Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers

Area of Science:

• Oncology
• Cancer Metabolism
• Radiotherapy

Background:

• The Warburg effect produces lactate, promoting tumor growth, metastasis, and treatment resistance.
• Glycolytic dependence in tumors correlates with poor clinical outcomes.
• Targeting lactate metabolism is a promising strategy to improve cancer therapy efficacy.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting lactate metabolism via MCT1, MCT4, and MPC.
• To evaluate the efficacy of 7ACC2, a lactate influx inhibitor, in sensitizing cancer cells to radiation.
• To assess the utility of liposomal encapsulation of 7ACC2 for improved drug delivery and efficacy.

Main Methods:

• Utilized PC3 and FaDu tumor cell models in 2D cultures and 3D spheroids.
• Investigated the role of lactate in fueling mitochondrial respiration and cell survival under hypoxia.
• Assessed the effects of 7ACC2 on oxygen consumption and radiosensitization.
• Developed and tested liposomal formulations of 7ACC2 using microfluidics.

Main Results:

• Lactate confirmed as a substrate for mitochondrial respiration supporting cell survival under hypoxia.
• Inhibition of lactate influx by 7ACC2 reduced oxygen consumption and sensitized tumor cells to radiation.
• Liposomal encapsulation of 7ACC2 preserved radiosensitizing activity and promoted reoxygenation.
• Liposomal 7ACC2 overcame pharmacological limitations of the free drug.

Conclusions:

• Inhibiting lactate influx with 7ACC2 shows therapeutic potential in sensitizing cancer cells to radiation.
• Liposomal formulation of 7ACC2 offers a promising approach to mitigate hypoxia-induced radioresistance.
• Targeting lactate metabolism represents a viable strategy to enhance conventional cancer therapies.