Tunable naphthalimide-based fluorogenic intracellular nanoaggregates trigger ROS-mediated DNA damage and apoptosis in...

Area of Science:

• Medicinal Chemistry
• Materials Science
• Cancer Biology

Background:

• Naphthalimide derivatives are explored for therapeutic applications.
• Developing targeted therapies for triple-negative breast cancer (TNBC) remains a significant challenge.
• Molecular aggregation properties influence drug efficacy and cellular uptake.

Purpose of the Study:

• To synthesize and characterize novel naphthalimide homodimers with diverse linker chemistries.
• To investigate the effect of linker functionality on molecular aggregation in aqueous media and cellular environments.
• To evaluate the anticancer activity of these derivatives against TNBC cells.

Main Methods:

• Synthesis of naphthalimide homodimers with varying linker functionalities (positively charged, amino acid-based).
• Characterization of aggregation properties using techniques like Variable Temperature NMR, Powder XRD, SEM, and TEM.
• Assessment of cellular activity, including aggregation, cytotoxicity, migration inhibition, reactive oxygen species generation, DNA damage, and apoptosis induction in MDA-MB-231 TNBC cells.

Main Results:

• Naphthalimide derivatives with positively charged linkers exhibited nanoaggregation but lacked cellular activity.
• Amino acid-infused naphthalimide derivatives demonstrated significant cellular aggregation, enhanced emission (AIE), and extended fluorescence lifetime.
• These derivatives showed prominent anticancer activity, impaired migration, and induced programmed cell death in TNBC cells.
• Chirality in the amino acid side chain further boosted anticancer efficacy by increasing ROS, DNA damage, and caspase activity.

Conclusions:

• Naphthalimide homodimers with amino acid linkers are effective in targeting TNBC cells through aggregation-induced mechanisms.
• The molecular basis of aggregation involves π-π stacking, leading to thread-like structures and nanoaggregates.
• Chiral naphthalimide derivatives show enhanced cytotoxicity, suggesting potential as novel therapeutics for chemoresistant TNBC.