Reactive Oxygen Species-Triggered Dissociation of a Polyrotaxane-Based Nanochelator for Enhanced Clearance of Systemic and Hepatic Iron

摘要

Chronic blood transfusions are used to alleviate DFO lion Ehmiraoor, anemic symptoms in thalassemia and sickle cell anemia patients from the Laws but can eventually result in iron overload (IO) and subsequently lead to severe oxidative stress in cells and tissues. itetgliary ammo Deferoxamine (DFO) is clinically approved to treat transfusional IO, but the use of the iron chelator is hindered by nonspecific toxicity and poor pharmacokinetic (PK) properties in humans, resulting in the need to administer the drug via long-term infusion regimens that can often lead to poor patient compliance. Herein, a nanochelator system that uses the characteristic IO physiological environment to dissociate was prepared through the incorporation of DFO and reactive oxygen species (ROS)-sensitive thioketal groups into anacyclodextrin-based polyrotaxane platform (rPR-DFO). ROS-induced dissociation of this nanochelator (ca. 10 nm)into constructs averaging 2 nm in diameter significantly increased urine and fecal elimination of excess iron in vivo. In addition to significantly improved PK properties, rPR-DFO was well-tolerated in mice and no adverse side effects were noted in single high dose or multiple dose acute toxicity studies. The overall features of rPR-DFO as a promising system for iron chelation therapy can be attributed to a combination of the nanochelator's improved PK, favorable distribution to the liver, and ROS-induced dissociation properties into constructs <6 nm for faster renal elimination. This ROS-responsive nanochelator design may serve as a promising alternative for safely prolonging the circulation of DFO and more rapidly eliminating iron chelates from the body in iron chelation therapy regimens requiring repeated dosing of nanochelators.