Characterization of DG4.0/DG4.5-Tacrine/Carbamazepine Complexes for Alzheimer ́s Treatment

MARTINEZ CS; IGARTUA DE; PRIETO MJ; ALONSO SDV

Congreso; LAFeBS 2016 - III Latin American Federation of Biophysical Societies; 2016

Alzheimer´s disease is a multifactorial neurodegenerative disease. The most accepted etiological hypotheses are related to a deficiency of acetylcholine and the formation of senile plaques of β-amyloid protein (Aβ) and neurofibrillary of hyperphosphorylated TAU protein (p-TAU). Tacrine (TAC) is an inhibitor of the enzyme acetylcholinesterase, which was approved by FDA for Alzheimer´s treatment. Due to their hepatotoxicity, TAC was removed from the market. In contrast, carbamazepine (CBZ) is an antiepileptic drug currently on use that was shown to reduce levels of Aβ and p-TAU. However, it has low solubility in aqueous media and inefficient pharmacokinetic profiles. Dendrimers (D) PAMAM DG4.0 and DG4.5 are three-dimensional polymers that bring unique properties to the field of drugs delivery systems. The complexed drugs assimilate D properties, which would increase significantly their solubility and brain arrival.Therefore, our aim was to obtain and characterize complexes of DG4.0 or DG4.5 with TAC or CBZ. In vitro drug release was studied using micro-dialysis and interactions D-drug was analyzed by FTIR. Additionally, toxicity in cell cultured was studied.Hydrophobic and ionic interactions between TAC and D were observed, but controlled release did not exist; no complexes between TAC and D were formed. Opposite to this, not only hydrophobic and ionic interactions between CBZ and D were observed, but 80% of the CBZ was released after 24 h of dialysis. Complexes between CBZ and D were achieved in a ratio 20:1. In assessing cell toxicity, the co-administration D-TAC failed to reduce the toxicity caused by free drug, whereas the D-CBZ complexes reduce this toxicity.