron-abstracting agent complex as claimed in claim 1, wherein: the iron-abstracting agent is [ Fe ]II(CN)6]4-And [ Fe ]III(CN)6]3-，[FeII(CN)6]4-/[FeIII(CN)6]3-Is 1:0.99 or 0.99: 1.
3. A therapeutically effective iron-abstracting agent complex as claimed in claim 1, wherein: the molecular weight range of chitosan is 3800-.
4. A therapeutically effective iron-abstracting agent complex as claimed in claim 1, wherein: the weight percentage of the chitosan is 30-60%.
5. A therapeutically effective iron-abstracting agent complex as claimed in claim 1, wherein: the iron content of the iron-capturing reagent is 0.1-50%.
6. A therapeutically effective iron-abstracting agent complex as claimed in claim 1, wherein: the size of the nano particle of the iron-abstracting agent compound is 5nm-300 nm.
7. A therapeutically effective iron-abstracting agent complex as claimed in claim 1, wherein: the nanoparticle surface potential (zeta potential) of the iron-abstracting agent complex ranges from 0 to 30 mV.
8. A process for the preparation of a therapeutically effective iron-abstracting agent as claimed in any one of claims 1 to 7, wherein: the iron-abstracting agent complex is prepared in an aqueous solution or hydrogel by an ionic gel method.
9. A method of using a therapeutically effective iron-abstracting complex as claimed in any one of claims 1 to 7, wherein: topical spraying of the iron-abstracting agent complex at the site of infection.
Technical Field
The invention relates to the technical field of medicines, in particular to an iron-abstracting agent compound with a treatment effect and a preparation method thereof.
Background
In recent years, the rate of emergence of drug-resistant pathogenic bacteria has outpaced the discovery of new antibiotics. In particular, the emergence of methicillin-resistant staphylococcus aureus (MRSA), i.e., a superbug that exhibits resistance to multiple antibiotic drugs, poses a global medical crisis, as more and more clinical antibiotics lose advantage in combating this deadly infection. This severe situation poses a great threat to global public health.
Currently, most clinical antibiotics are obtained by culturing microorganisms residing in soil. Having undergone extensive screening and searching for over seventy years, new antibiotics are now being discovered in the near future. In addition, limitations have been encountered in the discovery and development of synthetic antibiotics due to the lengthy and slow process required to design and synthesize compound libraries containing a variety of novel organic compounds. Now, there is an urgent need to develop a new generation of antibacterial agents to treat infections caused by gram-positive and gram-negative multi-drug resistant bacteria, achieving paradigm shift.
One potential strategy for antibacterial drug development is to simulate the innate immune system of humans and other mammals and interfere with the process of acquisition of pathogenic microorganisms and metabolism of iron to inhibit bacterial infection. Iron is an essential element for survival and growth of almost all forms of life, including microorganisms and all opportunistic pathogens. When invading human or other mammals, the pathogen acquires iron from the free iron stores of host cells by theft and robbery.
When infected, the human body or other mammals use iron as a defense mechanism against invading pathogens. This process of sequestering iron, commonly referred to as nutritional immunization, is a human or mammalian body that limits the possibility of free iron availability to free invading bacteria by mobilizing large amounts of iron transport and storage proteins.
After pathogenic microorganisms enter a host and are subjected to iron starvation, various complex mechanisms are utilized to escape from the nutritional immunity effect, and the iron is still obtained from the host, so that iron competition between host tissues and the invaded pathogenic microorganisms is continuous. Infection can be controlled to a large extent if the host does not stop competing for iron withholding. Otherwise, antibacterial drugs must be used to treat the infection.
In principle, it should be possible to use iron-deprivation as an effective means of treating bacterial infections alone without the use of any antibiotic drugs. However, the siderophore or heme molecules used by bacteria to acquire and absorb iron are strong iron chelators with higher binding constants to iron ions than any other known type of natural or synthetic small molecule iron chelators, and the use of natural or synthetic small molecule iron chelators has limited effectiveness in treating bacterial infections. At the same time, this view suggests that entrapment of iron by biomimetic methods may provide a better opportunity for the development of antibacterial agents.
