甘中 健登

Niosomes composed of non-ionic surfactants (NISs) are novel drug carriers that can deliver both hydrophilic and hydrophobic drugs similarly to liposomes, and have several advantages over liposomes, such as lower cost and higher availability owing to their relative abundance and variety. In this study, polyethylene glycol (PEG)-coated (PEGylated) Span 20 niosome was labeled with indium-111 using a remote-loading method, and its in vivo behavior was compared with that of the liposome. In addition, niosomes based on Span 20, 40, 60, and 80 were compared to evaluate the effects of differences in the lipophilic moiety of NIS. We succeeded in convenient labeling of PEGylated niosomes with high labeling efficiency (> 95%) and purity (> 95%). The stability of 111In-labeled niosomes in the serum was high enough to trace the in vivo behavior. Span 20 niosome exhibited significantly extended retention in the blood and high accumulation in the tumor at 48 h post-injection compared to the liposome. Niosomes composed of Span 80 with an unsaturated hydrocarbon chain showed decreased radioactivity in the blood and increased accumulation in the spleen compared with the other niosomes composed of Span 20, 40, and 60 with saturated hydrocarbon chain. Meanwhile, all studied niosomes were highly accu-mulated in the tumor. These results suggest that the PEGylated niosomes can be useful as tumor-targeting drug carriers.

Liposomes are highly biocompatible drug carriers in drug delivery systems (DDSs). Preferential accumulation of liposomes and acceleration of drug release at target tumor sites are essential for effective cancer therapy using liposomal formulations; however, conventional liposomes are unsuitable for on-demand drug release. We have previously reported that drug release can be accelerated via a bio-orthogonal inverse electron demand Diels-Alder (IEDDA) reaction between amphiphilic tetrazine (Tz)-containing liposomes and norbornene (NB) derivatives in vitro. In this study, we prepared HSTz-liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC) and Tz compound (2-hexadecyl-N-(6-(6-(pyridin-2-yl)-1,2,4,5-tetrazin-3-yl)pyridin-3-yl)octadecanamide) with particle sizes of 60-80 nm and ζ-potentials of -5 to 0 mV. Similar to our previous report, the addition of 5-norbornene-2-carboxylic acid (NBCOOH) to HSTz-liposomes accelerated drug release from the liposomes in vitro. In the biodistribution study using colon26 tumor-bearing mice, the radiolabeled HSTz-liposomes were accumulated and retained in the tumor at 6-48 h post-injection, whereas the radioactivity in the blood almost disappeared at 48 h. Therefore, the timing of the injection of NBCOOH was selected to be 48 h after the injection of the HSTz-liposome to avoid the IEDDA reaction in the bloodstream. We investigated the in vivo drug release by evaluating the intratumoral localization of doxorubicin (DOX) encapsulated in HSTz-liposomes labeled with fluorescent lipids. In the tumors treated with HSTz-liposomes and NBCOOH, DOX was more widely dispersed in the tumor compared with fluorescent lipid, suggesting that the release of encapsulated drugs (DOX) from HSTz-liposomes was enhanced in the tumor tissue via the bio-orthogonal IEDDA reaction. Furthermore, the combination of DOX-encapsulated HSTz-liposomes with NBCOOH significantly suppressed tumor growth compared to conventional DOX-encapsulated liposomes. In conclusion, the bio-orthogonal IEDDA reactions in the liposomal membrane enabled the acceleration of drug release from HSTz-liposomes in vivo, suggesting a promising strategy for effective cancer therapy.