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CN-122005794-A - MOF-based composite sensitizer and preparation method and application thereof

CN122005794ACN 122005794 ACN122005794 ACN 122005794ACN-122005794-A

Abstract

The invention relates to the technical field of composite materials, in particular to a MOF-based composite sensitizer and a preparation method and application thereof. The MOF-based composite sensitizer adopts Hf-TCPP as a nuclear layer, loads hemoglobin and boron phenylalanine, adopts pH-sensitive ZIF-8 as a nuclear shell, loads S-nitroso-N-acetyl-DL-penicillamine, relieves hypoxia, regulates energy metabolism of tumor cells, and synergistically improves BNCT curative effect, wherein a ZIF-8 shell layer is stable under normal physiological environment, prevents boron carrier from leaking in advance, is rapidly degraded under tumor microenvironment, realizes accurate controlled release of BPA and SNAP, prolongs blood circulation time, reduces immune clearance through hydrophilic polymer modification such as polyethylene glycol, and simultaneously utilizes folic acid for functional modification. The preparation method disclosed by the invention has mild reaction conditions, integrates multiple functions of boron loading, targeted delivery, hypoxia alleviation, synergistic sensitization and the like, does not need to be additionally combined with other medicines, and simplifies the clinical treatment flow.

Inventors

  • DING BAISUO
  • WANG QIANYOU
  • LIU HUALI
  • PENG QIANQIAN

Assignees

  • 理工清科(重庆)先进材料研究院有限公司

Dates

Publication Date
20260512
Application Date
20260331

Claims (10)

  1. 1. The MOF-based composite sensitizer is characterized by a core-shell structure modified by polyethylene glycol and folic acid by taking Hf-TCPP/Hb/BPA as a core and ZIF-8/SNAP as a shell.
  2. 2. The MOF-based composite sensitizer according to claim 1, wherein the Hf-TCPP/Hb/BPA comprises Hf-TCPP quantum dots, and hemoglobin and borophenylalanine supported on the Hf-TCPP quantum dots, wherein the mass ratio of hemoglobin to borophenylalanine is 1:2.
  3. 3. A MOF-based composite sensitizer according to claim 1, wherein the ZIF-8/SNAP comprises ZIF-8 and S-nitroso-N-acetyl-DL-penicillamine supported on ZIF-8, the S-nitroso-N-acetyl-DL-penicillamine being supported at a level of 20% of Hf-TCPP/Hb/BPA mass.
  4. 4. The MOF-based composite sensitizer according to claim 1, wherein the molar ratio of folic acid to polyethylene glycol is 1:1.
  5. 5. The preparation method of the MOF-based composite sensitizer is characterized by comprising the following steps of: adding HfCl 4 and tetra (4-carboxyphenyl) porphyrin into N, N dimethylformamide, stirring and dissolving, then placing into a reaction kettle, performing solvothermal reaction at 110-130 ℃ for 20-25 h, and washing and freeze-drying a lower precipitate obtained by centrifugation to obtain Hf-TCPP quantum dots; Dispersing Hf-TCPP/Hb/BPA in an ethanol solution, adding a hexadecyl trimethyl ammonium bromide solution as a surfactant, performing ultrasonic dispersion, sequentially adding Zn (NO 3 ) 2 , 2-methylimidazole, S-nitroso-N-acetyl-DL-penicillamine, stirring at room temperature for reacting for 5-7 hours, centrifuging, and drying to obtain Hf-TCPP/Hb/BPA@ZIF-8/SNAP nano particles; Dissolving Hf-TCPP/Hb/BPA@ZIF-8/SNAP nano particles, polyethylene glycol and folic acid in a solvent, removing the solvent by spin evaporation, adding a PBS buffer solution, filtering the obtained mixed solution, and freeze-drying the obtained filtrate to obtain the MOF-based composite sensitizer.
  6. 6. The process according to claim 5, wherein the molar ratio of HfCl 4 to tetra (4-carboxyphenyl) porphyrin is 1:2 and/or, The mass ratio of the hemoglobin to the borophenylalanine is 1:2, and/or, The mass ratio of the Hf-TCPP quantum dots to the hemoglobin is 100 (10-25).
  7. 7. The process according to claim 5, wherein the concentration of ethanol in the ethanol solution is 50% by volume and/or, The concentration of the cetyltrimethylammonium bromide solution is 0.01mol/L, the mass ratio of the Hf-TCPP/Hb/BPA to the cetyltrimethylammonium bromide is 100 (3.64-7.29), and/or, The Zn (mol ratio of NO 3 ) 2 to 2-methylimidazole is 1:4, and/or, The loading of the S-nitroso-N-acetyl-DL-penicillamine is 20% of the mass of Hf-TCPP/Hb/BPA.
  8. 8. The method according to claim 5, wherein the polyethylene glycol is Hf-TCPP/Hb/BPA@ZIF-8/SNAP nanoparticle in an amount of 8-12% by mass, the molar ratio of folic acid to polyethylene glycol is 1:1, and/or, The solvent is dichloromethane or ethyl acetate-ethanol mixed solution or chloroform, and the volume ratio of ethyl acetate to ethanol in the ethyl acetate-ethanol mixed solution is 9:1.
  9. 9. The method according to claim 5, wherein the mixed solution is filtered three times with a 0.6, 0.4 and 0.2 μm polycarbonate membrane filter in this order, and the obtained filtrate is freeze-dried to obtain the MOF-based composite sensitizer.
  10. 10. Use of a MOF-based composite sensitizer according to any one of claims 1-9 in the preparation of a boron neutron capture therapeutic drug.

