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CN-122005856-A - Astaxanthin and nicotinamide adenine dinucleotide co-loading nano-drug and application thereof

CN122005856ACN 122005856 ACN122005856 ACN 122005856ACN-122005856-A

Abstract

The invention relates to a co-loaded nano-drug of astaxanthin and nicotinamide adenine dinucleotide, a preparation method and application thereof, wherein the co-loaded nano-drug takes hollow mesoporous polydopamine nano-particles as a carrier, ASX and NAD + are sequentially loaded, and polyethylene glycol long-chain modification and drug encapsulation are carried out on the surfaces of the nano particles, so that the nano particles have better water solubility and stability. The co-loaded nano-drug is used for radiation protection, is used for preventing or relieving ionizing radiation injury, and has remarkable treatment effect on radioactive lung injury after being subjected to atomization targeting lung administration.

Inventors

  • LUO SHENGLIN
  • LI RONG
  • GAO MINGQUAN
  • YU XUDONG

Assignees

  • 中国人民解放军陆军军医大学

Dates

Publication Date
20260512
Application Date
20260410

Claims (10)

  1. 1. A nano-drug loaded with astaxanthin and nicotinamide adenine comprises astaxanthin and nicotinamide adenine dinucleotide (NAD + ) and hollow mesoporous polydopamine nanoparticles as carriers.
  2. 2. The co-supported nano-drug according to claim 1, wherein astaxanthin and NAD + are co-supported in the polydopamine nano-particle, and polyethylene glycol long chains are used for modifying the particle surface, and the drug is encapsulated.
  3. 3. A pharmaceutical composition comprising an astaxanthin-nicotinamide adenine co-supported nano-drug according to claim 1 or 2 and optionally a pharmaceutical excipient, preferably said composition is a powder inhalant.
  4. 4. A method for preparing the astaxanthin and nicotinamide adenine co-supported nano-drug according to claims 1-3, comprising the following steps: 1) Dissolving Pluronic F-127 in an organic solvent to form a milky solution, adding dopamine hydrochloride aqueous solution and 1,3, 5-trimethylbenzene, mixing, and then dropwise adding ammonia water for reaction to obtain hollow mesoporous polydopamine nanoparticles; 2) Dissolving Astaxanthin (ASX) in an organic solvent, adding a hollow mesoporous polydopamine nanoparticle (HMPDA) solution, mixing and stirring, and separating to obtain HMPDA@ASX nanoparticles; 3) Dissolving NAD + in water to prepare a solution, mixing with HMPDA@ASX nanoparticles, stirring, and separating to obtain HMPDA@ASX/NAD + nanoparticles; 4) And (3) re-suspending the HMPDA@ASX/NAD + nano-particles in a Tris buffer solution, adding NH 2 -PEG-COOH solution, mixing and stirring, and separating to obtain the co-supported nano-drug with polyethylene glycol (PEG) surface modification and drug encapsulation.
  5. 5. The preparation method of claim 4, wherein in the step 1), the mass ratio of Pluronic F-127 to dopamine hydrochloride is (3-10): 1-2, the mass volume ratio of dopamine hydrochloride to ammonia water is (0.5-1): 1-5 g/ml, and the volume ratio of 1,3, 5-trimethylbenzene to ammonia water is (1-5): 1-5.
  6. 6. The preparation method according to claim 4, wherein in step 2), the mass ratio of astaxanthin and hollow mesoporous polydopamine nanoparticles to astaxanthin is 1:1-1:3, preferably 1:2, and the mass ratio of HMPDA@ASX to NAD + is 1:6-1:10, preferably 3:26 (15 mg:130 mg).
  7. 7. The preparation method of claim 4, wherein in the step 4), the mass ratio of HMPDA@ASX/NAD + nanoparticles to NH 2 -PEG-COOH is 1:1-1:2, and the molecular weight of NH 2 -PEG-COOH is 1000-5000.
  8. 8. The process according to claim 4, wherein in step 1) or 2), the organic solvent is ethanol, propanol, isopropanol or N, N-dimethylformamide.
  9. 9. Use of astaxanthin in accordance with claim 1 or 2 together with a co-supported nano-drug or a pharmaceutical composition according to claim 3 for the manufacture of a radioprotectant or drug.
  10. 10. Use of astaxanthin co-supported nano-drug with nicotinamide adenine according to claim 1 or 2 or a pharmaceutical composition according to claim 3 for the manufacture of a medicament or agent for the prevention or treatment of radiation lung injury, said radiation comprising ionizing radiation such as x-rays, gamma-rays, beta-rays, etc.

