LipoGels for Chelation of Transfusional Iron-Overload

说明(申请人提供)：体内铁平衡只能通过平衡膳食铁，将其与蛋白质螯合，或储存在可再生器官(骨髓、脾和肝脏)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排出，以消除体内多余的铁。这一提议的意义可能会对依赖螯合疗法来缓解金属超负荷症状的各种疾病具有广泛的意义，因为小分子金属螯合剂传统上在体内停留时间较短，且不具有特异性的器官靶向。在这项建议中，我们将专门研究用于螯合输血铁负荷的纳米颗粒。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超载，需要新的和改进的技术。为了达到足够的治疗窗口，应该在肾脏清除和药代动力学之间取得平衡，这是目前小分子螯合剂目前所缺乏的。纳米技术已经极大地证明了它可以用于改善小分子药物的药代动力学，通过使用靶向配体来提高治疗的有效性和特异性。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”，用于螯合铁。LipoGels可以吸收两种形式的铁，Fe2和Fe3，这是铁螯合疗法的关键。我们创新技术的另一个独特方面是，脂凝胶可以一致地制造和定制，以满足所需的体内行为。优点包括循环时间长，剂量低，并根据需要通过配基靶向器官，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，具有推动螯合治疗领域向前发展的潜力。本建议的目的是1)系统地制备和表征体内铁的螯合作用的脂凝胶，2)研究体外的铁络合机制，以及脂凝胶的最大耐受量、体内药动学和生物相容性/安全性，以及3)在铁超载的大鼠模型上测试优化的脂凝胶的铁络合效果。

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.