DNA in human cells can be either loose or tightly bound to
proteins known as histones. When DNA is bound to histones, it cannot be
transcribed (read) and this is a typical method of gene control within a cell as
only the relevant portions of the DNA can be transcribed. Unlike normal cells, fast-growing
cancers have an excess of an enzyme which binds DNA to the histones very
tightly and affects how it is read changing how the cells DNA is interpreted.
It has been found that inhibitors of this enzyme, such as quisinostat, can
prevent the growth and spread of certain cancers. However, these inhibitors
have very poor uptake and delivery. Recently, researchers at Barrow
Neurological Institute and Arizona State University utilized mPEG-PLA (polyvivo
AK054) from PolySciTech (www.polyscitech.com)
to generate nanoparticles loaded with quisinostat. They found these nanoparticles
to be effective in slowing the growth of glioblastoma in an animal model. This
research holds promise for developing new therapeutic strategies for rapidly
growing cancers including brain-cancer. Read more: Householder, Kyle T.,
Danielle M. DiPerna, Eugene P. Chung, Rosa Luning, Duong Nguyen, Sarah
Stabenfeldt, Shwetal Mehta, and Rachael W. Sirianni. "pH Driven
Precipitation of Quisinostat onto PLA-PEG Nanoparticles Enables Treatment of
Intracranial Glioblastoma." Colloids and Surfaces B: Biointerfaces (2018).
https://www.sciencedirect.com/science/article/pii/S0927776518301231
“Highlights: Ionized quisinostat is loaded more efficiently
onto PLA-PEG nanoparticles. Quisinostat potency is maintained through
nanoparticle processing. Quisinostat-loaded nanoparticles administered IV slow
intracranial GL261 glioma tumors. Abstract: Histone deacetylases (HDACs) are
known to be key enzymes in cancer development and progression through their
modulation of chromatin structure and 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 therapy due to their potent in vitro efficacy, poor
delivery has been attributed to their failure in the clinic as monotherapies
against solid tumors. Thus, we were motivated to develop quisinostat loaded
poly(D,L-lactide)-b-methoxy poly(ethylene glycol) nanoparticles (NPs) to test
their ability to enable effective quisinostat delivery to 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; nanoparticle; HDAC; quisinostat (JNJ-26481585);
PLA-PEG; pH”
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