Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

Abstract

An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer’s disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood–brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 μL; 108 μg of K-604/mouse) was 772 ng·min/g, whereas that after oral administration (166 μg of K-604/mouse) was 8.9 ng·min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 μmol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

“…K-604 is a selective acyl-coenzyme A:cholesterol acyltransferase-1 inhibitor that blocks cholesterol esterification, which in the brain has been linked to the clearance of amyloid beta peptides and suppression of 24(S)-hydroxycholesterol induced neuronal cell death. Hence, it can have potentially beneficial effects in several neurodegenerative disorders, such as Alzheimer’s disease, also having recently been reported as a promising strategy to treat glioblastoma [ 13 , 33 ]. Nevertheless, alongside having poor blood−brain barrier permeability, its poor water solubility at neutral pH (0.05 mg/mL) makes it hard to formulate at high strength.…”

“…Nevertheless, alongside having poor blood−brain barrier permeability, its poor water solubility at neutral pH (0.05 mg/mL) makes it hard to formulate at high strength. Yet, since K-604′s solubility increases at a lower pH, Shibuya et al [ 13 ] prepared several solutions containing hydroxycarboxylic acids, either hyaluronic acid, gluconic acid or citric acid, for intranasal administration. These solutions, with pH values ranging from 3.0 to 3.8, were able to solubilize an increased amount of K-604, 10.8 mg/mL, which is 216 times higher than its solubility in purified water.…”

Blood-brain barrier permeability analysis of plant ceramides

“…In the BBB model, vascular endothelial cells are plated in the insert, pericytes under the bottom of the inserts, and astrocytes on the bottom of the well. This BBB model has various in vivo BBB features, and used for a variety of previous BBB researches [27][28][29][30]. These cells were cultured according to the manufacturer's instructions for 4−7 days to form a BBB-like structure, and transendothelial electrical resistance (TEER) was measured just before starting BBB permeability assays to ensure that the electrical resistance was higher than 150 O × cm 2 .…”

Genetic underpinnings of affective temperaments: a pilot GWAS investigation identifies a new genome-wide significant SNP for anxious temperament in ADGRB3 gene

“…Furthermore, functional prediction analyses implicated top SNPs for the anxious temperament to be associated with the expression of various genes in the central nervous system in areas relevant both for emotional reactivity and affective illnesses, such as SLC35F2 in the DLPFC, hypothalamus and nucleus accumbens, and implicated in GWASs for unipolar depression, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder 53 . Top SNPs for the anxious temperament also influence expression of ACAT1 encoding the acetyl-CoA Acetyltransferase1, the major isoform in the brain, which has been implicated in several neurodegenerative disorders and has recently emerged as a promising target in the treatment of Alzheimer’s disease 54 and glioblastoma 55 . Top SNPs for the anxious temperament also regulate the expression of ELMOD1 , which has previously been associated with personality 56 and delayed discounting measures 57 .…”