# Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers

## TL;DR

This paper explores using nanocarriers to target lactate metabolism in cancer cells, improving radiation therapy effectiveness by reducing hypoxia-induced resistance.

## Contribution

A novel liposomal formulation of 7ACC2 is proposed to overcome drug limitations and enhance radiosensitization.

## Key findings

- Lactate supports tumor cell survival under hypoxia by fueling mitochondrial respiration.
- 7ACC2 inhibits lactate influx and sensitizes tumor cells to radiation in 2D and 3D models.
- Liposomal 7ACC2 preserves radiosensitizing activity and promotes reoxygenation in tumor models.

## Abstract

Lactate, the main
product of the Warburg effect, exerts both intrinsic
effects on cancer cell metabolism and noncell autonomous effects that
promote tumor development, metastasis, and treatment resistance. As
such, glycolytic dependence in tumors is frequently associated with
poor clinical outcomes. Targeting lactate metabolism has emerged as
a promising strategy to enhance the efficacy of conventional therapies.
Here, we investigate the therapeutic potential of targeting lactate
metabolism via inhibiting MCT1, MCT4, and MPC in PC3 and FaDu tumor
cell models. We confirmed lactate as a substrate that fuels mitochondrial
respiration and supports cell survival under hypoxic conditions. Inhibition
of lactate influx mediated by 7ACC2 reduced oxygen consumption, sensitizing
tumor cells to radiation in both 2D-cell cultures and 3D-spheroid
models. Encapsulation of 7ACC2 in DPPC liposomes using microfluidics
preserved radiosensitizing activity in both systems, promoting reoxygenation,
while overcoming the pharmacological limitations of the free drug.
This liposomal formulation therefore represents a promising therapeutic
approach to help mitigate hypoxia-induced radioresistance.