A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3

Area of Science:

• Oncology
• Nanomedicine
• Cancer Biology

Background:

• Cancer stem cells (CSCs) drive tumor initiation, relapse, and therapeutic failure in non-small cell lung cancer (NSCLC).
• BBI608 targets CSCs by inhibiting signal transducer and activator of transcription 3 (STAT3), showing potential against chemoresistant NSCLC.

Purpose of the Study:

• To develop a stimuli-responsive nanoformulation of BBI608 to enhance its bioavailability and tumor accumulation for treating chemoresistant NSCLC.
• To evaluate the efficacy and mechanism of action of BBI608-loaded nanoparticles in preclinical NSCLC models.

Main Methods:

• BBI608 was encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl) methacrylamide (HPMA)-deoxy cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs).
• Cytotoxicity, proliferation, migration, and in vivo anti-tumor efficacy were assessed in chemoresistant NSCLC cell lines and xenograft models (CDX and PDX).
• Mechanistic studies investigated the effects on STAT3 and Wnt signaling pathways.

Main Results:

• BBI608-SS-NPs effectively suppressed NSCLC cell proliferation and migration, and specifically targeted stemness-high CSCs.
• The nanoparticles demonstrated comparable cytotoxicity to free BBI608 and released the drug in response to glutathione.
• BBI608-SS-NPs showed preferential tumor accumulation and superior anti-tumor efficacy in vivo, inhibiting both STAT3 and Wnt pathways.

Conclusions:

• Stimuli-responsive polymeric nanoparticles offer a promising strategy for delivering BBI608 in chemoresistant NSCLC.
• This nanoformulation effectively targets CSCs and enhances anti-tumor activity, showing potential for improved NSCLC treatment.