CN-117414347-B - Nanoparticle capable of controllably releasing carbon monoxide and preparation method and application thereof

Abstract

The invention discloses a nanoparticle capable of controllably releasing carbon monoxide, a preparation method and application thereof, and belongs to the technical field of nano-drugs. The nanometer particle capable of controllably releasing carbon monoxide comprises dodecacarbonyl ferroferric and Croc-PEG coated on the dodecacarbonyl ferroferric, wherein the Croc-PEG is a condensation product of Croc and MPEG-NH 2 . The nano particles provided by the invention can effectively improve the loading capacity of carbon monoxide, the biological safety of the nano particles and the controllable release of the carbon monoxide, thereby realizing high-efficiency low-toxicity CO gas therapy. The invention also provides a preparation method and application of the nanoparticle.

Inventors

• WANG HUAIYU
• GAO XIAOTING
• YAN LEI

Assignees

• 中国科学院深圳先进技术研究院

Dates

Publication Date

20260505

Application Date

20231018

Claims (10)

1. 1. A nanoparticle capable of controllably releasing carbon monoxide, wherein the nanoparticle comprises ferrododecacarbonyl and Croc-PEG coating the ferrododecacarbonyl, wherein the Croc-PEG is a condensation product of Croc and MPEG-NH 2 , and the molecular formula of Croc is: 。
2. 2. The nanoparticle of claim 1, wherein the molar ratio of the ferrododecacarbonyl to the Croc-PEG is 5-6:1 and/or the molecular weight of the MPEG-NH 2 is 2 k-5 k.
3. 3. The nanoparticle according to claim 1 or2, wherein the nanoparticle has a near spherical structure and/or the average size of the nanoparticle is 80-110 nm.
4. 4. A method of preparing the nanoparticle of any one of claims 1 to 3, comprising the steps of: s1, dispersing the dodecacarbonyl ferroferric in THF to obtain a dispersion A; Dispersing Croc-PEG in THF to obtain a dispersion B; s2, adding the dispersion liquid A and the dispersion liquid B into water, and mixing; s3, blowing protective gas into the mixture obtained in the step S2, and then passing the obtained mixture through a filter membrane to ultrafiltrate and concentrate the obtained filtrate.
5. 5. The method according to claim 4, wherein in step S1, the method for synthesizing Croc-PEG comprises the steps of: D1. reacting a reaction product of 4-carboxyphenylhydrazine hydrochloride and 3-methyl-2-butanone with croconic acid to obtain Croc; D2. The Croc and MPEG-NH 2 are subjected to an amide condensation reaction.
6. 6. The method according to claim 4, wherein in the step S1, the concentration of the dispersion A is 3.5 to 4.5mmol/mL, and/or the concentration of the dispersion B is 0.5 to 1 mmol/mL.
7. 7. The method according to claim 4, wherein in the step S2, the volume ratio of the dispersion liquid a to the water is 1:8-9.
8. 8. The method according to claim 4, wherein in the step S2, the mixing time period is 25 to 35min.
9. 9. The method according to claim 4, wherein in the step S3, the pore size of the filter membrane is 0.22. Mu.m, and/or the molecular weight cutoff of the ultrafiltration centrifuge tube used for the ultrafiltration concentration in the step S3 is 10 kilodaltons.
10. 10. Use of the nanoparticle according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of cardiovascular diseases, sepsis, shock, acute lung, kidney and liver injury, microbial infection, arthritis and cancer.

Description

Nanoparticle capable of controllably releasing carbon monoxide and preparation method and application thereof Technical Field The invention relates to the technical field of nano-drugs, in particular to a nano-particle capable of controllably releasing carbon monoxide, a preparation method and application thereof. Background Carbon monoxide (CO) is a gaseous messenger molecule with abundant biological effects and has therapeutic potential for many diseases. As a bioactive substance, CO has a regulatory role in many physiological and pathological aspects, mainly because CO can bind to respiratory chain complexes such as iron hemoglobin (Hb), affecting their function and triggering cascade effects. The CO can promote blood circulation to remove blood stasis, has oxidation resistance to reduce oxidative stress and relieve inflammation, has apoptosis inhibiting effect on mitochondrial pathway, and has repair promoting effect on promoting tissue regeneration, so that CO is an ideal disease therapeutic active agent. Carbon monoxide (CO) gas therapy is an emerging medical technology due to its many effects, and has been increasingly applied to the treatment of various diseases such as cardiovascular diseases, sepsis, shock, acute lung, kidney and liver injuries, microbial infections, cancer, etc. Gaseous CO is difficult to store and transport, its diffusivity makes its concentration and location in the body uncontrollable, easily causing a risk of inefficiency or poisoning. The treatment effect of CO gas treatment depends on the concentration and in-vivo position of CO, the concentration is too low without obvious treatment effect, the poisoning risk is brought about by the too high concentration, meanwhile, the CO can diffuse everywhere in the whole body without destination to easily cause the whole body toxicity, and the controllable and accurate release of the CO is important. The CO gas therapy must therefore rely on a specific platform to achieve accurate release as required. The construction of the gas generating platform is crucial for the application of CO gas treatment, and the nano material becomes an ideal choice due to the variety, structural variability and functional diversity, and materials such as liposome, hydrogel, polypeptide, protein, metal organic framework and the like are currently used for the construction of the gas generating nano platform (GGNs). Depending on the specific GGNs, the controlled release of CO is realized by adjusting the structure, shape, size, surface modification and the like of the nano particles, and meanwhile, GGNs can realize functional diversification, such as combined treatment, cooperative treatment, image guidance and the like. GGNs provides a valuable idea for the development and popularization of CO gas therapy. CO release molecules (CORMs) are gas-generating nano-platforms that release CO gas, and they can be used as gas cylinders to release CO gas in vivo or in vitro. Common CORMs include metalloporphyrin complexes, organic compounds, and mononuclear ferriporphyrin compounds. Metal carbonyls are complexes of transition metals (nickel, cobalt, ruthenium, vanadium, chromium, manganese, and iron) with CO that can be released under specific conditions. Manganese carbonyl and iron carbonyl are relatively suitable for biological applications in view of the safety of metal metabolites, and of these compounds, the gas storage amount of ferrododecacarbonyl (Fe 3(CO)12) is the highest and thus an ideal CO donor. However, these compounds have poor water solubility, biocompatibility, and controllability of CO release, which are to be improved. Disclosure of Invention The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides the carbon monoxide controllable release nano-particles, which can effectively improve the carbon monoxide loading capacity, the biological safety of the nano-particles and the controllable release of the carbon monoxide, thereby realizing the high-efficiency low-toxicity CO gas therapy. The invention also provides a preparation method of the nanoparticle. The invention also provides application of the nanoparticle. According to an embodiment of the first aspect of the present invention, there is provided a nanoparticle (abbreviated as Fe 3(CO)12 @ Croc-PEG) capable of controllably releasing carbon monoxide, the nanoparticle comprising ferrododecacarbonyl (Fe 3(CO)12) and Croc-PEG coating the ferrododecacarbonyl, the Croc-PEG being a condensation product of Croc (croconic acid cyanine dye) and MPEG-NH 2 (amino-terminated substituted polyethylene glycol), the Croc having the formula: the nano particles according to the embodiment of the invention have at least the following beneficial effects: (1) Fe 3(CO)12 is a metal carbonyl with higher gas storage capacity, can release CO under photothermal stimulation, and the metal element iron in the metal carbonyl is a trace element ne