A Long Acting Polymeric Iron Chelator for the Treatment of Transfusion Associated Iron Overload
Bibliographic record
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".