Polymeric nanoformulations aimed at cancer metabolism reprogramming with high specificity to inhibit tumor growth

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Nanotechnology

Background:

• Cancer cells exhibit metabolic vulnerabilities exploitable for targeted therapies.
• Cellular plasticity and metabolic heterogeneity in cancer pose challenges for selective elimination.
• Developing specific metabolic interventions requires overcoming these complexities.

Purpose of the Study:

• To design a nanoformulation for targeted reprogramming of cancer cell metabolism.
• To achieve selective cancer cell elimination through integrated extracellular and intracellular interventions.
• To evaluate the therapeutic efficacy and biosafety of the nanoformulation in vivo.

Main Methods:

• Fabrication of macrophage membrane-coated polymeric nanovesicles loaded with dual drugs.
• Investigating the nanoformulation's effect on cancer cell glucose uptake and metabolism.
• Assessing the impact on cellular citrate intake, reactive oxygen species (ROS) production, and NADPH levels.
• Evaluating tumor growth inhibition and macrophage phenotype modulation in tumor-bearing mice.

Main Results:

• The nanoformulation selectively targets cancer cells, reducing glucose intake and redirecting intracellular glucose metabolism.
• It inhibits citrate uptake, induces hydrogen peroxide (H2O2) production, and down-regulates NADPH, enhancing redox damage.
• Significant tumor growth inhibition and transformation of pro-tumor macrophages to a tumor-suppressive phenotype were observed in vivo.
• The nanoformulation demonstrated high selectivity towards cancer cells with minimal toxicity to normal cells.

Conclusions:

• The developed nanoformulation effectively reprograms cancer metabolism for selective toxicity.
• This approach offers a promising strategy for cancer therapy by exploiting metabolic vulnerabilities.
• The nanoformulation exhibits favorable biosafety and therapeutic potential in preclinical models.