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CN-122005793-A - Nanometer radiotherapy sensitizer based on LDH, and preparation method and application thereof

CN122005793ACN 122005793 ACN122005793 ACN 122005793ACN-122005793-A

Abstract

The invention belongs to the technical field of biological medicines, and discloses a nano radiotherapy sensitizer based on LDH, and a preparation method and application thereof. The nano radiotherapy sensitizer comprises a metal cation layer and interlayer anions, and is characterized in that the metal cation layer comprises first metal cations and second metal cations, wherein the atomic number Z of the first metal cations is more than or equal to 50, the first metal cations account for 10% -30% of the total mole ratio of the metal cations, and the second metal cations account for 70% -90% of the total mole ratio of the metal cations. The nanometer radiotherapy sensitizer can be used for preparing cancer radiotherapy sensitization medicines. The invention solves the problems of single function, poor biocompatibility and insufficient targeting of the existing radiotherapy sensitizer, and fills the technical blank that the LDH material is not applied to radiotherapy sensitization.

Inventors

  • GU ZHANJUN
  • ZHU SHUANG
  • YANG CHEN

Assignees

  • 中国科学院高能物理研究所

Dates

Publication Date
20260512
Application Date
20260311

Claims (10)

  1. 1. A nanometer radiotherapy sensitizer based on LDH comprises a metal cation layer and interlayer anions, and is characterized in that the metal cation layer comprises first-class metal cations and second-class metal cations, wherein the atomic number Z of the first-class metal cations is more than or equal to 50, the first-class metal cations account for 10% -30% of the total molar ratio of the metal cations, and the second-class metal cations account for 70% -90% of the total molar ratio of the metal cations.
  2. 2. The nanoradiotherapy sensitizer according to claim 1 wherein the first type of metal cations is selected from one or more of Gd 3 + 、Hf 4+ 、W 6+ 、Ta 5+ 、Bi 3+ , the second type of metal cations is selected from one or more of Ca 2+ 、Zn 2+ 、Co 2+ 、Fe 2+ 、Cu 2 + 、Mg 2+ 、Al 3+ 、Mn 2+ , and the interlayer anions are selected from one or more of Cl - 、NO 3 - 、CO 3 2- 、C 6 H 5 O 7 3- .
  3. 3. The nanoradiotherapy sensitizer according to claim 1 or 2, wherein the particle size of the nanoradiotherapy sensitizer is 20-500 nm and the zeta potential is +10 to +50 mV.
  4. 4. The preparation method of the nanometer radiotherapy sensitizer based on LDH comprises the following steps: Dissolving high-Z metal salt and auxiliary metal salt in deionized water according to a molar ratio of 1:4-1:6, and preparing or obtaining mixed salt solution with total metal ion concentration of 0.01-1 mol/L; Preparing or obtaining alkali solution with the concentration of 0.1-2 mol/L; under the conditions of constant-temperature water bath at 50-70 ℃ and inert gas protection and stirring at 400-600 rpm, the mixed salt solution and the alkali solution are synchronously added into deionized water in a dropwise manner, the pH=9-13 of a reaction system is maintained, and the mixture is continuously stirred for reaction to form white precipitate after the dropwise addition is finished, and the mixture is homogenized at high pressure or is crushed by ultrasound for 10-30 minutes with the power of 100-300W; And (3) after the reaction system is aged, centrifugally washing the reaction system by deionized water, and grinding the precipitate into fine powder after vacuum drying/freeze drying at 70-90 ℃ to obtain the nano-radiotherapy sensitizer based on LDH.
  5. 5. A carrier composite comprising a biocompatible substrate and the LDH-based nanoradiotherapy sensitizer of claim 1, wherein the LDH-based nanoradiotherapy sensitizer of claim 1 is coated or embedded in the biocompatible substrate.
  6. 6. The carrier composite of claim 5, wherein the biocompatible substrate is a hydrogel.
  7. 7. A method for preparing a carrier compound, which is characterized in that a biocompatible substrate is adopted to carry out package protection and controlled release on the nano-radiotherapy sensitizer based on LDH in claim 1, so as to obtain the carrier compound.
  8. 8. The method of claim 7 wherein the biocompatible substrate is a hydrogel and the LDH-based nanoradiotherapy sensitizer of claim 1 is dispersed in a hydrogel precursor solution to form a carrier complex by a cross-linking reaction.
  9. 9. Use of the nanoradiotherapy sensitizer of claim 1 in the preparation of a cancer radiotherapy sensitizer.
  10. 10. A method for improving the drug retention of the nano radiotherapy sensitizer of claim 1, which is characterized in that the nano radiotherapy sensitizer of claim 1 is reloaded into hydrogel, wherein the solute mass accounts for 0.1-50% of the total mass of the whole mixture.

