A Long Acting Polymeric Iron Chelator for the Treatment of Transfusion Associated Iron Overload
Notice bibliographique
Résumé
Abstract Abstract 486 Introduction Transfusion dependent patients with abnormal hemoglobins or bone marrow failure syndromes require treatment to prevent and reverse iron overload. Desferrioxamine (DFO) mesylate is effective in promoting iron excretion. However, its usefulness is limited by a short intravascular half-life (t1/2) which necessitates continuous 8–12 hr subcutaneous infusion, often leading to limited patient compliance. Using hyperbranched polyglycerol (HPG), we have generated DFO conjugates which have significantly prolonged t1/2, good tolerance and improved iron excretion efficiency in mice. Methods HPGs with molecular weight (MW) of 50 to 700 kDa were conjugated to varying numbers of DFO molecules (25–400) using Schiff-base chemistry. The influence of HPG MW and DFO density on DFO iron binding was determined using UV-visible spectroscopy. The safety of HPG-DFO was evaluated by examining activated partial thromboplastin time (APTT), prothrombin time (PT), thromboelastography (TEG), platelet activation and complement activation. The effect of HPG-DFO on cell viability was evaluated in human umbilical vein endothelial cells (HUVECs). Single dose tolerability in mice was studied by injecting up to 1000 mg/kg of HPG-DFO and monitoring body weight, lactate dehydrogenase level and histological examination of organs at 14 days. Tritium labeled HPG-DFO was used to determine the circulation t1/2 in mice. Iron excretion efficacy of HPG-DFO compared to DFO was tested in iron overloaded mice by treating the animals with 150 mg/kg DFO or DFO equivalent. The iron content of organs, urine and feces was analyzed to determine the amount of iron excreted. Histological examination of the organs was performed using the Prussian blue stain. Results Spectroscopic analysis demonstrated that the conjugation of DFO to HPGs did not change their iron binding properties; the maximum absorption was at 429 nm for every conjugate tested. HPG-DFOs did not activate platelets, coagulation or the complement system. In vitro cell tolerance studies showed there was no increase in toxicity compared to the DFO molecule after polymer conjugation. Mice tolerance studies showed that the HPG-DFO conjugates were non toxic up to the maximum injected dose of 1000 mg/kg. The t1/2 of HPG-DFO in normal mice was 16 h for the 50 kDa conjugate and 44 h for the 500 kDa conjugate. The iron excretion efficiency as measured by urinary iron of the 50kDa HPG-DFO in iron overloaded showed significant improvement compared to placebo (58 Ìg vs 19 Ìg, p=0.0002) and DFO treated mice (58 Ìg vs 30 Ìg, p=0.0011 Figure 1). Conclusions HPG-DFO conjugate chelators were well tolerated in mice with significantly improved t1/2 and iron excretion. This approach has the potential to significantly decrease the number and duration of injections required to offload significant amounts of organ and total body iron. Further studies to determine the optimal conjugate and dose of agent are currently ongoing. Disclosures: No relevant conflicts of interest to declare.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».