A liposomal formulation of the synthetic curcumin analog EF24 (Lipo-EF24) inhibits pancreatic cancer progression: towards future combination therapies

Journal of Nanobiotechnology

Research

Jörg Wenzel¹  Georg Feldmann²  Peter Brossart²  Jens Nolting²  Savita Bisht²  Rolf Schubert³  Alexander Rupp⁴  Stefan Holdenrieder⁴  Martin Schlesinger⁵  Gerd Bendas⁵ 

[1] Department of Dermatology, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Bonn, Germany;Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany;Department of Pharmaceutical Technology and Biopharmacy, Albert-Ludwigs-Universität, Freiburg im Breisgau, Germany;Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, Germany;Pharmaceutical Department, University of Bonn, Bonn, Germany;

关键词: Pancreatic cancer;    EF24;    Combination therapy;    Curcumin analogs;    Liposomal nanoparticles;    Drug delivery;   

DOI  :  10.1186/s12951-016-0209-6

 received in 2016-04-13, accepted in 2016-06-28,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundPancreatic 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.ResultsTransmission 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.ConclusionDue 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.

【 授权许可】

CC BY   
© The Author(s) 2016