The most typical iron-abstracting system is lactoferrin, which is a globular glycoprotein having a molecular weight of approximately 80 kilodaltons (kDa) and two iron-binding domains per lactoferrin. This is a particular type of iron transport and storage protein, which is present in components of the human innate immune system. Lactoferrin was originally found in the milk of humans and other mammals, and was later found to be present in a variety of other secretory body fluids as well, such as saliva, tears, nasal discharge, respiratory tract, intestinal tract, and even sweat.
The main function of lactoferrin is the binding and transport of iron, and by chelation of iron, lactoferrin can tightly control the amount of free iron ions at the cellular and systemic levels, thereby playing a crucial role in preventing bacterial growth. Lactoferrin has antibacterial activity, and also has antiviral, antiparasitic, anticancer, and antiallergic effects. Despite the many prophylactic uses of lactoferrin, the use of lactoferrin as a therapeutic agent requires very high doses to produce clinically significant therapeutic effects.
Disclosure of Invention
The invention aims to provide an iron-abstracting agent compound with a treatment effect and a preparation method thereof, which can realize broad-spectrum antibiosis, good antibiosis and antifungal effects and strong persistence.
In order to achieve the purpose, the invention provides an iron-abstracting agent compound with a therapeutic effect, wherein the iron-abstracting agent compound is a bionic iron-abstracting nano compound and comprises an iron-abstracting agent and chitosan.
Preferably, the iron-abstracting agent is [ Fe ]II(CN)6]4-And [ Fe ]III(CN)6]3-，[FeII(CN)6]4-/[FeIII(CN)6]3-Is 1:0.99 or 0.99: 1.
Preferably, the molecular weight of chitosan is in the range of 3800-20000 Da.
Preferably, the weight ratio of the chitosan is 30-60%.
Preferably, the iron-abstracting agent contains 0.1% to 50% of iron.
Preferably, the size of the nanoparticles of the iron-abstracting agent complex is 5nm to 300 nm.
Preferably, the surface potential (zeta potential) of the nanoparticles of the iron-abstracting agent complex is in the range of 0 to 30 mV.
A method for preparing iron-abstracting agent with therapeutic effect comprises preparing iron-abstracting agent complex in water solution or hydrogel by ionic gel method.
A method for using an iron-capturing compound for treatment comprises spraying the iron-capturing compound onto the affected area.
Therefore, the core of the iron-abstracting agent compound with the treatment effect and the preparation method thereof is to use the nanoparticle carrier as a main material and simulate the iron-abstracting and iron-transporting functions of the lactoferrin so as to achieve the non-drug treatment effects of antibiosis, antivirus, antiparasitic and anticancer.
The present document uses two strongest non-biological iron chelators, iron cyanide [ Fe ]III(CN)6]3-And ferrocyanide [ Fe ]II(CN)6]4-Ions. The former may optionally be combined with Fe2+Ion reaction of the latter with Fe3+Ion reaction to form an insoluble compound called Prussian blue FeIII 4[FeII(CN)6]3. Due to the dissociation constant (K) of Prussian bluesp＝3.0×10-41) Very low, release of Fe3+And [ Fe ]II(CN)6]4-The extremely low level of ions in aqueous solution, which is very effective in this iron-abstraction strategy, reduces the concentration of free iron ions to trace levels, rendering the iron no longer bioavailable for bacterial growth.
