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.

中文翻译：

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靶向ATB0，+（SLC6A14）的脂质体的内吞作用及其在胰腺癌中的治疗应用。

背景：SLC6A14（ATB0，+）是一种Na + / Cl偶联的中性/阳离子氨基酸转运蛋白，在许多癌症中均过表达。研究已经作为改善肝癌脂质体药物递送的靶标进行研究。研究设计和方法：在这里，我们探讨了ATB0 +介导的此类脂质体进入的机制。由于ATB0 +在胰腺癌中高表达，因此我们还研究了靶向ATB0 +的脂质体药物递送治疗该癌症的疗效。结果：赖氨酸共轭脂质体（LYS-LPs）在ATB0中的吸收更大， +阳性MCF7细胞。吸收过程包括两个步骤：结合和内在化。LYS-LPs与MCF7细胞的结合高于裸脂质体，并且该过程依赖于Na +和Cl-，并且可被ATB0 +底物或阻滞剂抑制。相反，内部化步骤与赖氨酸无关。ATB0 +促进了LYS-LPs的细胞进入，这是通过内吞作用发生的，内吞使ATB0 ++蛋白瞬时降解，随后恢复。此外，LYS-LPs还以依赖于ATB0 +的方式增强了吉西他滨在这些细胞中的摄取和细胞毒性。结论：我们得出结论：ATB0 +可以用于赖氨酸偶联脂质体的靶向药物递送，并且该方法代表了增强胰腺癌治疗的新策略。