Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo

Abstract

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.

Quinomycin A reduces cyst progression in polycystic kidney disease

“…negative effects of Quinomycin A, a recent study showed that actively targeted nano-delivery of Quinomycin A can efficiently target cancer cells to induce autophagic cell death instead of apoptosis or necrotic cell death. 40 In our studies, we found that ADPKD cells lose significant viability at a higher dose of 10 nmol/L Quinomycin A whereas, NHK cells retain their viability. Our in vitro studies also indicated that Quinomycin A specifically targeted cystic epithelial cells for apoptosis.…”

“…Recent studies in mice indicate that low doses (eg, 10 μg/kg body weight) of Quinomycin A are not toxic to normal cell hematopoiesis and selectively targets cancerous cells in acute myelocytic leukemia and bladder cancer 13,14 . To further combat the negative effects of Quinomycin A, a recent study showed that actively targeted nano‐delivery of Quinomycin A can efficiently target cancer cells to induce autophagic cell death instead of apoptosis or necrotic cell death 40 . In our studies, we found that ADPKD cells lose significant viability at a higher dose of 10 nmol/L Quinomycin A whereas, NHK cells retain their viability.…”

Hypoxia Pathway Proteins and Their Impact on the Blood Vasculature

“…Thus, while in vitro ACF treatment reduced hypoxia-induced overexpression of PGK-1 and VEGF in glioma cell lines, in vivo treatments with different ACF/polymer ratios in a preclinical model led to high survival rates in rats with gliosarcoma [161]. Echinomycin, another well-known direct HIF inhibitor, hampers the binding of HIF1α to the HRE sequence in the VEGF promoter [162], and a recent study by Thomas and collaborators (2005) has demonstrated that nano-delivery of echinomycin induces autophagy-mediated death in pancreatic cancer in vivo, wherein syndecan-1-encapsulated echinomycin, a custom-designed tumor-specific delivery method, resulted in significantly greater survival [163].…”

Nanotheranostics for Image-Guided Cancer Treatment

“…Large payloads delivered to the tumor as a result of the EPR effect leads to improved drug efficacy while minimizing off-target delivery and damage [ 46 ]. Further, surface modifications allow for active-targeting of tumor features, such as folate receptor [ 47 ] or syndecan-1 [ 48 ], for improvement over the EPR effect. Coating of liposomes with other materials, such as polymers (see below), have been investigated to further increase specificity to cancer.…”