ABSTRACTA key aspect for the applicability of 89Zr‐radioimmunoconjugates is inert modification and radiolabeling. The two commercially available bifunctional variants of the siderophore desferrioxamine (DFO), Fe‐DFO‐N‐suc‐TFP‐ester and p‐NCS‐Bz‐DFO, are most often used for clinical 89Zr‐immuno‐PET. The use of Fe‐DFO‐N‐suc‐TFP‐ester is advantageous with regard to higher radiolysis stability and more facile assessment of radiochemical purity as well as chelator‐to‐mAb ratio. However, not all mAbs withstand the Fe‐removal step at relatively low pH (4–4.5) using EDTA, which is needed after conjugation to allow 89Zr labeling. In this study, it was investigated whether hydroxybenzyl ethylenediamine (HBED) or the clinically approved deferiprone (DFP) can serve as an alternative for EDTA to establish a pH‐independent mild method for Fe‐removal and thereby broaden the applicability of Fe‐DFO‐N‐suc‐TFP‐ester. Carrier‐added [59Fe]Fe‐DFO‐N‐suc‐TFP‐ester was used for mAb modification to enable direct tracking of the Fe‐removal efficiency under various conditions. Whereas incomplete Fe‐removal with HBED was observed at pH 5 or higher, Fe‐removal with DFP was possible at a broad pH range (4–9). This provides a mild, pH‐independent method for Fe‐removal, improving the applicability and attractiveness of Fe‐DFO‐N‐suc‐TFP‐ester for 89Zr‐mAb preparation.

01 Sep 2022·Journal of Animal Physiology and Animal Nutrition

Safety and efficacy of a novel iron chelator (HBED; (N,N′‐Di(2‐hydroxybenzyl)ethylenediamine‐N,N′‐diacetic acid)) in equine (Equus caballus) as a model for black rhinoceros (Diceros bicornis)

Article

Author: Lavin, Shana R. ; Knutson, Mitchell ; Warren, Lori K. ; Valdes, Eduardo V. ; Livingston, Shannon ; Sullivan, Kathleen E.

AbstractWhile iron overload disorder (IOD) and related disease states are not considered a common occurrence in domestic equids, these issues appear prevalent in black rhinoceroses under human care. In addressing IOD in black rhinos, altering dietary iron absorption and excretion may be the most globally practical approach. A main option for treatment used across other species such as humans, is chelation therapy using iron‐specific synthetic compounds. As horses may serve as an appropriate digestive model for the endangered rhinoceros, we evaluated the potential use of the oral iron chelatorN,N‐bis(2‐hydroxybenzyl)ethylenediamine‐N,N‐diacetic acid (HBED) in horses for safety and efficacy prior to testing in black rhinoceros. Health and iron digestibility and dynamics were assessed in horses (n = 6) before, and after treatment with HBED (50 mg/kg body weight) for 8 days using a crossover design with serum, faecal and urine collection. A preliminary pharmacokinetic trial was also performed but no trace of HBED was found in serially sampled plasma through 8 h post‐oral dosing. HBED increased urinary iron output in horses compared to control by 0.7% of total iron intake (p < 0.01), for an average of 27 mg urinary iron/day, similar to human chelation goals. Blood chemistry, blood cell counts and overall wellness were not affected by treatment. As healthy horses are able to regulate iron absorption, the lack of change in iron balance is unsurprising. Short‐term HBED administration appeared to be safely tolerated by horses, therefore it was anticipated it would also be safe to administer to black rhinos for the management of iron overload.

01 Jan 2019·Journal of NeurotraumaQ2 · MEDICINE

Unique Properties Associated with the Brain Penetrant Iron Chelator HBED Reveal Remarkable Beneficial Effects after Brain Trauma

Q2 · MEDICINE

Article

Author: Ahmad, Abdullah Shafique ; Chamara, K.V.D. Ranga ; Khalaf, Saher ; Doré, Sylvain

Iron is postulated to contribute to secondary injury after brain trauma through various pathways including oxidative stress and inflammation. Therefore, one goal is to limit iron toxicity by either directly limiting iron activity, or limiting the secondary cascade mediated by iron, therefore rescuing the brain from damage after trauma. The N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid monohydrochloride (HBED) is a unique iron chelator that has the ability to cross the intact blood-brain barrier; it has a higher affinity to iron, and it has a longer half-life than most commonly used chelators. A controlled-cortical impact model of traumatic brain injury (TBI) was induced in mice. Mice were subcutaneously injected with HBED immediately after TBI, then at 12 h after, followed by a twice-a-day regimen until an end-point of 3 days. Neurobehavioral tests were performed daily. Cortical injury volume, hemispheric enlargement, and hippocampal swelling were quantified. Perls' iron immunostaining along with markers of gliosis, oxidative stress, and aquaporin (AQP) 4 were also performed. Data revealed that HBED treatment significantly decreases motor deficits and improves recovery after TBI. It also reduces cortical injury volume by 36.6 ± 6.8% (p < 0.001), hippocampal swelling by 23.4 ± 3.8% (p < 0.05), and total hemispheric volume by 13.3 ± 2.7% (p < 0.01). These effects are related to a reduction in microgliosis and oxidiative stress markers in the impacted corpus callosum area by 39.8 ± 7.3%, and by 80.5 ± 0.8% (p < 0.05), respectively. AQP4 staining is also attenuated in the hippocampus of HBED-treated mice. Therefore, our results suggest that HBED should be considered as a therapeutic tool to facilitate the recovery process following brain trauma.

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