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

ABSTRACT

Background

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.

Research design and methods

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.

Results

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.

Conclusions

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.

KEYWORDS:

• Targeted liposomes
• ATB^0,+
• cellular uptake
• drug delivery
• pancreatic cancer

Author contribution

Q Yao, V Ganapathy, and R Chen conceived the conception and design. L Kou did the experiments on endocytosis mechanism and related data analysis, and drafted the manuscript. H Huang, X Lin, and X Jiang did the experiments on pancreatic cancer cells and related data analysis. Y Wang, Q Luo, and J Sun reviewed the manuscript. All authors read the final version of the manuscript and approved it for submission, and all authors agreed to be accountable for all aspects of the work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary Material

Supplementary data for this article can be accessed here.

Additional information

Funding

This work was financially supported by the National Natural Science Foundation of China [81803443, 81903551], the Natural Science Foundation of Zhejiang Province [LQ19H300001], the Wenzhou Science and Technology Bureau [ZY2019007, Y20180180, Y20180208, Y20190177], and the start-up funds from the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University.