In addition, FeIII 4[FeII(CN)6]3Is an effective fenton catalyst because the continuous redox cycling reaction between fe (iii) and fe (ii) is likely to occur. In bacterial and mammalian cells, Fe2+Can react with hydrogen peroxide which is a byproduct of cell metabolism to generate hydroxyl OH-and hydroxyl free radical (OH-):
Fe2+(aq)+H2O2(a q)＝Fe3+(aq)+OH(aq)+OH(aq)
hydroxyl radicals are a class of reactive oxygen radicals. According to different concentrations, the sterilization capability of the active oxygen varies from weak to strong, and the temporary increase of the intracellular active oxygen level can not generate toxic and side effects on normal tissues. On the other hand, macrophages, which are part of immune cells in the host tissue, can be triggered by reactive oxygen species and attack invading pathogens at the site of bacterial infection as an innate immune response, constitutes another mechanism for treating bacterial infections.
Because intracellular iron is predominantly present in the fe (ii) form due to the presence of divalent metal reductases within the cell, and extracellular iron is predominantly present in the fe (iii) form due to the presence of iron binding proteins such as transferrin and lactoferrin. Thus, [ Fe ]III(CN)6]3-Ions and [ FeII(CN)6]4-The ions need to complement each other to ensure the depletion of iron inside and outside the bacterial cells.
And also, [ Fe ]III(CN)6]3-And [ Fe ]II(CN)6]4-Are all non-toxic, Na4[FeII(CN)6]·10H2O, commonly known as a yellow iron salt, can be added as an antagonist to food grade salts and various cheese products. Prussian blue is an antidote approved by the United states Food and Drug Administration (FDA) for the treatment of thallium and radioactive cesium-137 poisoning.
Chitosan is a biodegradable and biocompatible polymer that also exhibits mild antibacterial and antifungal activity by itself. The chitosan-coated nanoparticles can enable the drug to be released continuously, have positive surface charges and are adhesives. The anionic iron-abstracting agent is prepared into the charge neutral nano composite material by the polymer with positive charge, so that the high ionic charge- [ FeIII(CN)6]3-Or [ Fe ]II(CN)6]4-Can not directly penetrate the bacterial cell membrane, and becomes an effective iron-capturing medicament.
The technical solution of the present invention is further described in detail by the following examples.
Detailed Description
The embodiments of the present invention will be further explained below.
An iron-abstracting agent compound with therapeutic effect is a bionic iron-abstracting nano compound, and comprises an iron-abstracting agent and chitosan.
The iron-abstracting agent is [ Fe ]II(CN)6]4-And [ Fe ]III(CN)6]3-，[FeII(CN)6]4-/[FeIII(CN)6]3-Is 1:0.99 or 0.99: 1.
The molecular weight range of chitosan is 3800-.
The weight percentage of the chitosan is 30-60%.
The iron content of the iron-capturing reagent is 0.1-50%.
The size of the nano particle of the iron-abstracting agent compound is 5nm-300 nm.
The nanoparticle surface potential (zeta potential) of the iron-abstracting agent complex ranges from 0 to 30 mV.
A method for preparing iron-abstracting agent with therapeutic effect comprises preparing iron-abstracting agent complex in water solution or hydrogel by ionic gel method.
A method for using an iron-capturing compound for treatment comprises spraying the iron-capturing compound onto the affected area.
The iron-abstracting agent complex of the present document is a novel nanoparticle composed of biocompatible chitosan, ferricyanide and ferrocyanide, has high affinity to bacterial cell membranes, can rapidly chelate extracellular and intracellular free iron at the site of infection, and can be used to inhibit bacterial growth.
And prussian blue Fe, a product of chelation reaction of free iron at a site infected with bacteria with ferricyanide and ferrocyanide4[Fe(CN)6]3Can be used as Fenton catalyst, and hydrogen peroxide (H) generated by respiratory metabolism of bacteria2O2) Reacting to generate Reactive Oxygen Species (ROS) to cooperate with the iron-reducing effect of the nano particles, thereby achieving the purpose of eradicating bacterial pathogens. The generated active oxygen can stimulate human body to have great effectPhagocytosis, attack of invading pathogens, and generation of immune antibacterial effect.