title: Liposomal carfilzomib nanoparticles effectively target multiple myeloma cells and demonstrate enhanced efficacy in vivo.
abstract: Carfilzomib, a recently FDA-approved proteasome inhibitor, has remarkable anti-myeloma (MM) activity. However, its effectiveness is limited by associated severe side-effects, short circulation half-life, and limited solubility. Here, we report the engineering of liposomal carfilzomib nanoparticles to overcome these problems and enhance the therapeutic efficacy of carfilzomib by increasing tumoral drug accumulation while decreasing systemic toxicity. In our design, carfilzomib was loaded into the bilayer of liposomes to yield stable and reproducible liposomal nanoparticles. Liposomal carfilzomib nanoparticles were efficiently taken up by MM cells, demonstrated proteasome inhibition, induced apoptosis, and exhibited enhanced cytotoxicity against MM cells. In vivo, liposomal carfilzomib demonstrated significant tumor growth inhibition and dramatically reduced overall systemic toxicity compared to free carfilzomib. Finally, liposomal carfilzomib demonstrated enhanced synergy in combination with doxorubicin. Taken together, this study establishes the successful synthesis of liposomal carfilzomib nanoparticles that demonstrates improved therapeutic index and the potential to improve patient outcome in MM.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashley
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Jared F
authors.initials: JF
authors.lastname: Stefanick
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Freimann Life Science Center, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.affiliation: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA; Freimann Life Science Center, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Alves
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rikio
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Advanced Diagnostics and Therapeutics, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: bbilgicer@nd.edu.
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Advanced Diagnostics and Therapeutics, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: tkiziltepe@nd.edu.
authors.forename: Basar
authors.initials: B
authors.lastname: Bilgicer
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000187:drug effects; D016023:Integrins / Q000096:biosynthesis; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy*; D053758:Nanoparticles; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010316:Particle Size; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012995:Solubility; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D039041:Integrin alpha4beta1; D016023:Integrins; D008081:Liposomes; D009842:Oligopeptides; D011480:Protease Inhibitors; C524865:carfilzomib; D004317:Doxorubicin
keywords: Carfilzomib; Liposome; Multiple myeloma; Nanoparticle; Proteasome inhibitor