title: Combination Nanopreparations of a Novel Proapoptotic Drug - NCL-240, TRAIL and siRNA.
abstract: To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells.
  
  
  
  Polyethylene glycol-phosphoethanolamine (PEG-PE) - based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles. All the micelles were characterized for size, zeta potential, and drug encapsulation efficiency. Different cancer cells were used to study the cytotoxicity potential of the individual as well as the combination formulations. Other cell based assays included cellular association studies of transferrin-targeted NCL-240 micelles and study of cellular survivin protein downregulation by anti-survivin siRNA-S-S-PE containing micelles.
  
  
  
  NCL-240 micelles and the combination NCL-240/TRAIL micelles significantly increased cytotoxicity in the resistant strains of SKOV-3, MCF-7 and A549 as compared to free drugs or single drug formulations. The NCL-240/TRAIL micelles were also more effective in NCI/ADR-RES cancer cell spheroids. Anti-survivin siRNA micelles alone displayed a dose-dependent reduction in survivin protein levels in A2780 cells. Treatment with NCL-240/TRAIL after pre-incubation with anti-survivin siRNA inhibited cancer cell proliferation. Additionally, a single multifunctional system composed of NCL-240/TRAIL/siRNA PM also had significant cytotoxic effects in vitro in multiple cell lines.
  
  
  
  These results demonstrate the efficacy of a combination of small-molecule PI3K inhibitors, TRAIL, and siRNA delivered by micellar preparations in multiple cancer cell lines.
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Riehle
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA.
authors.forename: Bhushan
authors.initials: B
authors.lastname: Pattni
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Jhaveri
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Thakur
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 140 The Fenway, Room 236, 360 Huntington Avenue, Boston, Massachusetts, 02115, USA. v.torchilin@neu.edu.|Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia. v.torchilin@neu.edu.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Torchilin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002733:Chlorophenols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008823:Micelles; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology*; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D002733:Chlorophenols; D051034:Inhibitor of Apoptosis Proteins; D008823:Micelles; C000611383:NCL-240; D010714:Phosphatidylethanolamines; D034741:RNA, Small Interfering; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014230:Triazoles; C067972:dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine; D011092:Polyethylene Glycols
keywords: NCL-240; TRAIL; multifunctional delivery; siRNA