Cationic Albumin-Conjugated Chelating Agent As a Novel Brain Drug Delivery System in Neurodegeneration Publisher Pubmed



Kamalinia G^{1, 2, 3} ; Khodagholi F⁴ ; Shaerzadeh F⁴ ; Tavssolian F¹ ; Chaharband F¹ ; Atyabi F^{1, 2} ; Sharifzadeh M⁵ ; Amini M⁶ ; Dinarvand R^{1, 2} Show Affiliations
Source: Chemical Biology and Drug Design Published:2015

Abstract

The critical role of metal ions and in particular iron in oxidative stress and protein aggregation offers chelation therapy as a sensible pharmaceutical strategy in oxidative stress-induced neuronal damages. In this research, we conjugated an iron-chelating agent, deferasirox, to cationized human serum albumin molecules in order to develop a novel brain delivery system for the management of neurodegenerative disorders due to the significant role of oxidative stress-induced neuronal injury in such diseases. Cationized albumin is known to be able to transport to brain tissue via adsorptive-mediated transcytosis. The developed structures were molecularly characterized, and their conjugation ratio was determined. PC12 cell line was utilized to evaluate the neuroprotective features of these newly developed molecules in the presence of hydrogen peroxide neuronal damage and to identify the mechanisms behind the observed neuronal protection including apoptotic and autophagic pathways. Furthermore, a rat model of Alzheimer's disease was utilized to evaluate the impact of conjugated structures in vivo. Data analysis revealed that the conjugated species were able to hinder apoptotic cell death while enhancing autophagic process. The developed conjugated species were also able to attenuate amyloid beta-induced learning deficits when administered peripherally. This manuscript reports a novel cationized albumin-conjugated drug formulation followed by characterization and physicochemical evaluation, cell culture studies for evaluating any related neuroprotective effect as well as the residing molecular mechanisms behind it and an in vivo evaluation of its capability in attenuating Aβ-induced learning and memory deficits. We have demonstrated that cationized albumin-conjugated deferasirox can be exploited as a brain drug delivery system in neurodegenerative disorders by reducing apoptotic and enhancing autophagic pathways. © 2015 John Wiley & Sons A/S.