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.

Intravenously Administered, Retinoid Activating Nanoparticles Increase Lifespan and Reduce Neurodegeneration in the SOD1G93A Mouse Model of ALS

“…molecules within nanoparticles can increase delivery, reduce toxicities, and enhance CNS activity, even when nanoparticles have not been designed for specific passage across the bloodbrain barrier (Cook et al, 2015;Householder et al, 2015Householder et al, , 2018. Importantly, our prior studies demonstrated neuroprotective effects of adapalene in primary spinal motor neuron cultures (Kolarcik and Bowser, 2012) and we hypothesized a nanoparticle formulation would also have low to no toxicity in vivo.…”

“…Our lab previously demonstrated that delivery of drugs from polymeric nanoparticles can improve the efficacy of therapeutic candidates while reducing toxicity for the treatment of intracranial tumors via enhancements in bioavailability (Zhou et al, 2013;Cook et al, 2015;Householder et al, 2015Householder et al, , 2018. We have previously studied the fate of intravenously administered nanoparticles and encapsulated payloads in the central nervous system, demonstrating that delivery of hydrophobic payloads to the brain and spinal cord can be achieved even if the nanoparticles have not been designed for BBB passage (Cook et al, 2015;Medina et al, 2017).…”

β-Cyclodextrin-Poly (β-Amino Ester) Nanoparticles Are a Generalizable Strategy for High Loading and Sustained Release of HDAC Inhibitors

“…[11][12][13] We and others have developed nanoparticle encapsulation strategies to improve drug tolerability, pharmacokinetics, and site-specific delivery of HDAC inhibitors. [14][15][16][17] However, each of these reports has developed approaches for encapsulation of individual HDAC inhibitors, requiring development of unique loading strategies for individual drugs. These intensive efforts have thus far yielded only modest loading.…”

“…Although these quisinostat loaded PLA-PEG nanoparticles were highly loaded and useful for treating intracranial glioblastoma by intravenous injection, in vitro studies demonstrated that drug was released rapidly once nanoparticles were exposed to an aqueous environment. 14 Presumably this rapid release occurred because quisinostat was only associated with the surface of the nanoparticle, instead of being embedded within a particle core.…”

Lumbrokinase/paclitaxel nanoparticle complex: potential therapeutic applications in bladder cancer

“…In the past few decades, biomedical research has focused more and more on DDS research. 26 A variety of nanocarriers have been widely developed and used, for example, poly(d, l-lactide)-b-methoxy poly(ethylene glycol) (PLA-PEG) 27 and layer-by-layer microcarriers, 28 which loads the chemicals or protein drugs with the same chemical property (oppositely charged bio-polyelectrolytes). However, carriers capable of carrying two different chemical properties at the same time are rare.…”