Chitosan-decorated selenium nanoparticles as protein carriers to improve the in vivo half-life of the peptide therapeutic BAY 55-9837 for type 2 diabetes mellitus

Abstract

Lei Rao,* Yi Ma,* Manjiao Zhuang, Tianjie Luo, Yayu Wang, An Hong Department of Cell Biology, Guangdong Province Key Lab of Bioengineering Medicine, National Engineering Research Center of Gene Engineering Medicine, Institute of Biological Medicine, Jinan University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Purpose: As a potential protein therapeutic for type 2 diabetes mellitus (T2DM), BAY 55-9837 is limited by poor stability and a very short half-life in vivo. The purpose of this study was to construct a novel nanostructured biomaterial by conjugating BAY 55-9837 to chitosan-decorated selenium nanoparticles (CS-SeNPs) to prolong the in vivo half-life of BAY 55-9837 by reducing its renal clearance rate.Materials and methods: BAY 55-9837-loaded CS-SeNPs (BAY-CS-SeNPs) were prepared, and their surface morphology, particle size, zeta potential, and structure were characterized. The stability, protein-loading rate, and in vitro release of BAY 55-9837 from CS-SeNPs were also quantified. Additionally, a sensitive high-performance liquid chromatography (HPLC) assay was developed for the quantification of BAY 55-9837 in mouse plasma. Thereafter, mice were injected via the tail vein with either BAY 55-9837 or BAY-CS-SeNPs, and the plasma concentration of BAY 55-9837 was determined via our validated HPLC method at different time intervals postinjection. Relevant in vivo pharmacokinetic parameters (half-life, area under the curve from time 0 to last sampling point, observed clearance) were then calculated and analyzed.Results: BAY-CS-SeNPs were successfully synthesized, with diameters of approximately 200 nm. BAY-CS-SeNPs displayed good stability with a high protein-loading rate, and the release process of BAY 55-9837 from the CS-SeNPs lasted for over 70 hours, with the cumulative release reaching 78.9%. Moreover, the conjugation of CS-SeNPs to BAY 55-9837 significantly reduced its renal clearance to a rate of 1.56 mL/h and extended its half-life to 20.81 hours.Conclusion: In summary, our work provides a simple method for reducing the renal clearance rate and extending the half-life of BAY 55-9837 in vivo by utilizing CS-SeNPs as nanocarriers. Keywords: BAY 55-9837, selenium nanoparticles, clearance, half-life, type 2 diabetes