Description

Astaxanthin and nicotinamide adenine dinucleotide co-loading nano-drug and application thereof Technical Field The invention belongs to pharmaceutical chemistry, and in particular relates to an astaxanthin and nicotinamide adenine dinucleotide co-loaded nano-drug and application thereof. Background Radiation lung injury is a common complication of radiotherapy of malignant tumors of the chest (such as lung cancer and esophageal cancer), and the pathogenesis of the radiation lung injury involves multiple targets including oxidative stress unbalance, inflammatory injury, energy metabolism breakdown and the like. In the aspect of oxidative stress, ionizing radiation directly hydrolyzes water molecules to generate a large amount of Reactive Oxygen Species (ROS), and the ROS exceed the antioxidant capacity (such as SOD and GSH depletion) of lung tissues, so that the ROS not only directly damage DNA, lipid and protein, but also continuously activate pro-inflammatory pathways such as NF- κB and the like to form an 'oxidation-inflammation' vicious circle, while the traditional antioxidants (such as NAC) have short half-life and poor lung tissue targeting property, and are difficult to maintain effective concentration at damaged parts. In the aspect of inflammatory injury, radiation also activates alveolar macrophages to release cytokines such as TNF-alpha, IL-6 and the like, recruits neutrophil infiltration, causes continuous inflammation of lung parenchyma and even further forms a positive feedback loop, and conventional anti-inflammatory drugs cannot block multi-node signals. In energy metabolism. Ionizing radiation can lead to mitochondrial dysfunction, the NAD + level is reduced by 40-60%, tricarboxylic acid circulation is stopped, ATP supply is insufficient to cause alveolar epithelial cell apoptosis, and lung tissue repair capability is lost, while NAD + is directly supplemented to face the limitations of chemical instability, low cell membrane permeability, systemic side effects and the like. At present, although the clinical treatment is mainly based on glucocorticoid, the defects of insufficient targeting, high risk of infection, large side effect and the like caused by immunosuppression after long-term use exist, and meanwhile, the multi-target therapeutic intervention cannot be performed. Currently, some transition metal oxide nanoparticle nano-drugs are used for research on the aspect of treating radioactive lung injury, mainly based on the excellent antioxidant and free radical scavenging capability, but the targeting is insufficient and toxicity possibly exists, so that the nano-drugs are limited, and many natural antioxidants such as astaxanthin, vitamin E, tea polyphenol and the like are also deeply focused by researchers, but the problems of poor water solubility, short half-life, insufficient tissue damaged by targeted radiation and the like exist. Inhalation is the preferred route of administration for the treatment of pulmonary diseases. Compared with the traditional systemic radiation including oral administration and intravenous administration, the aerosol inhalation has the advantages of enabling the medicine to accumulate into the lung more quickly and improving the local medicine concentration in the aspect of treating the radioactive lung injury, and can alleviate the problems of systemic immunosuppression, liver and kidney metabolism burden and the like caused by the medicine. Of course, aerosol inhalation administration also faces the challenge of physiological barriers in the respiratory tract, particularly in terms of the size effects of drug particles in the respiratory system. Particles larger than 5 μm are deposited mainly on the upper respiratory tract, drug particles with diameters of 1-5 μm are easy to deposit on bronchioles and alveoli, and particles smaller than 1 μm are easy to exhale. Particles smaller than 200nm can penetrate lung mucus and be internalized by alveolar cells. This illustrates that the choice of particle size is a key consideration in inhalable drug delivery. Based on the clinical unmet needs, the invention develops the nanoparticle which has multiple targets, targeting and ROS responsiveness and is suitable for pulmonary aerosol inhalation. The invention designs and prepares the co-loaded nano-drug of astaxanthin and nicotinamide adenine dinucleotide for treating the radiation lung injury by utilizing the multi-target cooperativity of Astaxanthin (ASX) and nicotinamide adenine (NAD +) and the high-efficiency drug loading property of hollow mesoporous polydopamine nano-particles. The astaxanthin is the substance with the strongest antioxidant capacity in natural carotenoid, can inhibit lipid peroxidation by scavenging ROS and has the function of reducing inflammatory reaction, and nicotinamide adenine (NAD +) is the 'pivot coenzyme' of cell energy metabolism, participates in tricarboxylic acid circulation and oxidative phosphorylation to generate ATP, and is u