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CN-122005820-A - Long-acting hydrogen release granule for targeting anchoring of apoplexy inflammatory blood vessel, and preparation method and application thereof

CN122005820ACN 122005820 ACN122005820 ACN 122005820ACN-122005820-A

Abstract

A targeted anchoring long-acting hydrogen release granule for a blood vessel of a stroke inflammation, a preparation method and application thereof, wherein the preparation method comprises the following steps of 1.1) completely and uniformly mixing ZrSi2 raw material powder, a dispersing agent and a solvent with the mass ratio of 100 (50-1000) (10-10000), 1.2) transferring the mixture into a ball mill for ball milling at the speed of 200-1000 rpm for 1-7 days, 1.3) collecting 50-200 nm particles from the ball-milled solution through fractional centrifugation, 1.4) washing, centrifuging again to obtain the required ZrSi2 nm particles, dispersing the ZrSi2 nm particles into the solvent, and storing the ZrSi2 nm particles in a nitrogen environment. In stroke, the nanoparticles anchored on the inflammatory vessel do not need to cross the blood brain barrier, thereby avoiding the potential safety risk to the brain parenchyma. In addition, it can generate H2 in local hydrolysis, H2 crosses the blood brain barrier again, and realizes safe and effective brain cell protection. Can release hydrogen continuously, thus realizing continuous treatment and avoiding the accumulation of nano particles in brain parenchyma.

Inventors

  • HE QIANJUN
  • YU YUANMAN
  • FAN MINGJIAN
  • DING WENJIANG

Assignees

  • 上海交通大学
  • 上海交通大学深圳研究院

Dates

Publication Date
20260512
Application Date
20260221

Claims (10)

  1. 1. The preparation method of the ZrSi 2 nano-particles is characterized by comprising the following steps: 1.1 100 (50-1000) of ZrSi 2 raw material powder (10-10000), dispersing agent and solvent are completely mixed uniformly; 1.2 Transferring the mixture into a ball mill for ball milling at the speed of 200-1000 rpm for 1-7 days; 1.3 The ball-milled solution is subjected to fractional centrifugation to collect 50-200 nm particles; 1.4 The required ZrSi 2 nanoparticles were obtained by centrifugation again, dispersed in a solvent and stored under nitrogen.
  2. 2. The method for preparing ZrSi 2 nano-particles according to claim 1, wherein the mass ratio of the ZrSi 2 raw material powder, the dispersant and the solvent in the step 1.1 is 100:300:8000.
  3. 3. The method for preparing ZrSi 2 nano-particles according to claim 1, wherein the dispersing agent in the step 1.1 is one or more of polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol.
  4. 4. The method for preparing ZrSi 2 nano-particles according to claim 1, wherein the solvent in the step 1.1 is one or more of ethanol, acetone, ethylene glycol and glycerol.
  5. 5. The preparation method of the targeted anchored inflammation blood vessel long-acting hydrogen release nano-particle is characterized by comprising the following steps: 2.1 Dissolving the P-selectin binding peptide in N, N-dimethylformamide, and adding 3-isocyanatopropyl trimethoxysilane under stirring; 2.2 After 1-2 hours of reaction, adding ZrSi 2 nano-particles prepared by the preparation method of the ZrSi 2 nano-particles according to any one of claims 1-4, and reacting for 1-3 hours under the reflux condition of 50-80 ℃; The molar ratio of the P-selectin binding peptide to the N, N-dimethylformamide to the 3-isocyanatopropyl trimethoxysilane to the ZrSi 2 nano-particles is 1 (20-1000) (0.8-1.2) (5-20); 2.3 Centrifuging to collect nano particles, alternately washing with ultra-dry DMF and ultra-dry ethanol twice to obtain the P-selectin binding peptide modified nano particles capable of targeting and anchoring long-acting hydrogen release of inflammatory blood vessels of stroke, and storing at 0-10 ℃ in a nitrogen environment.
  6. 6. The targeted and anchored inflammation blood vessel long-acting hydrogen release nano-particle prepared by the preparation method of the targeted and anchored inflammation blood vessel long-acting hydrogen release nano-particle as claimed in claim 5.
  7. 7. The use of the targeted anchored inflammatory blood vessel long-acting hydrogen-releasing nanoparticle as a drug in targeted anchored therapeutic inflammatory blood vessels as claimed in claim 5.
  8. 8. The use of claim 7, wherein the targeted anchored inflammatory vascular long-acting hydrogen-releasing nanoparticle is used to modulate cerebral stroke redox and immune balance to coordinate multicellular recovery processes.
  9. 9. The use of claim 7, wherein the targeted anchored inflammatory vascular long-acting hydrogen-releasing nanoparticle is used to induce cerebral apoplexy microglial mediated angiogenesis and neurogenesis.
  10. 10. The use of claim 7, wherein the targeted anchored inflammatory vascular long-acting hydrogen-releasing nanoparticles are used to maintain blood brain barrier integrity, reduce tissue necrosis after reperfusion, improve intracranial perfusion, reduce astrocyte proliferation, increase Glut-1+ neovascularization in infarct core and periinfarct area, reduce proinflammatory cytokine levels, up-regulate expression of anti-inflammatory cytokine IL-4, reduce pro-inflammatory microglial-induced neuronal damage, increase the number of proliferating neural precursor cells in cortex, increase the number of hippocampal dcx+ neural precursor cells and extend their migration distance to ischemic cortical areas, and enhance c-Fos expression in infarct area.

