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Open AccessArticle

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

1
Department of Hematology Oncology, Wake Forest Baptist Health, Winston-Salem, NC 27157, USA
2
Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA
3
Department of Surgery, University of Louisville, Louisville, KY 40202, USA
4
Department of Cancer Predisposition, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
5
Department of Surgery, University of California Davis, Sacramento, CA 95616, USA
6
Department of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USA
7
Department of Pathology, University of Alabama Birmingham, Birmingham, AL 35294, USA
*
Author to whom correspondence should be addressed.
Equal contribution of first author.
Cancers 2020, 12(8), 2279; https://doi.org/10.3390/cancers12082279
Received: 30 June 2020 / Revised: 1 August 2020 / Accepted: 3 August 2020 / Published: 14 August 2020
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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. View Full-Text
Keywords: echinomycin; autophagy; autophagic cell death; active targeted liposome; pancreatic cancer; alternative cancer therapy; multispectral optoacoustic tomography echinomycin; autophagy; autophagic cell death; active targeted liposome; pancreatic cancer; alternative cancer therapy; multispectral optoacoustic tomography
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MDPI and ACS Style

Thomas, A.; Samykutty, A.; Gomez-Gutierrez, J.G.; Yin, W.; Egger, M.E.; McNally, M.; Chuong, P.; MacCuaig, W.M.; Albeituni, S.; Zeiderman, M.; Li, M.; Edil, B.H.; Grizzle, W.E.; McMasters, K.M.; McNally, L.R. Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo. Cancers 2020, 12, 2279. https://doi.org/10.3390/cancers12082279

AMA Style

Thomas A, Samykutty A, Gomez-Gutierrez JG, Yin W, Egger ME, McNally M, Chuong P, MacCuaig WM, Albeituni S, Zeiderman M, Li M, Edil BH, Grizzle WE, McMasters KM, McNally LR. Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo. Cancers. 2020; 12(8):2279. https://doi.org/10.3390/cancers12082279

Chicago/Turabian Style

Thomas, Alexandra; Samykutty, Abhilash; Gomez-Gutierrez, Jorge G.; Yin, Wenyuan; Egger, Michael E.; McNally, Molly; Chuong, Phillip; MacCuaig, William M.; Albeituni, Sabrin; Zeiderman, Matthew; Li, Min; Edil, Barish H.; Grizzle, William E.; McMasters, Kelly M.; McNally, Lacey R. 2020. "Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo" Cancers 12, no. 8: 2279. https://doi.org/10.3390/cancers12082279

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