Challenges and Opportunities of Deferoxamine Delivery for Treatment of Alzheimer's Disease, Parkinson's Disease, and Intracerebral Hemorrhage.

Deferoxamine mesylate (DFO) is an FDA-approved, hexadentate iron chelator routinely used to alleviate systemic iron burden in thalassemia major and sickle cell patients. Iron accumulation in these disease states results from the repeated blood transfusions required to manage these conditions. Iron accumulation has also been implicated in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), and secondary injury following intracerebral hemorrhage (ICH). Chelation of brain iron is thus a promising therapeutic strategy for improving behavioral outcomes and slowing neurodegeneration in the aforementioned disease states, though the effectiveness of DFO treatment is limited on several accounts. Systemically administered DFO results in nonspecific toxicity at high doses, and the drug's short half-life leads to low patient compliance. Mixed reports of DFO's ability to cross the blood-brain barrier (BBB) also appear in literature. These limitations necessitate novel DFO formulations prior to the drug's widespread use in managing neurodegeneration. Herein, we discuss the various dosing regimens and formulations employed in intranasal (IN) or systemic DFO treatment, as well as the physiological and behavioral outcomes observed in animal models of AD, PD, and ICH. The clinical progress of chelation therapy with DFO in managing neurodegeneration is also evaluated. Finally, the elimination of intranasally administered particles via the glymphatic system and efflux transporters is discussed. Abundant preclinical evidence suggests that intranasal DFO treatment improves memory retention and behavioral outcome in rodent models of AD, PD, and ICH. Several other biochemical and physiological metrics, such as tau phosphorylation, the survival of tyrosine hydroxylase-positive neurons, and infarct volume, are also positively affected by intranasal DFO treatment. However, dosing regimens are inconsistent across studies, and little is known about brain DFO concentration following treatment. Systemic DFO treatment yields similar results, and some complex formulations have been developed to improve permeability across the BBB. However, despite the success in preclinical models, clinical translation is limited with most clinical evidence investigating DFO treatment in ICH patients, where high-dose treatment has proven dangerous and dosing regimens are not consistent across studies. DFO is a strong drug candidate for managing neurodegeneration in the aging population, but before it can be routinely implemented as a therapeutic agent, dosing regimens must be standardized, and brain DFO content following drug administration must be understood and controlled via novel formulations.

Nanomaterial Additives for Fabrication of Stimuli-Responsive Skeletal Muscle Tissue Engineering Constructs.

Volumetric muscle loss necessitates novel tissue engineering strategies for skeletal muscle repair, which have traditionally involved cells and extracellular matrix-mimicking scaffolds and have thus far been unable to successfully restore physiologically relevant function. However, the incorporation of various nanomaterial additives with unique physicochemical properties into scaffolds has recently been explored as a means of fabricating constructs that are responsive to electrical, magnetic, and photothermal stimulation. Herein, several classes of nanomaterials that are used to mediate external stimulation to tissue engineered skeletal muscle are reviewed and the impact of these stimuli-responsive biomaterials on cell growth and differentiation and in vivo muscle repair is discussed. The degradation kinetics and biocompatibilities of these nanomaterial additives are also briefly examined and their potential for incorporation into clinically translatable skeletal muscle tissue engineering strategies is considered. Overall, these nanomaterial additives have proven efficacious and incorporation in tissue engineering scaffolds has resulted in enhanced functional skeletal muscle regeneration.