Metabolic regulation-driven nanoparticles for tumor vulnerabilization and enhanced photodynamic therapy

Area of Science:

• Biochemistry
• Nanotechnology
• Oncology

Background:

• Tumor cells display metabolic plasticity, supporting growth and therapeutic resistance.
• Targeting tumor metabolism is crucial for effective cancer therapy.
• Metabolic adaptability presents a significant challenge in cancer treatment.

Purpose of the Study:

• To develop a glutathione (GSH)-responsive peptide-based nanocomplex for dual metabolic intervention and photodynamic therapy (PDT).
• To induce metabolic collapse in tumor cells by disrupting key metabolic pathways.
• To enhance antitumor efficacy by overcoming tumor metabolic adaptability.

Main Methods:

• Constructed a nanoplatform co-delivering siRNA targeting monocarboxylate transporter 4 (siMCT4), Etomoxir (fatty acid oxidation inhibitor), and chlorin e6 (Ce6).
• Utilized a disulfide-containing peptide and DSPE-PEG2k-FA for nanocomplex assembly and GSH-triggered release.
• Investigated the combined effects of inhibiting lactate efflux, fatty acid oxidation, and PDT in 4T1 tumor-bearing mice.

Main Results:

• The nanocomplex successfully delivered therapeutic agents, triggering synchronized release upon cellular internalization.
• siMCT4 inhibited lactate efflux, leading to glycolysis suppression, while Etomoxir blocked fatty acid oxidation.
• Combined metabolic disruption and PDT induced severe metabolic imbalance and significant tumor growth inhibition in vivo.

Conclusions:

• The developed nanocomplex effectively targets and disrupts tumor cell metabolism through a multi-pronged approach.
• This strategy overcomes tumor metabolic adaptability, offering a promising metabolism-oriented therapeutic avenue.
• The combined intervention demonstrates significant potential for enhancing antitumor efficacy.