Alzheimer’s disease has become a public health priority, so an investigation of new therapies is required. Tacrine (TAC) was licensed for treatments; however, its oral administration caused hepatotoxicity, so it is essential to reduce the side effects. PAMAM dendrimer generation 4.0 and 4.5 (DG4.0 and DG4.5) can be used as drug delivery systems and as nanodrugs per se. Our work aims to propose a combined therapy based on TAC and PAMAM dendrimer co-administration. The toxicity profile of co-administration was evaluated in human red blood cells, in Neuro-2a cell culture, and in zebrafish larvae. For neurotoxicity studies, changes in the locomotor activity of Zebrafish larvae were studied, because it could reflect the cerebral damage, as well as a morphological or lethal effect, caused by different treatments.
For treatments, three embryos at 1 dpf were placed in each well of a 96-well plate containing E3 medium and maintained for 4 days at 28°C. At 5 dpf, the medium was replaced by 250 μL of serial dilutions of TAC (0.3–30 μM) and DG4.0-TAC or DG4.5-TAC (0.0018–0.18 μM of dendrimers with 0.3–30 μM of TAC), all prepared in E3 medium. As a negative control, larvae incubated only with E3 medium were used. At 1, 4, 24, and 48-h post-incubation (hpi), the viability and the spontaneous movement (neurotoxicity) were studied.
Concerning the viability, no formulation produced lethal effects up to treatments of 1, 4, or 24 h. But after 48 h, the administration of 30 μM of TAC and the co-administration of 30 μM of drug with 0.18 μM of dendrimers caused the mortality of 20% of the larvae. However, none of the treatments, in any of the tested concentrations, modified the swimming activity of Zebrafish larvae after 1, 4, 24, and 48 h of treatment.
AAPS PharmSciTech. 2020 Mar 25;21(3):110. doi: 10.1208/s12249-020-01652-w
Igartúa DE, Martinez CS, Alonso S , Prieto MJ