Tumor-Triggered Disassembly of a Multiple-Agent-Therapy Probe for Efficient Cellular Internalization.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapeutics

Background:

• Multiple agent therapy (MAT) probes offer promise for cancer treatment but face challenges with cellular uptake of agents with diverse properties.
• Optimizing the delivery and performance of individual therapeutic agents within a single probe remains a significant hurdle.

Purpose of the Study:

• To develop a self-assembling probe that enhances the internalization efficiency of individual therapeutic agents for improved cancer treatment.
• To investigate a dual-pathway cellular internalization strategy for optimized drug delivery.

Main Methods:

• A peptide-conjugated-AIEgen (FC-PyTPA) was designed to self-assemble with siRNA into FC_siRNA -PyTPA.
• The probe was engineered to respond to extracellular MMP-2 near tumor cells, cleaving into FC_siRNA and PyTPA.
• FC_siRNA was designed for macropinocytosis, while PyTPA was designed for caveolae-mediated endocytosis.

Main Results:

• The dual-pathway internalization strategy significantly improved the uptake efficiency of each therapeutic agent.
• Inside cancer cells, the probe activated self-assembly of precursor F, gene interference by C_siRNA, and reactive oxygen species (ROS) production by PyTPA.
• These combined actions effectively inhibited tumor growth.

Conclusions:

• The presented peptide-conjugated-AIEgen probe offers a sophisticated approach to MAT for cancer therapy.
• This strategy overcomes limitations of single-probe delivery by enabling differential cellular internalization and sequential activation of therapeutic components.
• The findings highlight the potential of targeted, multi-modal nanomedicine for enhanced cancer treatment outcomes.