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

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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 the co-administration with DG4.5 reduced cytotoxicity of TAC on the Neuro-2a cell line. Moreover, in vivo co-administration of both DG4.0-TAC and DG4.5-TAC reduced the morphological and hepatotoxic effects of TAC in zebrafish larvae. The reduction of TAC toxicity was not accompanied by a reduction in its activity since the anti-acetylcholinesterase activity remains when it is co-administrated with dendrimers. In conclusion, the co-administration of TAC with both DG4.0 and DG4.5 is a novel therapy since it was less-toxic, was more biocompatible, and has the same effectiveness than the free drug.

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Abbreviations

AChE:

acetylcholinesterase

AD:

Alzheimer’s disease

Aβ:

β-amyloid protein

CV:

crystal violet

D:

dendrimer

DG4.0:

generation 4.0 polyamidoamine dendrimer

DG4.5:

generation 4.5 polyamidoamine dendrimer

dpf:

days post-fecundation

DTNB:

5,5-dithio-bis-(2-nitrobenzoic acid)

FBS:

fetal bovine serum

FTIR:

Fourier transform infrared spectroscopy

G:

generation

hpi:

hours post-incubation

MTT:

3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide

NR:

neutral red

PBS:

phosphate buffer saline

TAC:

tacrine

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Acknowledgements

Daniela E. Igartúa is grateful for the PhD fellowship granted by the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, N° Res 4845/15). M. Jimena Prieto, Carolina S. Martinez, and Silvia del V. Alonso are members of the Scientific Research Program from the CONICET. This work was supported by Universidad Nacional de Quilmes (PUNQ 1388/15 and PUNQ 1076/15) and Consejo Nacional de Investigaciones Científicas y Técnicas.

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Authors and Affiliations

  1. Departamento de Ciencia y Tecnología, Laboratorio de Bio-Nanotecnología, Universidad Nacional de Quilmes, Roque Saenz Peña 352, (B1876BXD), Bernal, Buenos Aires, Argentina

    Daniela E. Igartúa, Carolina S. Martinez, Silvia del V. Alonso & M. Jimena Prieto

  2. Grupo de Biología Estructural y Biotecnología, Instituto Multidisciplinario de Biología Celular, Consejo Nacional de Investigaciones Científicas y Técnicas, CIPBA, UNLP, La Plata, Buenos Aires, Argentina

    Daniela E. Igartúa, Carolina S. Martinez & Silvia del V. Alonso

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  1. Daniela E. Igartúa
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Correspondence to Daniela E. Igartúa.

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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.

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Igartúa, D.E., Martinez, C.S., del V. Alonso, S. et al. Combined Therapy for Alzheimer’s Disease: Tacrine and PAMAM Dendrimers Co-Administration Reduces the Side Effects of the Drug without Modifying its Activity. AAPS PharmSciTech 21, 110 (2020). https://doi.org/10.1208/s12249-020-01652-w

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