Design, Synthesis and Biological Evaluation of New 3,4-Dihydro-2(1H)-Quinolinone-Dithiocarbamate Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Background: Alzheimer's disease (AD) belongs to neurodegenerative disease, and the increasing number of AD patients has placed a heavy burden on society, which needs to be addressed urgently. ChEs/MAOs dual-target inhibitor has potential to treat AD according to reports. Purpose: To obtain effective multi-targeted agents for the treatment of AD, a novel series of hybrid compounds were designed and synthesized by fusing the pharmacophoric features of 3,4-dihydro-2 (1H)-quinolinone and dithiocarbamate. Methods: All compounds were evaluated for their inhibitory abilities of ChEs and MAOs. Then, further biological activities of the most promising candidate 3e were determined, including the ability to cross the blood-brain barrier (BBB), kinetics and molecular model analysis, cytotoxicity in vitro and acute toxicity studies in vivo. Results: Most compounds showed potent and clear inhibition to AChE and MAOs. Among them, compound 3e was considered to be the most effective and balanced inhibitor to both AChE and MAOs (IC50=0.28 µM to eeAChE; IC50=0.34 µM to hAChE; IC50=2.81 µM to hMAO-B; IC50=0.91 µM to hMAO-A). In addition, 3e showed mixed inhibition of hAChE and competitive inhibition of hMAO-B in the enzyme kinetic studies. Further studies indicated that 3e could penetrate the BBB and showed no toxicity on PC12 cells and HT-22 cells when the concentration of 3e was lower than 12.5 µM. More importantly, 3e lacked acute toxicity in mice even at high dose (2500 mg/kg, P.O.). Conclusion: This work indicated that compound 3e with a six-carbon atom linker and a piperidine moiety at terminal position was a promising candidate and was worthy of further study.

Biodegradable Core-Shell Copolymer-Phospholipid Nanoparticles for Combination Chemotherapy: An In Vitro Study.

In the present study, we developed novel core-shell-type lipid/particle assemblies comprising poly(lactic-co-glycolic acid) nanoparticle cores coated with a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine shell. Hydrophobic dihydroartemisinin and hydrophilic doxorubicin were co-loaded in the core-shell-type lipid/particle assemblies for combination chemotherapy. The physicochemical properties of the dual drug-loaded core-shell-type lipid/particle assemblies were characterized. The results of colorimetric cell viability assay and cellular uptake experiments demonstrated that the lipid/particle hybrid could increase the accumulation of doxorubicin accumulation in cell nuclei, thus enhancing cell cytotoxicity. This effect contributed to the high treatment efficiency of dihydroartemisinin and doxorubicin. These biodegradable lipid/polymer hybrid particles could be promising delivery systems to improve combination chemotherapy.

A physical model for the size-dependent cellular uptake of nanoparticles modified with cationic surfactants.

BACKGROUND: The aim of this work was to improve oral bioavailability. The uptake of a series of quaternary ammonium salt didodecyl dimethylammonium bromide (DMAB)-modified nanoparticles (with uniform sizes ranging from 50 nm to 300 nm) into heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2) and human colon adenocarcinoma cells (HT-29) was investigated. METHODS: Coumarin-6 (C6) loaded poly (lactide-co-glycolide) (PLGA) nanoparticles were prepared with DMAB using the emulsion solvent diffusion method. The physicochemical properties and cellular uptake of these nanoparticles were studied. Deserno's model was applied to explain the experimental observations. RESULTS: The results showed that the surface modification of PLGA nanoparticles with DMAB notably improved the cellular uptake. The cellular uptake was size-dependent and had an optimal particle size of 100 nm. The experimental data was integrated numerically, and was in agreement with the theoretical model. CONCLUSION: These results indicated that the interactions between the charged nanoparticles and the cells resulted from various forces (eg, electrostatic forces, hydrophobic forces, bending and stretching forces, and limited receptor-mediated endocytosis), and the uptake of the nanoparticles occurred as a result of competition.