Description

Nanometer radiotherapy sensitizer based on LDH, and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a nano-scale radiotherapy sensitizer for adjuvant therapy of cancer radiotherapy, which is constructed by taking Layered Double Hydroxide (LDH) as a carrier and combining high-atomic number (high Z) metal elements and functional auxiliary metal elements through co-doping, and an application of the nano-scale radiotherapy sensitizer with multiple functions of radiotherapy sensitization, immune activation and metastasis inhibition in radiotherapy sensitization of various solid tumors (including primary foci and metastasis foci). Background Radiation therapy is one of the core means of cancer treatment, which mainly induces DNA damage to tumor cells by high-energy radiation to achieve the effect of killing tumors, and is widely used for relieving tumor-related symptoms, controlling local tumor growth and reducing recurrence risk. However, the existing radiotherapy technology has the remarkable limitations that on one hand, the conventional radiotherapy has poor treatment effect on tumor metastasis (such as breast cancer bone metastasis and lung cancer brain metastasis), the induced DNA damage response is easily counteracted by a repairing mechanism of tumor cells, the local recurrence risk is caused, and about 2/3 of solid tumor patients still face the remote metastasis risk after radiotherapy according to statistics, on the other hand, the rays of the conventional external irradiation radiotherapy are difficult to accurately focus on tumor tissues, and the surrounding healthy tissues (such as bone marrow and digestive tract mucous membrane) are easily damaged, so that the generated dose limiting toxicity not only restricts the further improvement of the radiation dose, but also remarkably influences the survival quality of the patients. To solve the above problems, nanotechnology-based radiotherapy sensitizer is becoming a research hotspot. The mainstream strategies are focused on utilizing the strong photoelectric effect of high Z elements (such as gadolinium (Gd), hafnium (Hf) and tungsten (W)) to enhance local radiation dose deposition through selective enrichment in tumor regions so as to amplify the killing effect on tumor cells. For example, gadolinium-containing nanoparticles AGuIX have entered clinical research. However, the sensitizer has the partial defects of single function, focusing on physical sensitization, lack of cooperative function for inhibiting tumor invasion and metastasis or activating systemic anti-tumor immunity, limited biocompatibility, easy accumulation of partial materials in organs, lack of tumor targeting, mainly dependence on enhancing permeation and retention effects and limited tumor selectivity. These deficiencies make it difficult to address complex conditions such as breast cancer bone metastases that are both locally destructive and highly metastatic. The Layered Double Hydroxide (LDH) is an inorganic nano material with a typical layered structure, is composed of a positively charged metal hydroxide layer and interlayer anions, has the unique advantages of ① good biocompatibility, being used as an antacid (such as Daxi) in clinic in the early stage, being proved by subsequent researches to be degradable into nontoxic metal ions in vivo, having no obvious organ toxicity, ② composition and structure high adjustability, wherein the metal cation layer can be flexibly doped with different metal elements to realize function customization, ③ pH responsiveness, being degradable gradually in an acidic tumor microenvironment (pH of 5.0-6.5), triggering interlayer ions/drug release, and having natural tumor targeting. However, in the prior art, the application of LDH is focused on drug delivery, immunoregulation and bone disease treatment, and no report on development of LDH as a radiotherapy sensitizer has been made, and the synergistic therapeutic effect of "radiotherapy sensitization-immune activation-metastasis inhibition" is achieved by utilizing the high-Z element doping capability and pH response characteristics of LDH. Aiming at the defects of the existing radiotherapy sensitizer and the application blank of LDH materials, the invention firstly provides the design of the LDH as the multifunctional nano radiotherapy sensitizer, fills the application blank of the LDH in the field of radiotherapy, and provides a new scheme for the radiotherapy synergy of cancers (especially metastatic cancers). Disclosure of Invention The invention aims to provide an LDH-based nano radiotherapy sensitizer and a preparation method and application thereof, so as to solve the problems of single function, poor biocompatibility and insufficient targeting of the existing radiotherapy sensitizer, and fill up the technical blank that an LDH material is not applied to radiotherapy sensitization, an