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

Kyle T. Householder, Danielle M. DiPerna, Eugene P. Chung, Anne Rosa Luning, Duong T. Nguyen, Sarah Stabenfeldt, Shwetal Mehta, Rachael W. Sirianni

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)37-44
Number of pages8
JournalColloids and Surfaces B: Biointerfaces
Volume166
DOIs
StatePublished - Jun 1 2018

Fingerprint

Histone Deacetylases
Glioblastoma
Nanoparticles
Polyethylene glycols
tumors
Tumors
nanoparticles
Neoplasms
chromatin
apoptosis
progressions
inhibitors
Oncology
mice
Ethylene Glycol
enzymes
glycols
delivery
drugs
ethylene

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Surfaces and Interfaces
  • Physical and Theoretical Chemistry
  • Colloid and Surface Chemistry

Cite this

pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma. / Householder, Kyle T.; DiPerna, Danielle M.; Chung, Eugene P.; Luning, Anne Rosa; Nguyen, Duong T.; Stabenfeldt, Sarah; Mehta, Shwetal; Sirianni, Rachael W.

In: Colloids and Surfaces B: Biointerfaces, Vol. 166, 01.06.2018, p. 37-44.

Research output: Contribution to journalArticle

Householder, Kyle T. ; DiPerna, Danielle M. ; Chung, Eugene P. ; Luning, Anne Rosa ; Nguyen, Duong T. ; Stabenfeldt, Sarah ; Mehta, Shwetal ; Sirianni, Rachael W. / pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma. In: Colloids and Surfaces B: Biointerfaces. 2018 ; Vol. 166. pp. 37-44.
@article{cd347ad9b71740b98a963419a2e7fe8d,
title = "pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma",
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, pH, PLA-PEG, Quisinostat (JNJ-26481585)",
author = "Householder, {Kyle T.} and DiPerna, {Danielle M.} and Chung, {Eugene P.} and Luning, {Anne Rosa} and Nguyen, {Duong T.} and Sarah Stabenfeldt and Shwetal Mehta and Sirianni, {Rachael W.}",
year = "2018",
month = "6",
day = "1",
doi = "10.1016/j.colsurfb.2018.02.048",
language = "English (US)",
volume = "166",
pages = "37--44",
journal = "Colloids and Surfaces B: Biointerfaces",
issn = "0927-7765",
publisher = "Elsevier",

}

TY - JOUR

T1 - pH driven precipitation of quisinostat onto PLA-PEG nanoparticles enables treatment of intracranial glioblastoma

AU - Householder, Kyle T.

AU - DiPerna, Danielle M.

AU - Chung, Eugene P.

AU - Luning, Anne Rosa

AU - Nguyen, Duong T.

AU - Stabenfeldt, Sarah

AU - Mehta, Shwetal

AU - Sirianni, Rachael W.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

KW - Glioblastoma

KW - HDAC

KW - Nanoparticle

KW - pH

KW - PLA-PEG

KW - Quisinostat (JNJ-26481585)

UR - http://www.scopus.com/inward/record.url?scp=85043363344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043363344&partnerID=8YFLogxK

U2 - 10.1016/j.colsurfb.2018.02.048

DO - 10.1016/j.colsurfb.2018.02.048

M3 - Article

C2 - 29533842

AN - SCOPUS:85043363344

VL - 166

SP - 37

EP - 44

JO - Colloids and Surfaces B: Biointerfaces

JF - Colloids and Surfaces B: Biointerfaces

SN - 0927-7765

ER -