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J Control Release. 2014 Dec 28;196:113-21. doi: 10.1016/j.jconrel.2014.10.005. Epub 2014 Oct 12.

Liposomal carfilzomib nanoparticles effectively target multiple myeloma cells and demonstrate enhanced efficacy in vivo.

Author information

1
Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA.
2
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.
3
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
4
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.
5
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.

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.

KEYWORDS:

Carfilzomib; Liposome; Multiple myeloma; Nanoparticle; Proteasome inhibitor

PMID:
25312543
DOI:
10.1016/j.jconrel.2014.10.005
[Indexed for MEDLINE]

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