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CN-121971638-A - Hyaluronic acid modified metal coordination albumin nanoparticle as well as preparation method and application thereof

CN121971638ACN 121971638 ACN121971638 ACN 121971638ACN-121971638-A

Abstract

The invention relates to the technical field of biological medicines, and discloses hyaluronic acid modified metal coordination albumin nanoparticles, and a preparation method and application thereof. The hyaluronic acid modified metal coordination albumin nanoparticle comprises a core formed by self-assembling albumin-drug complex, poly-L-aspartic acid and ferric iron through coordination, and a hyaluronic acid shell layer connected to the surface of the core through coordination or adsorption. The hyaluronic acid modified metal coordination albumin nanoparticle and the preparation method and application thereof are adopted, the preparation method is simple, convenient and rapid, does not need complex covalent modification, has mild conditions, is easy for large-scale production, ensures uniform particle size and good stability of the prepared nanoparticle, has active targeting capability on CD44 receptor high-expression tumor cells due to the surface modified hyaluronic acid, remarkably improves the enrichment and treatment effects of the drug on tumor sites, and has wide application prospects in preparing antitumor drugs.

Inventors

  • HUANG YUE
  • SONG JINXUAN
  • WEN HANG
  • CHEN YUXIN
  • XU PINGBO

Assignees

  • 浙江省肿瘤医院

Dates

Publication Date
20260505
Application Date
20260212

Claims (10)

  1. 1. The hyaluronic acid modified metal coordination albumin nanoparticle is characterized by comprising a core formed by self-assembling albumin-drug complex, poly-L-aspartic acid and ferric iron ions through coordination, and a hyaluronic acid shell layer connected to the surface of the core through coordination or adsorption.
  2. 2. The hyaluronic acid modified metal coordination albumin nanoparticle of claim 1, wherein the albumin-drug complex comprises one or more of paclitaxel, docetaxel, doxorubicin or hydrophobic antitumor drugs with carboxyl and amino active sites.
  3. 3. The hyaluronic acid-modified metal-coordinated albumin nanoparticle according to claim 1, wherein the molecular weight of the poly-L-aspartic acid is 5 kDa to 50 kDa and the molecular weight of the hyaluronic acid is 10 kDa to 200 kDa.
  4. 4. The hyaluronic acid-modified metal-coordinated albumin nanoparticle according to claim 1, wherein the particle size of the metal-coordinated albumin nanoparticle is 50 nm to 200 nm, the polydispersity index is less than 0.25, the surface potential of the core of the metal-coordinated albumin nanoparticle is negative, and the potential shifts to a more negative direction after the hyaluronic acid is modified.
  5. 5. The method for preparing the hyaluronic acid modified metal coordination albumin nanoparticle according to any of claims 1-4, comprising the following steps: Step 1, preparing core nanoparticles, namely mixing albumin-drug complex solution with poly-L-aspartic acid solution, slowly adding ferric ion solution under the stirring condition, and forming Fe-PAsp@HSA-drug core nanoparticles through coordination self-assembly reaction; Step 2, targeted modification, namely mixing Fe-PAsp@HSA-drug core nanoparticles with hyaluronic acid solution, and performing incubation reaction to enable the hyaluronic acid to be modified on the surfaces of the core nanoparticles; And 3, purifying the reacted mixed solution to remove free small molecules and polymers, thereby obtaining the purified hyaluronic acid modified metal coordination albumin nanoparticle.
  6. 6. The method for preparing hyaluronic acid modified metal coordination albumin nanoparticle according to claim 5, wherein in step 1, the mass ratio of albumin-drug complex to poly-L-aspartic acid is 10:1 to 1:2, and the molar ratio of ferric ion to carboxyl in poly-L-aspartic acid is 1:4 to 1:1.
  7. 7. The method for preparing hyaluronic acid modified metal coordination albumin nanoparticle according to claim 5, wherein in step 1, the ferric ion is one or more of ferric chloride, ferric ammonium citrate or ferric sulfate, and the pH value of the ferric ion solution is 2.5-4.5.
  8. 8. The method for preparing the hyaluronic acid modified metal coordination albumin nanoparticle according to claim 5, wherein in the step 2, the mass ratio of the Fe-PAsp@HSA-drug core nanoparticle to the hyaluronic acid is 5:1 to 1:5, the temperature of the incubation reaction is 20-37 ℃ and the time is 2-12 h, and in the step 3, the purification method is one of dialysis or high-speed centrifugation.
  9. 9. Use of the hyaluronic acid modified metal-coordinated albumin nanoparticle of any of claims 1-4 for the manufacture of a medicament for the treatment of a CD44 receptor high-expression tumor comprising breast cancer, lung cancer, stomach cancer, colon cancer, ovarian cancer or pancreatic cancer.
  10. 10. A medicament for treating CD44 receptor high expression tumor is characterized by comprising the hyaluronic acid modified metal coordination albumin nanoparticle and a pharmaceutically acceptable salt or carrier according to any one of claims 1-4.

