Dendrimer Donepezil Conjugates for Improved Brain Delivery and Better in Vivo Pharmacokinetics

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Abstract
In neurodegenerative disorders, crossing the blood-brain barrier to achieve higher brain uptake of drugs has attracted considerable interest of researchers in recent years. The present approach is designed with a hypothesis that polyamidoamine (PAMAM) dendrimer can be suitable for better brain delivery of donepezil (DZ) utilizing the conjugation strategy. Amine-terminated 4.0 G PAMAM dendrimers (utilizing ethylenediamine core) were synthesized and characterized by different spectroscopic methods (1H and 13C NMR, UV–vis, Fourier transform infrared, electrospray ionization mass). The synthesized PAMAM dendrimer was then conjugated with DZ-ester and finally DZ (ester)-PAMAM conjugate (PDZ) was prepared. The chemical shifts of −CHO (δ = 9.92) and O–CH3 (δ = 3.153) in 1H NMR spectrum confirmed the synthesis of PDZ. The percent drug conjugation of DZ was approximately 26%, and 16 DZ molecules were conjugated with each PAMAM molecule. The size and ζ-potential observed of PDZ conjugate were 122 ± 1.88 nm and 0.434 ± 0.322, respectively. In vitro release studies suggested that DZ release was in a sustained fashion until 120 h at physiological pH conditions. The in vitro acetylcholine esterase (AChE) inhibition activity of PDZ formulation was significantly higher (p < 0.05) than that of the DZ alone at 1 μM dose. In the in vivo studies, the brain uptake of PDZ was quite higher than that of DZ following intravenous administration in Sprague-Dawley rats. The plasma drug concentration studies resulted into improved pharmacokinetic parameters. Half-life (t1/2), volume of distribution (Vd), and clearance were found to be 5.75 ± 0.41 h–1, 0.135 ± 0.02 L, and 0.016 ± 0.0021 L/h, respectively, in the case of PDZ formulation and 1.09 ± 0.10 h–1, 0.172 ± 0.016 L, and 0.108 ± 0.014 L/h, respectively, in the case of DZ solution. The improved half-life and 4-fold increase in brain uptake was observed in the case of the dendrimer-conjugated formulation, which suggested that the synthesized conjugates provide significantly higher DZ brain delivery. The prepared PDZ-conjugated formulation improved AChE inhibition in vitro and the brain delivery in vivo. This strategy may be explored further for better delivery of DZ to the brain.
Funding Information
  • University Grants Commission (F.30-18/2014)
  • Anusandhan National Research Foundation (SB/YS/LS-1002014)

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