LipoGels for Chelation of Transfusional Iron-Overload

描述（由申请人提供）：体内铁稳态只能通过膳食铁的平衡，将其螯合到蛋白质，或通过将其储存在RES器官（骨髓，脾脏和肝脏）来调节。出于这个原因，螯合剂（无论是静脉注射还是口服）必须依靠肾脏清除和粪便清除来清除体内多余的铁。这一建议的意义可能是广泛的，因为小分子金属螯合剂传统上在体内停留时间短，并且非特异性器官靶向，对于依赖螯合治疗来缓解金属超载症状的各种疾病。在这个建议中，我们将专门研究纳米颗粒螯合输铁过载。令人惊讶的是，只有三种fda批准的小分子螯合剂可用于治疗铁超载，这需要新的和改进的技术。为了获得足够的治疗窗口期，应该在肾清除率和药代动力学之间取得平衡，这是目前小分子螯合剂所缺乏的。纳米技术已经戏剧性地证明，它可以用来改善小分子药物的药代动力学，通过使用靶向配体提高治疗的疗效和特异性。据我们所知，我们是第一个研究新型纳米颗粒设计的实验室，我们称之为“脂凝胶”，用于铁螯合。脂凝胶可以吸收两种形式的铁，Fe2+和Fe3+，这对铁螯合治疗至关重要。我们的创新技术的另一个独特的方面是，脂凝胶可以一致地制造和定制所需的体内行为。优点包括循环时间长，剂量低，通过配体靶向所需的器官，同时试图平衡肾脏和粪便中铁结合降解产物的消除。我们相信这是一个令人兴奋的项目，有潜力推动螯合治疗领域向前发展。本研究的目的是：1)系统制备体内铁螯合脂凝胶并对其进行表征；2)研究体外铁螯合机制、最大耐受剂量、体内药代动力学和生物相容性/安全性；3)在铁超载大鼠模型上测试优化后的脂凝胶的铁螯合效果。

DESCRIPTION (provided by applicant): Body iron homeostasis can only be regulated through balance of dietary iron, chelating it to proteins, or by storing it in RES organs (bone marrow, spleen, and liver). For this reason, chelators (whether i.v. or oral) must rely on renal clearance and fecal elimination to remove excess iron from the body. The significance of this proposal could be wide-ranging for a variety of diseases that relies on chelation therapy to alleviate symptoms of metal overload, since small molecule metal chelators have traditionally suffered from a short residence time in the body and unspecific organ targeting. In this proposal, we will specifically investigate nanoparticles for chelation of transfusional iron overload. Surprisingly, there are only three FDA-approved small molecule chelators available for treating iron overload and there is a need for new and improved technology. In order to achieve a sufficient window of therapy, a balance between renal clearance and pharmacokinetics should be achieved, which current small molecule chelators currently lack. Nanotechnology has already dramatically demonstrated that it can be used to improve the pharmacokinetics of small molecule drugs, with enhanced efficacy and specificity of therapies through the use of targeting ligands. We are the first lab, to the best of our knowledge, to investigate novel designs of nanoparticles we call "lipoGels" for chelation of iron. LipoGels can pick up both forms of iron, Fe2+ and Fe3+, which is critical for iron chelation therapy. Another unique aspect of our innovative technology is that lipoGels can be consistently fabricated and tailored to desired in vivo behavior. Advantages include prolonged circulation, lower doses, and targeting via ligands to organs as desired, while attempting to balance renal and fecal elimination of iron-bound degradation products. We believe that this is an exciting project with potential to push the field of chelation therapy forward. The aims in this proposal are to 1) systematically prepare and characterize lipoGels for in vivo chelation of iron, 2) investigate the mechanism of iron chelation in vitro, and maximum tolerated dose, pharmacokinetics, and biocompatibility/safety of lipoGels in vivo, and 3) test the iron chelation efficacy of optimized lipoGels in rat models of iron overload.