Description

Hyaluronic acid modified metal coordination albumin nanoparticle as well as preparation method and application thereof Technical Field The invention relates to the technical field of biological medicine, in particular to hyaluronic acid modified metal coordination albumin nanoparticles, and a preparation method and application thereof. Background The nano drug delivery system can improve the solubility of insoluble drugs, prolong the blood circulation time, and passively target tumor tissues by enhancing the osmotic retention effect, and is an important strategy for improving the curative effect of chemotherapy and reducing the toxic and side effects. Albumin (such as human serum albumin HSA) has been successfully used for delivery of drugs such as paclitaxel, as a natural carrier with excellent biocompatibility. However, conventional albumin nanoparticle preparation methods (e.g., high pressure homogenization) or complex functionalization modifications based thereon (e.g., chemically coupled targeting molecules) are cumbersome in process and may affect protein activity and drug stability. The coordination chemistry of metal, especially the coordination of ferric ion and polymer containing phenolic hydroxyl or carboxyl, provides new thought for the assembly of nanometer material. The method has mild condition, rapid reaction and good biological safety of Fe 3+. The poly-L-aspartic acid is a biodegradable polyamino acid, and the side chain is rich in carboxyl, so that the poly-L-aspartic acid is an ideal metal coordination unit. Hyaluronic acid is a natural polysaccharide, can be specifically combined with CD44 receptors overexpressed on the surfaces of various tumor cells, and is an ideal targeting molecule. How to combine the drug delivery advantage of albumin, the simple and convenient assembly characteristic of metal coordination and the active targeting capability of hyaluronic acid efficiently and controllably, develop a novel nano drug with simple synthesis and excellent performance, and solve the technical problems in the prior art. Disclosure of Invention The invention aims to provide the hyaluronic acid modified metal coordination albumin nanoparticle, and the preparation method and application thereof, wherein the preparation method is simple, convenient and rapid, does not need complex covalent modification, has mild conditions, is easy for large-scale production, has uniform particle size and good stability, has active targeting capability on CD44 receptor high-expression tumor cells due to the surface modified hyaluronic acid, remarkably improves the enrichment and treatment effects of the drug at tumor sites, and has wide application prospects in preparing antitumor drugs. In order to achieve the above object, the present invention provides a hyaluronic acid-modified metal-coordinated albumin nanoparticle comprising a core formed by self-assembling albumin-drug complex, poly-L-aspartic acid and ferric ion by complexation, and a hyaluronic acid shell layer attached to the surface of the core by complexation or adsorption. Further, in the albumin-drug complex, the drug is one or more of paclitaxel, docetaxel, doxorubicin or hydrophobic antitumor drugs with carboxyl and amino active sites. Further, the molecular weight of the poly-L-aspartic acid is 5 kDa to 50 kDa, and the molecular weight of the hyaluronic acid is 10 kDa to 200 kDa. Further, the particle size of the metal coordination albumin nanoparticle is 50 nm-200 nm, the polydispersity index is less than 0.25, the surface potential of the core of the metal coordination albumin nanoparticle is negative, and the potential shifts to a more negative direction after modifying hyaluronic acid. Furthermore, the invention also provides a preparation method of the hyaluronic acid modified metal coordination albumin nanoparticle, which comprises the following steps: Step 1, preparing core nanoparticles, namely mixing albumin-drug complex solution with poly-L-aspartic acid solution, slowly adding ferric ion solution under the stirring condition, and forming Fe-PAsp@HSA-drug core nanoparticles through coordination self-assembly reaction; Step 2, targeted modification, namely mixing Fe-PAsp@HSA-drug core nanoparticles with hyaluronic acid solution, and performing incubation reaction to enable the hyaluronic acid to be modified on the surfaces of the core nanoparticles; And 3, purifying the reacted mixed solution to remove free small molecules and polymers, thereby obtaining the purified hyaluronic acid modified metal coordination albumin nanoparticle. Further, in the step 1, the mass ratio of the albumin-drug complex to the poly-L-aspartic acid is 10:1 to 1:2, and the molar ratio of the ferric ion to the carboxyl in the poly-L-aspartic acid is 1:4 to 1:1. Further, in the step 1, the ferric ion is one or more of ferric chloride, ferric ammonium citrate or ferric sulfate, and the pH value of the ferric ion solution is 2.5-4.5. Further, in the step 2, the