Pyridinium-Substituted Tetraphenylethylenes Functionalized with Alkyl Chains as Autophagy Modulators for Cancer...

Area of Science:

• Biomedical Engineering
• Molecular Biology
• Oncology

Background:

• Controlled modulation of autophagy is a potential strategy for cancer therapy, yet remains a significant challenge.
• Pyridinium-substituted tetraphenylethylene salts (PTPEs) are investigated for their ability to target mitochondria and modulate autophagy.

Purpose of the Study:

• To develop and evaluate PTPEs for their efficacy in cancer therapy by targeting mitochondria and disrupting autophagy.
• To investigate the structure-activity relationship of PTPEs, specifically the effect of alkyl chain length on mitochondrial affinity and autophagy induction.

Main Methods:

• Synthesis and characterization of PTPE 1-3 salts with varying alkyl chain lengths.
• In vitro and in vivo studies to assess mitochondrial targeting, autophagy disruption, complex formation with albumin, tumor penetration, and tumor suppression.
• Utilizing aggregation-induced emission (AIE) properties for mitochondrial targeting and imaging.

Main Results:

• PTPEs demonstrate enhanced mitochondrial affinity and autophagy-inducing activity with increased alkyl chain length.
• PTPEs exhibit proautophagic activity and block mitophagy, leading to autophagosome-lysosome fusion failure and cancer cell death.
• Fast complex formation with albumin facilitates biomimetic delivery and deep tumor penetration, showing efficient tumor accumulation and suppression in vitro and in vivo.

Conclusions:

• PTPE 1-3 salts possess dual functionality, acting as mitochondrial targeting agents with imaging capabilities due to AIE effects.
• These PTPEs are promising candidates for advanced cancer therapy, demonstrating effective tumor suppression through controlled autophagy modulation and targeted delivery.