LipoGels for Chelation of Transfusional Iron-Overload

描述（由申请人提供）：身体铁稳态只能通过平衡膳食铁，将其螯合到蛋白质中或通过将其储存在RES器官（骨髓，脾脏和肝脏）中来调节。出于这个原因，螯合剂（无论是静脉注射或口服）必须依靠肾脏清除和粪便消除，以消除体内多余的铁。该提议的意义对于依赖螯合疗法来缓解金属过载症状的各种疾病可能是广泛的，因为小分子金属螯合剂传统上在体内的停留时间短且靶向器官不特异。在这个提议中，我们将专门研究用于螯合输血铁过载的纳米颗粒。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过载，并且需要新的和改进的技术。为了实现足够的治疗窗口，应实现肾清除率和药代动力学之间的平衡，这是目前小分子螯合剂目前缺乏的。纳米技术已经戏剧性地证明，它可以用于改善小分子药物的药代动力学，通过使用靶向配体增强治疗的功效和特异性。我们是第一个实验室，据我们所知，研究纳米粒子的新设计，我们称之为“脂质凝胶”，用于螯合铁。LipoGels可以吸收两种形式的铁，Fe 2+和Fe 3+，这对铁螯合治疗至关重要。我们的创新技术的另一个独特方面是，lipoGels可以始终如一地制造和定制所需的体内行为。优点包括延长循环、较低剂量和根据需要通过配体靶向器官，同时试图平衡铁结合降解产物的肾脏和粪便消除。我们相信这是一个令人兴奋的项目，有可能推动螯合治疗领域的发展。 本提案的目的是1）系统地制备和表征用于体内铁螯合的lipoGels，2）研究体外铁螯合的机制，以及lipoGels体内的最大耐受剂量、药代动力学和生物相容性/安全性，3）在铁过载的大鼠模型中测试优化的lipoGels的铁螯合功效。

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.