Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Expert Opin Drug Deliv. 2020 Mar;17(3):395-405. doi: 10.1080/17425247.2020.1723544. Epub 2020 Feb 5.
: SLC6A14 (ATB), a Na/Clcoupled 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.: Here we explored the mechanism of ATB-mediated entry of such liposomes. As ATB is highly expressed in pancreatic cancer, we also examined the therapeutic utility of ATB-targeted liposomal drug delivery to treat this cancer.: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB-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 substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB occurred via endocytosis with transient endosomal degradation of ATB protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB-dependent manner.: We conclude that ATB 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.
SLC6A14（ATB）是一种对中性/阳离子氨基酸具有转运功能的 Na+/Cl-偶联转运体，在许多癌症中过度表达；它已被研究作为提高脂质体药物递送至治疗肝癌的靶点。在这里，我们探索了 ATB 介导的此类脂质体进入的机制。由于 ATB 在胰腺癌中高度表达，我们还研究了 ATB 靶向脂质体药物递送治疗这种癌症的治疗效用。赖氨酸缀合的脂质体（LYS-LP）在 ATB 阳性 MCF7 细胞中的摄取量更大。摄取过程包括两个步骤：结合和内化。LYS-LP 与 MCF7 细胞的结合高于裸脂质体，该过程依赖于 Na 和 Cl，并且可以被 ATB 底物或阻滞剂抑制。相比之下，内化步骤与赖氨酸无关。ATB 促进的 LYS-LP 进入细胞是通过内吞作用发生的，其中 ATB 蛋白的内体降解是短暂的，随后会恢复。此外，LYS-LP 还以 ATB 依赖的方式增强了这些细胞中吉西他滨的摄取和细胞毒性。我们得出结论，ATB 可用于以赖氨酸缀合的脂质体的形式进行靶向药物递送，并且该方法代表了增强胰腺癌治疗的新策略。
