Wednesday, February 28, 2018

mPEG-PLA from PolySciTech used in development of novel quisinostat-loaded nanoparticles for brain-cancer therapy

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 ( 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).

“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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