Sequential enzyme-activated macrotheranostic probe for selective tumor mitochondria targeting.

Area of Science:

• Biomedical Engineering
• Cancer Theranostics
• Molecular Imaging

Background:

• Subcellular organelle targeting is crucial for cancer theranostics but lacks tumor selectivity.
• Existing methods often compromise efficacy and safety due to off-target effects.

Purpose of the Study:

• To develop a tumor-selective organelle-targeted macrotheranostic probe for cancer imaging and therapy.
• To improve the specificity and efficiency of cancer treatment through targeted mitochondrial intervention.

Main Methods:

• Conjugation of a near-infrared (NIR) hemicyanine fluorophore (CyNH2) with an acetylated lysine group to create the PLCy probe.
• Sequential enzymatic activation by histone deacetylases (HDACs) and cathepsin L (CTSL) in cancer cells.
• In vitro and in vivo studies to evaluate fluorescence turn-on, cytotoxicity, and tumor growth inhibition.

Main Results:

• The PLCy probe demonstrated selective mitochondrial targeting in cancer cells.
• Sequential activation by HDACs and CTSL successfully unmasked fluorescence and cytotoxicity.
• Activated probe decreased mitochondrial membrane potential and increased reactive oxygen species (ROS) levels.
• Efficient inhibition of tumor growth was observed in vivo.
• The probe induced apoptosis in tumor cells without external light irradiation.

Conclusions:

• The developed macrotheranostic probe (PLCy) offers specific, enzyme-activated, mitochondria-targeted imaging and therapy for cancer.
• This strategy provides a general approach for organelle-targeted theranostics with high specificity and efficiency.
• The probe's ability to induce apoptosis via ROS elevation offers a promising avenue for chemotherapy.