Multiplex Methionine Modulating Hydrogel for Cancer Metabolic Therapy

Area of Science:

• Oncology
• Biomedical Engineering
• Cancer Therapeutics

Background:

• Tumor cells exhibit high dependence on methionine, making it a potential therapeutic target.
• Systemic methionine restriction can cause side effects due to methionine's essential metabolic roles.

Purpose of the Study:

• To develop a localized drug delivery system for multilayered methionine blockade within tumors.
• To investigate the therapeutic efficacy of a novel hydrogel in preclinical cancer models.

Main Methods:

• Encapsulation of small molecule inhibitors (PF9366, adenosine dialdehyde) and JPH203 into tumor-targeting nanoparticles (NPs).
• Co-loading of NPs into a reactive oxygen species-sensitive hydrogel to form the multiplex methionine modulating hydrogel (3 M Gel).
• Evaluation of 3 M Gel efficacy in murine models of triple-negative breast cancer, hepatocellular carcinoma, and colorectal cancer.

Main Results:

• 3 M Gel effectively restricted S-adenosyl methionine generation and histone methylation in tumors.
• The treatment stimulated immunogenic cell death and potent immune responses, restraining tumor progression.
• 3 M Gel remodeled the tumor microenvironment, overcoming immune checkpoint blockade resistance in triple-negative breast cancer.

Conclusions:

• The developed 3 M Gel provides a localized triple regulation strategy for methionine metabolism.
• This approach offers a novel pathway for amino acid starvation-based cancer therapy with enhanced efficacy and reduced systemic side effects.