Pancreatic cancer remains a recalcitrant
neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could offer a new treatment approach. We repurpose
echinomycin, an
antibiotic encapsulated within a
syndecan-1 actively targeted nanoparticle, for treatment of
pancreatic cancer.
Tumor-specific uptake, biodistribution, efficacy of nanodelivered
echinomycin, and mechanism of cell death were assessed in aggressive, metastatic models of
pancreatic cancer. In these autophagic-dependent
pancreatic cancer models,
echinomycin treatment resulted in autophagic cell death noted by high levels of LC3 among other autophagy markers, but without hallmarks of apoptosis, e.g.,
caspase activation and
chromatin fragmentation, or
necrosis, e.g., plasma membrane degradation and
chromatin condensation/degrading. In vivo, biodistribution of syndecan-1-targeted nanoparticles indicated preferential S2VP10 or S2CP9
tumor uptake compared to the liver and kidney (S2VP10 p = 0.0016, p = 0.00004 and S2CP9 p = 0.0009, p = 0.0001). Actively targeted nanodelivered
echinomycin resulted in significant survival increases compared to
Gemzar (S2VP10 p = 0.0003, S2CP9 p = 0.0017) or
echinomycin only (S2VP10 p = 0.0096, S2CP9 p = 0.0073). We demonstrate that actively targeted nanodelivery of
echinomycin results in autophagic cell death in pancreatic and potentially other high-autophagy, apoptosis-resistant
tumors. Collectively, these findings support syndecan-1-targeted delivery of
echinomycin and dysregulation of autophagy to induce cell death in
pancreatic cancer.