Bi-functional sterically hindered phenol lipid-based delivery systems as potential multi-target agents against Alzheimer's disease via an intranasal route. Issue 25 (23rd June 2020)

• Record Type: Journal Article
• Authors: Burilova, Evgenia A.; Pashirova, Tatiana N.; Zueva, Irina V.; Gibadullina, Elmira M.; Lushchekina, Sofya V.; Sapunova, Anastasia S.; Kayumova, Ramilya M.; Rogov, Alexey M.; Evtjugin, Vladimir G.; Sudakov, Igor A.; Vyshtakalyuk, Alexandra B.; Voloshina, Alexandra D.; Bukharov, Sergey. V.; Burilov, Alexander R.; Petrov, Konstantin A.; Zakharova, Lucia Ya.; Sinyashin, Oleg G.
• Is Part Of: Nanoscale. Volume 12:Issue 25(2020)
• Page Start: 13757
• Page End: 13770
• Publication Date: 2020-06-23
• Subjects: Nanoscience -- Periodicals; Nanotechnology -- Periodicals; 620.505
• DOI: 10.1039/d0nr04037a
• Languages: English
• ISSNs: 2040-3364

Abstract

Abstract : New lipid-based nanomaterials based on sterically hindered phenols were developed as potential drugs against Alzheimer's disease via intranasal administration. Abstract : New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP- s -R, with s = 2, 3) of varying hydrophobicity (R = CH2 Ph and C n H2 n +1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP- s -R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP- s -R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-α-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg −1 . The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD.