Near-Infrared Upconversion Modulation of Intracellular Protons for Autophagy-Induced Apoptosis

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapeutics

Background:

• Intracellular pH is crucial for cancer cell function, making pH modulation a potential therapeutic strategy.
• Precise spatiotemporal control of proton levels in tumors remains a significant challenge in cancer therapy.

Purpose of the Study:

• To develop a near-infrared (NIR)-controlled nanoscale proton delivery system for precise cancer treatment.
• To investigate the efficacy of proton delivery in suppressing tumor growth and inducing cancer cell apoptosis.

Main Methods:

• Utilized upconversion nanoparticles (UCNPs) coated with photoacid (PA) and ferrocene (Fc) for proton delivery.
• Activated proton release in vivo using 980 nm NIR stimulation, leading to tumor microenvironment acidification.
• Incorporated Fc for real-time visual quantification of proton accumulation via luminescence changes.

Main Results:

• NIR stimulation triggered transient H+ release, reducing tumor cell glucose uptake by 50% and suppressing mTOR signaling.
• Induced excessive autophagy leading to mitochondrial dysfunction and apoptosis, termed proton-mediated autophagy-induced apoptosis (PAA).
• Achieved a six-fold reduction in tumor weight and elevated proton levels in glioma following intravenous administration.

Conclusions:

• Established a spatiotemporally controlled platform for intratumoral proton dynamics using NIR-activated UCNPs.
• Demonstrated the potential of precision cancer theranostics through non-invasive NIR irradiation.
• The developed nanoagent effectively triggers PAA, offering a promising strategy for glioma treatment.