Endocytosis of ATB ^0,+ (SLC6A14)-targeted liposomes for drug delivery and its therapeutic application for pancreatic cancer

Abstract

<b>Background</b>: SLC6A14 (ATB^0,+), a Na⁺/Cl^-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.<b>Research design and methods</b>: Here we explored the mechanism of ATB^0,+-mediated entry of such liposomes. As ATB^0,+ is highly expressed in pancreatic cancer, we also examined the therapeutic utility of ATB^0,+-targeted liposomal drug delivery to treat this cancer.<b>Results</b>: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB^0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na⁺ and Cl^-, and inhibitable by ATB^0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB^0,+ occurred via endocytosis with transient endosomal degradation of ATB^0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB^0,+-dependent manner.<b>Conclusions</b>: We conclude that ATB^0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.