Development of In-111-labeled niosomes for evaluation of pharmacokinetics of the niosomes

1467 Introduction: Non-ionic surfactant (NIS)-based vesicles, also known as niosomes, are novel nanocarriers for drug delivery possessing an aqueous core enclosed in bilayer structure. Niosomes have attracted much attention because they can improve the biodistribution of both hydrophilic and hydrophobic drugs like liposomes, clinically available nanocarriers. Compared to phospholipids in liposomes, NIS makes it easier to design most suitable formulation for encapsulating drugs due to the high stability, low cost, and abundance of varieties. On the other hand, molecular imaging technologies have the potential to predict therapeutic effects of drugs because of their ability to investigate biodistribution of drugs in living subjects. In this study, we therefore developed In-111 (111In)-labeled niosomes for evaluation of pharmacokinetics of niosomes. Methods: We prepared niosomes composed of NIS (sorbitan ester (Span) 20, 40, 60, and 80), cholesterol, dicetyl phosphate, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] at molar ratio of 93:93:4:10 by sonication method, and determined size distributions and zeta potentials using dynamic light scattering measurements. 111In-diethylene- triaminepentaacetic acid (DTPA) was encapsulated in niosomes by remote loading method. The encapsulation efficiencies and purities of 111In-labeled niosomes were analyzed by using gel filtration chromatography. Stability in serum was evaluated by analyzing the purities of 111In-labeled niosomes at 24 hours after the incubation in fetal bovine serum at 37 ℃. In biodistribution analyses, 111In-labeled Span 20 niosome or liposome (control) were intravenously administered in mice inoculated with colon 26 tumors (0.2 μmol total lipids/mouse, 37 kBq/mouse). At 1, 6, 24, and 48 hours after administration, the radioactivities in resected tumors and tissues of interest were measured. Results: Particle sizes and zeta potentials of all studied niosomes were almost 50 nm and -5 mV, respectively. The niosomes were successfully radiolabaled with 111In at high labeling efficiency (about 90%) and purities (˃90%) regardless of types of NIS in formulation. High purities (about 85~95%) of the 111In-labeled niosomes were observed at 24 hours after incubation in serum, suggesting the studied 111In-labeled niosomes were available to trace the in vivo behavior of the niosomes. In the biodistribution studies of 111In-labeled Span 20 niosome, high accumulation of radioactivity was observed in the spleen, liver, and kidney. In the tumor, relatively high accumulation was also shown. Their distribution patterns were very similar to those of liposome, and the accumulation in tumor of Span 20 niosomes was as high as that of the liposome. Conclusions: These results showed that 111In-labeled niosomes enabled to investigate the in vivo behaviors of niosomes, and Span 20 niosomes would be useful nanocarriers alternative to liposomes. Aknowledgement: Support for this work includes the Kobe Pharmaceutical University President9s Discretionary Expenses.