title: Acridine Orange Conjugated Polymersomes for Simultaneous Nuclear Delivery of Gemcitabine and Doxorubicin to Pancreatic Cancer Cells.
abstract: Considering the systemic toxicity of chemotherapeutic agents, there is an urgent need to develop new targeted drug delivery systems. Herein, we have developed a new nuclear targeted, redox sensitive, drug delivery vehicle to simultaneously deliver the anticancer drugs gemcitabine and doxorubicin to the nuclei of pancreatic cancer cells. We prepared polymeric bilayer vesicles (polymersomes), and actively encapsulated the drug combination by the pH gradient method. A redox-sensitive polymer (PEG-S-S-PLA) was incorporated to sensitize the formulation to reducing agent concentration. Acridine orange (AO) was conjugated to the surface of the polymersomes imparting nuclear localizing property. The polymersomes' toxicity and efficacy were compared with those of a free drug combination using monolayer and three-dimensional spheroid cultures of pancreatic cancer cells. We observed that the redox sensitive, nuclear-targeted polymersomes released more than 60% of their encapsulated contents in response to 50 mM glutathione. The nanoparticles are nontoxic; however, the drug encapsulated vesicles have significant toxicity. The prepared formulation can increase the drug's therapeutic index by delivering the drugs directly to the cells' nuclei, one of the key organelles in the cells. This study is likely to initiate research in targeted nuclear delivery using other drug formulations in other types of cancers.
authors: Department of Pharmaceutical Sciences, and ‡Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
authors: Tayebeh
authors: T
authors: Anajafi
authors: Department of Pharmaceutical Sciences, and ‡Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
authors: Michael D
authors: MD
authors: Scott
authors: Department of Pharmaceutical Sciences, and ‡Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
authors: Seungyong
authors: S
authors: You
authors: Department of Pharmaceutical Sciences, and ‡Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
authors: Xiaoyu
authors: X
authors: Yang
authors: Department of Pharmaceutical Sciences, and ‡Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
authors: Yongki
authors: Y
authors: Choi
authors: Department of Pharmaceutical Sciences, and ‡Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
authors: Steven Y
authors: SY
authors: Qian
authors: Department of Pharmaceutical Sciences, and ‡Department of Physics, North Dakota State University , Fargo, North Dakota 58108, United States.
authors: Sanku
authors: S
authors: Mallik
mesh_terms: D000165:Acridine Orange / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004317:Doxorubicin / Q000008:administration & dosage*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011108:Polymers / Q000737:chemistry*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; D003841:Deoxycytidine; D004317:Doxorubicin; D000165:Acridine Orange; D000093542:Gemcitabine