Description

Long-acting hydrogen release granule for targeting anchoring of apoplexy inflammatory blood vessel, and preparation method and application thereof Technical Field The invention relates to the technical field of medical treatment, in particular to a targeting anchoring hydrogen-producing nanoparticle for a cerebral apoplexy inflammatory blood vessel, a preparation method and application thereof, and specifically relates to a novel targeting/anchoring hydrogen-producing nanoparticle for an inflammatory blood vessel, a preparation method thereof and application thereof in cerebral apoplexy ischemia reperfusion injury repair, wherein P-selectin binding peptide is modified on the surface of the hydrogen-producing nanoparticle. Background Ischemic stroke is a major concern in the world health field, and its morbidity and mortality are significantly increased by its severe disruption of neurological function. Although reperfusion therapies such as venous thrombolysis and intravascular thrombosis have improved treatment of ischemic stroke, they have failed to adequately address the pathological cascade initiated by ischemia reperfusion. Edaravone, which is commonly used clinically, is a free radical scavenger, however its low bioavailability, limited Blood Brain Barrier (BBB) penetration and potential toxic effects hamper its overall therapeutic effect. To date, no drug has clearly demonstrated efficacy in improving functional recovery in large-scale stroke trials, which highlights the necessity of innovative therapeutic strategies. Nanotechnology has become an revolutionary approach to stroke treatment that exploits the properties of precise targeting, enhanced Blood Brain Barrier (BBB) permeability, and controlled drug release. However, penetration of the blood brain barrier remains a significant challenge. Although receptor targeting systems and biomimetic platforms show improved blood brain barrier permeability, their delivery efficiency is still not satisfactory. Moreover, even if the blood brain barrier is successfully penetrated, excessive accumulation of nanomaterials within the brain can induce endoplasmic reticulum stress and induce neurotoxicity with potential safety risks to the brain parenchyma. Hydrogen molecules (H 2) have several significant advantages over traditional drug molecules, including excellent blood brain barrier permeability, rapid distribution within tissues, high biosafety, and antioxidant and immunomodulatory effects. The combined use of H 2 (intravenous or oral hydrogen-enriched water) with minocycline has entered the clinical trial phase involving ischemic stroke patients (NCT 03320018) receiving tissue plasminogen activator or thrombectomy. This highlights the safety and transformation potential of H 2 in neuroprotection. However, due to its rapid diffusion and lack of targeting, neither intravenous/oral hydrogen-rich water nor inhalation of hydrogen gas can achieve high H 2 bioavailability at the lesion site, thereby significantly limiting the effectiveness of hydrogen therapy. Recent studies report directed intracranial injection of polylactic-co-glycolic acid (PLGA) -coated magnesium nanoparticles into lateral ventricles for hydrogen therapy of acute ischemic stroke. Despite the improved delivery of H 2, a number of key issues remain, including iatrogenic tissue damage from intracranial injection, safety concerns for long-term nanoparticle retention in the lateral ventricle, and significant local alkalization and corrosion due to Mg (OH) 2 byproduct accumulation. Achieving sustained hydrogen release at the site of stroke while avoiding intracranial nanoparticle accumulation remains a key challenge. Disclosure of Invention In order to overcome the limitation, a new strategy for rivet inflammation blood vessel hydrogen release is provided, and a novel inflammation blood vessel targeting/anchoring hydrogen production nano particle is developed. In stroke, the nanoparticles anchored on the inflammatory vessel do not need to cross the blood brain barrier, thereby avoiding the potential safety risk to the brain parenchyma. In addition, it can generate H 2,H2 by local hydrolysis and then cross the blood brain barrier, thus realizing safe and effective brain cell protection. Unlike conventional drug delivery systems, the present design is capable of sustained release of hydrogen, thereby achieving sustained treatment and avoiding nanoparticle accumulation in the brain parenchyma. Mechanistically, targeted hydrogen release nanoparticles coordinate the multicellular recovery process through H 2 -mediated redox balance and immunomodulation. Meanwhile, the targeted hydrogen release nano-particles induce microglial cell mediated angiogenesis and neurogenesis, guide axons to project along the new blood vessel track, and promote communication between microglial cells and neurons through a non-classical Wnt/Ca2+ pathway. The neural vascular network reconstruction formed by the method can realiz