Description

MOF-based composite sensitizer and preparation method and application thereof Technical Field The invention relates to the technical field of composite materials, in particular to a MOF-based composite sensitizer and a preparation method and application thereof. Background Boron Neutron Capture Therapy (BNCT) is used as an accurate targeted radiotherapy technology, and becomes an important direction for treating refractory tumors (such as glioblastoma, melanoma, head and neck tumors and the like) by virtue of the high selective killing capacity of the BNCT on tumor cells. The BNCT has the core principle that a boron carrier rich in 10 B is conveyed into a patient, after the boron carrier is specifically enriched in tumor tissues, a low-energy thermal neutron or a epithermal neutron of 10,000eV is used for irradiating a tumor area 10 B to perform nuclear reaction with neutrons, alpha particles with short range and 7 Li heavy ions (the alpha particles have the range of about 5-9 mu m and 7 Li ions have the range of about 1-2 mu m) are generated, the DNA of tumor cells can be accurately destroyed, and the damage to surrounding normal tissues is very small. BNCT is therefore a promising cancer treatment, utilizing boron carriers to selectively target cancer cells by neutron irradiation. However, the tumor hypoxia microenvironment can reduce the curative effect of BNCT, hypoxia can lead to the enhancement of the repair capability of tumor cells to DNA damage, and simultaneously influence the intratumoral transport efficiency of boron vectors, and part of tumors can also generate tolerance to BNCT due to rapid proliferation, so that the treatment effect is further restricted. Therefore, the current research focus is on developing BNCT drugs carrying boron, which will exert the greatest therapeutic effect if the boron neutron capture therapy and radiotherapy sensitization effect are combined. At present, nanoscale metal-organic frameworks (MOFs) composed of metal ions and organic ligands have made remarkable progress in tumor treatment, and researches show that the nanoscale MOFs can be used as excellent carriers for delivering drugs to treat nervous system diseases. Although MOF has remarkable advantages in tumor treatment, the existing MOF-based sensitizer cannot meet the core requirements of BNCT, and the problems of insufficient boron loading capacity, poor tumor targeting, incapacity of relieving BNCT tolerance caused by tumor hypoxia and the like generally exist. Disclosure of Invention In view of the above, the invention aims to provide an MOF-based composite sensitizer and a preparation method and application thereof, which realize high boron loading, low toxicity, high efficiency and stable tumor boron neutron therapy sensitization. The invention solves the technical problems by the following technical means: In a first aspect, an embodiment of the present invention provides a MOF-based composite sensitizer, where the MOF-based composite sensitizer uses Hf-TCPP/Hb/BPA as a core, uses ZIF-8/SNAP as a shell, and performs polyethylene glycol and folic acid modification on the core-shell structure. With reference to the first aspect, in some embodiments, the Hf-TCPP/Hb/BPA includes Hf-TCPP quantum dots, and hemoglobin and borophenylalanine supported on the Hf-TCPP quantum dots in a mass ratio of 1:2. In combination with the first aspect, in some embodiments, the ZIF-8/SNAP comprises ZIF-8 and S-nitroso-N-acetyl-DL-penicillamine supported on ZIF-8, the S-nitroso-N-acetyl-DL-penicillamine being supported at 20% of Hf-TCPP/Hb/BPA mass. In combination with the first aspect, in some embodiments, the molar ratio of folic acid to polyethylene glycol is 1:1. In a second aspect, the embodiment of the invention discloses a preparation method of an MOF-based composite sensitizer, which comprises the following steps: adding HfCl 4 and tetra (4-carboxyphenyl) porphyrin into N, N dimethylformamide, stirring and dissolving, then placing into a reaction kettle, performing solvothermal reaction at 110-130 ℃ for 20-25 h, washing a lower precipitate obtained by centrifugation, and freeze-drying to obtain Hf-TCPP quantum dots with the wavelength of 5-10 nm; Dispersing Hf-TCPP/Hb/BPA in an ethanol solution, adding a hexadecyl trimethyl ammonium bromide solution as a surfactant, performing ultrasonic dispersion, sequentially adding Zn (NO 3)2, 2-methylimidazole, S-nitroso-N-acetyl-DL-penicillamine, stirring at room temperature for reacting for 5-7 hours, centrifuging, and drying to obtain Hf-TCPP/Hb/BPA@ZIF-8/SNAP nano particles; Dissolving Hf-TCPP/Hb/BPA@ZIF-8/SNAP nano particles, polyethylene glycol and folic acid in a solvent, removing the solvent by spin evaporation, adding a PBS buffer solution, filtering the obtained mixed solution, and freeze-drying the obtained filtrate to obtain the MOF-based composite sensitizer. In combination with the second aspect, in some embodiments, the molar ratio of HfCl 4 to tetra (4-carboxyphen