Esterase-Activated, pH-Responsive, and Genetically Targetable Nano-Prodrug for Cancer Cell Photo-Ablation

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Activatable prodrugs offer specific cancer cell targeting.
• Current phototheranostic prodrugs lack dual organelle targeting and synergistic effects.
• Drug uptake is hindered by cell membranes, exocytosis, and the extracellular matrix.

Purpose of the Study:

• To develop an intelligent nano-prodrug for enhanced cancer cell ablation.
• To achieve dual organelle targeting (lysosomes and mitochondria) for synergistic effects.
• To overcome limitations of current phototherapy, including reduced drug uptake and hampered efficacy.

Main Methods:

• Synthesized an esterase-activated DM nano-prodrug conjugated with MG-2I and DPP-OH.
• Utilized a pH-responsive and genetically targetable structure for dual organelle targeting.
• Investigated the nano-prodrug's properties in acidic environments and its release mechanism via esterase.

Main Results:

• DM nanoparticles exhibited enhanced pH-responsive photothermal/photodynamic properties.
• Released moieties specifically targeted lysosomes and mitochondria in CT-26 Mito-FAP cells.
• Achieved parallel damage in dual organelles, inducing mitochondrial dysfunction and apoptotic death.

Conclusions:

• The developed DM nano-prodrug demonstrates excellent photo-ablation effects.
• Esterase-activated, pH-responsive, and genetically targetable activities optimize phototherapy.
• This intelligent prodrug design offers a promising strategy for effective cancer treatment.