Improving the Thrombocytopenia Adverse Reaction of Belinostat Using Human Serum Albumin Nanoparticles

Int J Nanomedicine. 2024 Oct 25:19:10785-10800. doi: 10.2147/IJN.S475823. eCollection 2024.

Abstract

Background: Belinostat, a histone deacetylase inhibitor used for hematological cancer treatments, however, it caused thrombocytopenia, poor solubility, and rapid clearance. To mitigate these issues, human serum albumin (HSA) was utilized as the core material for its high protein binding affinity and self-binding capabilities. The study focused on developing belinostat-loaded HSA nanoparticles to improve solubility, extend circulation time, and reduce adverse effects.

Methods: Belinostat-loaded HSA nanoparticles were synthesized using a desolvation method, optimized for size, charge, and entrapment efficiency, and characterized by molecular docking and Fourier-transform infrared spectroscopy (FTIR). Cytotoxicity was assessed in vitro against HuT-78 cells, and in vivo pharmacokinetics and toxicology studies were conducted to evaluate therapeutic efficacy and safety.

Results: The prepared belinostat-HSA nanoparticles exhibited the size of 150 nm with a charge of ~-50 mV and a high entrapment efficiency (90%). Molecular docking confirmed that belinostat and HSA had a strong binding affinity (-9.5 kcal mol-1), and the entrapment of belinostat within HSA nanoparticles was also confirmed via FTIR. Belinostat-HSA nanoparticles were cytotoxic against HuT-78 with the dose-response relation (1-100 μM). The highly concentrated (100 μM) belinostat-HSA nanoparticles maintained the viability of the peripheral blood mononuclear cells with 50% survival, which did not survive when exposed to belinostat (100 μM). The belinostat-HSA nanoparticles proved suitable for intravenous administration without causing hemolysis, exhibited prolonged circulation times, and improved in vivo platelet counts significantly (p < 0.05).

Conclusion: In conclusion, the belinostat-loaded HSA nanoparticles significantly enhance the solubility and half-life of belinostat, reduce its adverse hematological effects, and maintain sustained drug release. These attributes underscore the potential of belinostat-HSA nanoparticles as a viable intravenous option for the treatment of hematological malignancies.

Keywords: belinostat; human serum albumin nanoparticles; peripheral T-cell lymphoma; pharmacokinetics; thrombocytopenia.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Carriers / chemistry
  • Drug Carriers / pharmacokinetics
  • Histone Deacetylase Inhibitors* / administration & dosage
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacokinetics
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Hydroxamic Acids* / administration & dosage
  • Hydroxamic Acids* / chemistry
  • Hydroxamic Acids* / pharmacokinetics
  • Hydroxamic Acids* / pharmacology
  • Male
  • Molecular Docking Simulation*
  • Nanoparticles* / chemistry
  • Particle Size
  • Serum Albumin, Human* / chemistry
  • Serum Albumin, Human* / pharmacokinetics
  • Solubility
  • Sulfonamides* / administration & dosage
  • Sulfonamides* / chemistry
  • Sulfonamides* / pharmacokinetics
  • Sulfonamides* / pharmacology
  • Thrombocytopenia* / chemically induced
  • Thrombocytopenia* / drug therapy

Substances

  • Sulfonamides
  • Hydroxamic Acids
  • belinostat
  • Histone Deacetylase Inhibitors
  • Serum Albumin, Human
  • Drug Carriers