Twice-Weekly Subcutaneous Liposome Chelator to Treat Transfusional Iron Overload

描述（由申请人提供）：每年约有100,000名婴儿出生时患有严重的地中海贫血型血液疾病或镰状细胞性贫血，导致终身输血。然而，身体不能有效地去除铁，因此输血中多余的铁会积累起来。这会导致血液中的毒性积聚，肝脏和脾脏中的铁储存蛋白饱和，导致铁诱导的肝病、内分泌紊乱和心肌病。如果不及时治疗，铁诱发的心肌病不可避免地会在孩子成年之前导致死亡。输血铁超载可通过螯合治疗。经批准的铁螯合剂存在严重缺陷，我们的目标是通过靶向螯合剂递送策略来克服这些缺陷。我们设计了一种新型的，稳定的纳米脂质体（LDFO）配方，含有高浓度的铁螯合剂去铁胺（DFO）。我们将验证以下假设：皮下注射新型低聚甘油醚可导致肝脏和脾脏中的治疗性低聚甘油醚浓度和血液中持续水平的低聚甘油醚。在目标1中，我们将优化脂质体- dfo配方。在目标2中，我们将建立脂质体DFO制剂的储存稳定性。在目标3中，我们将确定通过静脉注射和皮下给药时脂质体DFO的药代动力学和生物分布概况。这种有针对性地将DFO输送到体内主要的铁储存部位，将比输注DFO更有效地从深层组织部位去除铁

DESCRIPTION (provided by applicant): About 100,000 babies are born each year with severe thalassemia type blood disorders or sickle cell anemia, leading to a lifelong regime of blood transfusions. However, the body cannot efficiently remove iron hence the extra iron in the transfused blood accumulates. This causes a toxic build up in the blood, saturation of the iron storage proteins in the liver and spleen leading to iron-induced liver disease, endocrine disorders and cardiomyopathy. If left untreated, iron induced cardiomyopathy inevitably leads to death, before the child reaches adulthood. Transfusional iron overload can be treated by chelation. Approved iron chelators suffer from severe drawbacks that we aim to overcome with a targeted chelator delivery strategy. We have devised a novel, stable nanoliposome (LDFO) formulation containing a high concentration of the iron chelator desferroxamine (DFO). We will test the hypothesis that the subcutaneous (SC) administration of the novel LDFO results in a therapeutic DFO concentration in the liver and spleen and a sustained level of DFO in the blood. Three specific aims will be completed: In aim 1, we will optimize the Liposomal-DFO formulation. In aim 2, we will establish the Storage Stability of the Liposomal DFO Formulations. In aim 3 we will determine the liposomal DFO pharmacokinetics and biodistribution profile when administered by I.V. and subcutaneous routes. This targeted delivery of DFO to the main iron storage sites in the body will more effectively remove iron from deep tissue sites than infusion of non-encapsulated DFO, will infuse 1/8th of the currently used DFO dose in 1/40th of the current infusion time. The formulation will be easier and safer to administer than Desferal(R). If LDFO is validated, it would be a significant advance for the clinical treatment of transfusional iron overload in pediatric patients.