pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma

Kyle T. Householder, Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd, Phoenix, AZ, 85013, USA; School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ, 85287, USA.
Danielle M. DiPerna, Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd, Phoenix, AZ, 85013, USA.
Eugene P. Chung, Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd, Phoenix, AZ, 85013, USA.
Anne Rosa Luning, Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd, Phoenix, AZ, 85013, USA.
Duong T. Nguyen, School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ, 85287, USA.
Sarah E. Stabenfeldt, School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ, 85287, USA.
Shwetal Mehta, Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd, Phoenix, AZ, 85013, USA.
Rachael W. Sirianni, Barrow Brain Tumor Research Center, Barrow Neurological Institute, 350 W. Thomas Rd, Phoenix, AZ, 85013, USA; School of Biological and Health Systems Engineering, Ira A. Fulton Schools of Engineering, Arizona State University, P.O. Box 879709, Tempe, AZ, 85287, USA. Electronic address: rachael.sirianni@dignityhealth.org.

Document Type

Article

Abstract

Histone deacetylases (HDACs) are known to be key enzymes in cancer development and progression through their modulation of chromatin structure and the expression and post-translational modification of numerous proteins. Aggressive dedifferentiated tumors, like glioblastoma, frequently overexpress HDACs, while HDAC inhibition can lead to cell cycle arrest, promote cellular differentiation and induce apoptosis. Although multiple HDAC inhibitors, such as quisinostat, are of interest in oncology due to their potent in vitro efficacy, their failure in the clinic as monotherapies against solid tumors has been attributed to poor delivery. Thus, we were motivated to develop quisinostat loaded poly(D,L-lactide)-b-methoxy poly(ethylene glycol) nanoparticles (NPs) to test their ability to treat orthotopic glioblastoma. In developing our NP formulation, we identified a novel, pH-driven approach for achieving over 9% (w/w) quisinostat loading. We show quisinostat-loaded NPs maintain drug potency in vitro and effectively slow tumor growth in vivo, leading to a prolonged survival compared to control mice.

Keywords

Glioblastoma, HDAC, Nanoparticle, PLA-PEG, Quisinostat (JNJ-26481585), pH

Medical Subject Headings

Animals; Drug Delivery Systems; Glioblastoma (drug therapy); Humans; Hydrogen-Ion Concentration; Hydroxamic Acids (chemistry, therapeutic use); Mice; Polyethylene Glycols (chemistry)

Publication Date

6-1-2018

Publication Title

Colloids and surfaces. B, Biointerfaces

E-ISSN

1873-4367

Volume

166

First Page

37

Last Page

44

PubMed ID

29533842

Digital Object Identifier (DOI)

10.1016/j.colsurfb.2018.02.048

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