Combined Therapy for Alzheimer’s Disease: Tacrine and PAMAM Dendrimers Co-Administration Reduces the Side Effects of the Drug without Modifying its Activity

Abstract

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. TAC and dendrimer interactions were studied by in vitro drug release, drug stability, and FTIR. The toxicity profile of co-administration was evaluated in human red blood cells, in Neuro-2a cell culture, and in zebrafish larvae. Also, the anti-acetylcholinesterase activity was studied in cell culture. It was possible to obtain DG4.0-TAC and DG4.5-TAC suspensions, without reducing the drug solubility and stability. FTIR and in vitro release studies confirmed that interaction between TAC and DG4.5 was of the electrostatic type. No toxicity effects on human red blood cells were observed, whereas Highlights • Proposal of co-administration of TAC with DG4.0 or DG4.5 for Alzheimer's therapy. • FTIR and release studies confirmed that TAC electrostatically interacts with DG4.5. • Co-administration reduced the effects of TAC on cell viability and metabolic activity. • Co-administration reduced the hepatotoxicity of TAC in zebrafish larvae. • Co-administration maintained the anti-acetylcholinesterase activity of TAC.

Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer's Disease

“…In vivo/zebrafish larvae In vitro/neuro-2a cell culture Ex vivo/human red blood cell [ 250] PAMAM/tacrine (TAC) -Respiratory route/olfactory route In vivo/zebrafish larvae In vitro/neuro-2a cell culture Ex vivo/human red blood cell [ 250] was co-administrated with dendrimers. The results of this study suggest the use of this combination therapy due to its low toxicity for the treatment of AD through transdermal and intranasal routes.…”

“…The results of this study suggest the use of this combination therapy due to its low toxicity for the treatment of AD through transdermal and intranasal routes. [250] Dendrimers can play a major role in drug delivery to the brain by having the ability to carry hydrophobic or protein drugs. However, PAMAM dendrimers showed rapid clearance from blood circulation by the phagocyte system and a high amount of administrated dendrimers accumulated in various organs.…”

“…The results of this study suggest the use of this combination therapy due to its low toxicity for the treatment of AD through transdermal and intranasal routes. [ 250 ]…”

Functional Hybrid Nanoemulsions for Sumatriptan Intranasal Delivery

“…The counting results were expressed as the percentage of beats per minute in relation to the control (larvae in the E3 medium). Spontaneous movement was analyzed in a multichannel ADC system (WMicrotracker, Designplus SRL) with infrared rays that are interrupted by the larvae's swimming activity (n = 24) (Igartúa et al, 2020). Spontaneous movement was expressed as the percentage of locomotor activity in relation to the control.…”

Aging process of polyamidoamine dendrimers: Effect of pH and shaking in the fluorescence emission and aggregation‐state

“…In this context, we aimed to characterize the PAMAM dendrimers through the aging process at different storage conditions. For this, we selected PAMAM dendrimers of generation 4.0 (DG4.0) and 4.5 (DG4.5), both with ethylenediamine core, since they are the most used as drug delivery systems [21][22][23][24][25][26][27]. The DG4.0 has 64 amine terminal groups, while the DG4.5 has 128 carboxylic terminal groups, so these dendrimers have opposite charges under physiological conditions that could modify their behavior through the aging process.…”