Glucose Transporter 1-Mediated Transcytosis of Glucosamine-Labeled Liposomal Ceramide Targets Hypoxia Niches and Cancer Stem Cells to Enhance Therapeutic Efficacy

Lu Yi Yu, Pei Wei Shueng, Hsin Cheng Chiu, Yu Wei Yen, Tzu Yu Kuo, Chieh Ru Li, Ming Wei Liu, Chia Hsin Ho, Tzu Hao Ho, Bo Wei Wang, Cheng En Li, Ming Hung Chen, Yao An Shen*, Chun Liang Lo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Tumour hypoxia plays an important role in modulating tumorigenesis, angiogenesis, invasion, immunosuppression, resistance to treatment, and even maintenance of the stemness of cancer stem cells (CSCs). Moreover, the targeting and treatment of hypoxic cancer cells and CSCs to reduce the influence of tumor hypoxia on cancer therapy remains an imperative clinical problem that needs to be addressed. Since cancer cells upregulate the expression of glucose transporter 1 (GLUT1) through the Warburg effect, we considered the possibility of GLUT1-mediated transcytosis in cancer cells and developed a tumor hypoxia-targeting nanomedicine. Our experimental results indicate that glucosamine-labeled liposomal ceramide can be efficiently transported between cancer cells by GLUT1 transporters and substantially accumulated in the hypoxic area in in vitro CSC spheroids and in vivo tumor xenografts. We also verified the effects of exogenous ceramide on tumor hypoxia, including important bioactivities such as upregulation of p53 and retinoblastoma protein (RB), downregulation of hypoxia-inducible factor-1 alpha (HIF-1α) expression, disruption of the OCT4-SOX2 network of stemness, and inhibition of CD47 and PD-L1 expression. To achieve an ideal therapeutic outcome, we combined treatment of glucosamine-labeled liposomal ceramide with paclitaxel and carboplatin, and we found an excellent synergistic effect, with tumor clearance being noted in three-fourths of the mice. Overall, our findings provide a potential therapeutic strategy for the treatment of cancer.

Original languageEnglish
Pages (from-to)13158-13175
Number of pages18
JournalACS Nano
Volume17
Issue number14
DOIs
StatePublished - 25 Jul 2023

Keywords

  • cancer stem cells
  • ceramide
  • glucose transporter
  • hypoxia-targeting
  • transcytosis

Fingerprint

Dive into the research topics of 'Glucose Transporter 1-Mediated Transcytosis of Glucosamine-Labeled Liposomal Ceramide Targets Hypoxia Niches and Cancer Stem Cells to Enhance Therapeutic Efficacy'. Together they form a unique fingerprint.

Cite this