title: A liposomal formulation of the synthetic curcumin analog EF24 (Lipo-EF24) inhibits pancreatic cancer progression: towards future combination therapies.
abstract: BACKGROUND
  Pancreatic cancer is one of the most lethal of human malignancies known to date and shows relative insensitivity towards most of the clinically available therapy regimens. 3,5-bis(2-fluorobenzylidene)-4-piperidone (EF24), a novel synthetic curcumin analog, has shown promising in vitro therapeutic efficacy in various human cancer cells, but insufficient water solubility and systemic bioavailability limit its clinical application. Here, we describe nano-encapsulation of EF24 into pegylated liposomes (Lipo-EF24) and evaluation of these particles in preclinical in vitro and in vivo model systems of pancreatic cancer.
  
  
  RESULTS
  Transmission electron microscopy and size distribution studies by dynamic light scattering confirmed intact spherical morphology of the formed liposomes with an average diameter of less than 150 nm. In vitro, treatment with Lipo-EF24 induced growth inhibition and apoptosis in MIAPaCa and Pa03C pancreatic cancer cells as assessed by using cell viability and proliferation assays, replating and soft agar clonogenicity assays as well as western blot analyses. Lipo-EF24 potently suppressed NF-kappaB nuclear translocation by inhibiting phosphorylation and subsequent degradation of its inhibitor I-kappa-B-alpha. In vivo, synergistic tumor growth inhibition was observed in MIAPaCa xenografts when Lipo-EF24 was given in combination with the standard-of-care cytotoxic agent gemcitabine. In line with in vitro observations, western blot analysis revealed decreased phosphorylation of I-kappa-B-alpha in excised Lipo-EF24-treated xenograft tumor tissues.
  
  
  CONCLUSIONS
  Due to its promising therapeutic efficacy and favorable toxicity profile Lipo-EF24 might be a promising starting point for development of future combinatorial therapeutic regimens against pancreatic cancer.
authors.affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Savita
authors.initials: S
authors.lastname: Bisht
authors.affiliation: Pharmaceutical Department, University of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlesinger
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rupp
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, Albert-Ludwigs-Universität, Freiburg im Breisgau, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schubert
authors.affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Nolting
authors.affiliation: Department of Dermatology, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Bonn, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Wenzel
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Holdenrieder
authors.affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Pharmaceutical Department, University of Bonn, Bonn, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Bendas
authors.affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. georg.feldmann@uni-bonn.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018450:Disease Progression; D004339:Drug Compounding; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007279:Injections, Subcutaneous; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D008081:Liposomes; D016328:NF-kappa B; D010881:Piperidones; D003841:Deoxycytidine; D051550:I-kappa B Kinase; D000093542:Gemcitabine
keywords: Combination therapy; Curcumin analogs; Drug delivery; EF24; Liposomal nanoparticles; Pancreatic cancer