Supramolecular self-assembly of triazine-based small molecules: targeting the endoplasmic reticulum in cancer cells

Area of Science:

• Biochemistry
• Nanotechnology
• Cancer Biology

Background:

• The endoplasmic reticulum (ER) is crucial for cellular functions and its dysregulation is implicated in cancer.
• Targeting the ER in cancer cells is challenging due to a lack of specific chemical tools.
• Effective anti-cancer therapies require precise targeting of cancer cell organelles.

Purpose of the Study:

• To engineer a novel supramolecular self-assembled nanoparticle for specific endoplasmic reticulum targeting in cancer cells.
• To investigate the therapeutic potential of these ER-targeting nanoparticles (ER-NPs) in inducing cancer cell death.
• To explore the combined effect of ER-NPs and chloroquine on cancer cell apoptosis.

Main Methods:

• Supramolecular self-assembly of tri-substituted triazine and 5-fluorouracil (5-FU) into ER-NPs.
• Characterization of ER-NPs for ER-targeting moiety, fluorescence tag, ER-stress inducer, and DNA damaging drug.
• Internalization and localization studies in HeLa cervical cancer cells using macropinocytosis.
• Assessment of ER stress, DNA damage, apoptosis, and autophagy induction by ER-NPs.

Main Results:

• Engineered ER-NPs specifically localized to the ER in HeLa cells.
• ER-NPs successfully induced ER stress and DNA damage, leading to cancer cell apoptosis.
• ER-NPs initiated autophagy, which, when inhibited by chloroquine, augmented cancer cell death.

Conclusions:

• Supramolecular self-assembly provides a viable strategy for developing ER-specific nanoparticles for cancer therapy.
• ER-NPs demonstrate potential as a dual-action therapeutic agent inducing ER stress and DNA damage.
• Combination therapy with ER-NPs and autophagy inhibitors may enhance anti-cancer efficacy.