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Nutritional Glutamine-Modified Iron-Delivery System with Enhanced Endocytosis for Ferroptosis Therapy of Pancreatic
Yang Chen1, Wenzhe Xu1, Hao Jin1
1State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.
Abstract:
Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.
Insights
This study developed an iron-delivery system (IDS) modified with glutamine (Gln) to target pancreatic cancer cells. Combining IDS with a Gln transporter inhibitor enhances nutrient uptake and delivers iron for effective ferroptosis therapy.
Area of Science:
- Oncology
- Nanotechnology
- Metabolic Engineering
Background:
- Oncogenes reprogram nutrient metabolism, presenting targets for cancer therapy.
- Pancreatic cancer exhibits glutamine (Gln) addiction, a metabolic vulnerability.
- Heterogeneous nutrient metabolism in tumors poses challenges for drug delivery.
Purpose of the Study:
- To design an iron-delivery system (IDS) for enhanced ferroptosis therapy in pancreatic cancer.
- To leverage Gln addiction for targeted drug delivery and metabolic reprogramming.
- To develop a novel therapeutic strategy combining nutrient-modified nanodrugs with transporter inhibitors.
Main Methods:
- Engineered an IDS modified with Gln for enhanced endocytosis by Gln-addicted cancer cells.
- Loaded the IDS with V9302, a Gln transporter inhibitor (ASCT2), to induce Gln deprivation and enhance macropinocytosis.
- Combined the IDS with l-buthionine sulfoximine (BSO), a ferroptosis inducer.
- Evaluated therapeutic efficacy in mouse pancreatic tumor models.
Main Results:
- Gln-modified IDS demonstrated enhanced endocytic uptake by pancreatic tumor cells.
- V9302 treatment induced Gln deprivation, promoting IDS uptake via RAS-stimulated macropinocytosis.
- The synergistic effect of Gln modification and V9302 facilitated efficient iron and BSO delivery.
- The combined approach significantly enhanced ferroptosis in pancreatic tumor models.
Conclusions:
- The Gln-modified IDS effectively targets pancreatic cancer cells by exploiting their metabolic dependencies.
- Combining nutrient-modified nanodrugs with transporter inhibitors offers a promising strategy for intracellular drug delivery in tumors with heterogeneous metabolism.
- This approach provides a novel platform for ferroptosis-based cancer therapy.
