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Updated: Jun 29, 2026
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Size switchable nanomodulator achieving ratio-precise dual-drug codelivery for synergistic glutamine metabolism
Hongrui Fan1, Xuwen Li1, Haolin Song1
1Department of Pharmaceutics, School of Pharmaceutical Sciences, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Shanghai, 201203, China.
Abstract:
Under the nutrient-deprived tumor microenvironment (TME) and near-universal KRAS mutations, pancreatic ductal adenocarcinoma (PDAC) exhibits voracious addiction to glutamine metabolism. This aberrant metabolism not only sustains the rapid proliferation of malignant cells, but also shapes a tumor-permissive TME characterized by stromal desmoplasia and immunosuppression, culminating in the clinical refractoriness of PDAC. Although multi-target synergistic modulation of glutamine metabolism is recognized as a requisite antitumor strategy, its implementation is still hampered by the uncontrolled in vivo multi-drug biodistribution. Therefore, glutamine metabolism modulation is in urgent need of precision codelivery of multiple drugs. Herein, we propose an upstream-downstream synergistic glutamine metabolism modulation strategy and develop a size switchable metabolic nanomodulators (J&V@T-PPLN NPs) for precision codelivery of metabolic modulators. This nanomodulator achieves in vivo ratio-precise dual-drug codelivery, synergistically blocking the uptake and utilization of glutamine by PDAC cells. Beyond cutting off nutrient supply to malignant cells, the nanomodulator also demonstrates the capacity to remodel the TME and reactivate antitumor immunity, thereby eliciting enhanced tumor suppression. Through the ratio-precise codelivery system, this study discussed the possibility of translating in vitro validated synergistic metabolism modulation into a controllable in vivo combination therapy modality, providing a generalizable strategy for metabolism modulating cancer therapy and the rational design of precision drug delivery systems.
Insights
Pancreatic cancer cells rely on glutamine metabolism. New nanomodulators precisely deliver drugs to block glutamine uptake, suppress tumors, and enhance immunity.
Area of Science:
- Oncology
- Nanotechnology
- Metabolic Engineering
Background:
- Pancreatic ductal adenocarcinoma (PDAC) thrives on glutamine metabolism within a nutrient-poor tumor microenvironment (TME).
- Aberrant glutamine metabolism fuels PDAC proliferation and creates a tumor-supportive TME, leading to treatment resistance.
- Effective synergistic modulation of glutamine metabolism is hindered by challenges in controlling multi-drug biodistribution in vivo.
Purpose of the Study:
- To develop a precision codelivery system for synergistic glutamine metabolism modulation in PDAC.
- To create size-switchable metabolic nanomodulators (J&V@T-PPLN NPs) for ratio-precise dual-drug delivery.
- To investigate the potential of this nanomodulator in remodeling the TME and reactivating antitumor immunity.
Main Methods:
- Development of size-switchable metabolic nanomodulators (J&V@T-PPLN NPs) for precision codelivery.
- In vivo administration of nanomodulators to achieve ratio-precise dual-drug codelivery.
- Evaluation of the nanomodulator's effects on glutamine metabolism, TME modulation, and antitumor immunity.
Main Results:
- The J&V@T-PPLN NPs achieved ratio-precise codelivery of metabolic modulators in vivo.
- Synergistic blockade of glutamine uptake and utilization by PDAC cells was observed.
- The nanomodulator demonstrated TME remodeling and reactivation of antitumor immunity, leading to enhanced tumor suppression.
Conclusions:
- A novel nanomodulator enables controllable in vivo synergistic glutamine metabolism modulation for PDAC.
- This approach offers a generalizable strategy for metabolism-modulating cancer therapy.
- The study provides a rational design for precision drug delivery systems targeting metabolic pathways.
