Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles

Abstract

A potent cell division cycle 7 (CDC7) kinase inhibitor, known as PHA-767491, has been described to reduce the transactive response DNA binding protein of 43 KDa (TDP-43) phosphorylation in vitro and in vivo, which is one of the main proteins found to aggregate and accumulate in the cytoplasm of motoneurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. However, the main drawback of this compound is its low permeability to the central nervous system (CNS), limiting its use for the treatment of neurological conditions. In this context, the use of drug delivery systems like nanocarriers has become an interesting approach to improve drug release to the CNS. In this study, we prepared and characterized biodegradable nanoparticles in order to encapsulate PHA-767491 and improve its permeability to the CNS. Our results demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles with an average radius between 145 and 155 nm could be used to entrap PHA-767491 and enhance the permeability of this compound through the blood–brain barrier (BBB), becoming a promising candidate for the treatment of TDP-43 proteinopathies such as ALS.

Improved Controlled Release and Brain Penetration of the Small Molecule S14 Using PLGA Nanoparticles

“…were invariable according to previously optimized conditions (Table 2) [26]. In all cases, this method was able to provide a good number of nanoparticles (from 32 to 78 mg), which increased with the amount of the drug used with great reproducibility.…”

“…The drug and the polymer are dissolved in the same water-miscible organic solvent, tetrahydrofuran (THF) in this case, and PVA was selected as surfactant because it gave the best outcome in the previous methodology. Nanoprecipitation methodology was performed by duplicate using increasing amounts of the drug (10, 20, 30 and 40 mg), while surfactant and polymer concentrations Nanoprecipitation methodology was performed by duplicate using increasing amounts of the drug (10, 20, 30 and 40 mg), while surfactant and polymer concentrations were invariable according to previously optimized conditions (Table 2) [26]. In all cases, this method was able to provide a good number of nanoparticles (from 32 to 78 mg), which increased with the amount of the drug used with great reproducibility.…”

PLGA-Based Nanoparticles for Neuroprotective Drug Delivery in Neurodegenerative Diseases

“…PHA prevents phosphorylation by CDC7 of TDP-43, a nuclear protein encoded by TARDBP gene-regulating several RNA processes as transcription, mRNA transport, and microRNA biosynthesis. To address low permeability, rapid metabolism, and unspecific distribution issues, Rojas-Prats et al, used PHA-loaded PLGA NPs [ 81 ]. They were prepared by nanoprecipitation method and observed by SEM microscopy using gold-coated NPs.…”

“…: 24% E.E. : 12 to 18% In vitro: SH-SY5Y cell model of ALS Reduce TDP-43 phosphorylation [ 81 ] Multiple Sclerosis Interferon-β-1a Double emulsion/solvent evaporation ø: 150 to 165 nm PdI: 0.081 to 0.093 ζ potential: 17.7 to 18.8 mV D.L. : 0.7 to 2.5% E.E.…”

From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

“…These data confirm the difficulty of MTDLs to maintain good pharmacokinetic profiles but show two of the new MTDLs as potential brain penetrant compounds and therefore suitable agents to treat AD and other dementias.F urther studies aiming to improve brain penetration of these compounds using PLGA nanoencapsulation are ongoing. [39,40]…”