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

Abstract

Jia-Yu Liu,1 Chia-Hung Yen,2,3 Ya-Fan Lin,4 Yin-Hsun Feng,5 Yi-Ping Fang1,6,7 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Chemistry, National Dong Hwa University, Hualien, Taiwan; 5Division of Hematology and Oncology, Department of Internal Medicine, ChiMei Medical Center, Tainan, Taiwan; 6Regeneration Medicine and Cell Therapy Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Yi-Ping Fang, School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, San Ming District, Kaohsiung, 80708, Taiwan, Tel [phone] ext. 2261, Email [email protected]: 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, thrombocytopenia, pharmacokinetics

Keywords

• belinostat
• human serum albumin nanoparticles
• peripheral t-cell lymphoma
• thrombocytopenia
• pharmacokinetics