Endocytosis of ATB <sup>0,+</sup> (SLC6A14)-targeted liposomes for drug delivery and its therapeutic application for pancreatic cancer
Longfa Kou, Huirong Huang, Xinlu Lin, Xinyu Jiang, Yi Wang, Qiuhua Luo, Jin Sun, Qing Yao, Vadivel Ganapathy, Ruijie Chen
Abstract
Background SLC6A14 (ATB0,+), 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.Research design and methods Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-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 ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions We conclude that ATB0,+ 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.