Cancer stem cells (CSCs) have been demonstrated to be involved in
tumor initiation and relapse, and the presence of CSCs in the
tumor tissue often leads to therapeutic failure.
BBI608 has been identified to eliminate CSCs by inhibiting
signal transducer and activator of transcription 3 (STAT3). In this study, we confirm that
BBI608 can efficiently suppress the proliferation and migration of
non-small cell lung cancer (NSCLC) cells, and specifically kill the stemness-high population in chemoresistant NSCLC cells. To improve its bioavailability and
tumor accumulation,
BBI608 is successfully encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl)
methacrylamide (
HPMA)-deoxy
cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs). The BBI608-SS-NPs can release the drug in response to high concentrations of intracellular
glutathione, and exhibit cytotoxicity against
lung cancer cells and CSCs comparable to the free drug
BBI608. Furthermore, the BBI608-SS-NPs preferentially accumulate in
tumor sites, resulting in a superior anti-
tumor efficacy in both
cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of
BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.