Self-assembled iron(III) hosts for MRI-guided delivery of chemotherapeutics

摘要 图像引导给药是一种很有前途的方法，以提高肿瘤的吸收，并防止积累 有毒化疗药物的毒性。成像剂用于提供关于以下的信息： 生物分布和药物输送，以更好地为治疗提供信息。图像引导的药物递送的大多数示例具有 脂质体或纳米颗粒作为药物和成像载体。我们的方法涉及创新的Fe（III）自- 组装的融合器是有效的T1 MRI造影剂。四个Fe（III）离子紧密连接在一个 四面体形状，以形成坚固的复合物，其高度溶于水，并具有用于 包封金属离子络合物。我们的一个Fe（III）笼与血清白蛋白结合，并在体内积累。 小鼠肿瘤模型，如MRI研究所示。这种肿瘤摄取和积聚表明， 将是MRI引导药物递送的有效试剂。我们的总体目标是开发方法， 将Pt（II）和Pt（IV）抗癌剂递送至鼠肿瘤模型以确定这种方法的可行性。 approach.具体目标包括制备不同的Fe（III）笼衍生物，其具有不同的总体结构， 电荷和对血清白蛋白的结合亲和力。这一目标将检验我们的假设，即白蛋白结合是 笼的肿瘤摄取。Fe（III）笼生物分布和药代动力学清除率将在 健康小鼠和随后在含有来自患者来源的异种移植物的皮下肿瘤的小鼠中 （PDX）。第二个目的涉及将Pt（II）或Pt（IV）药物，主要是卡铂衍生物，包封在 Fe（III）笼。将在溶液中研究Pt药物从笼中的释放，并检测 为了深入了解Pt药物的细胞摄取和释放，在癌细胞系中进行了细胞毒性试验。第三 目的是研究NSG（NOD scid gamma）小鼠对Fe（III）笼中Pt药物的摄取， 皮下PDX模型。来自鳞状非小细胞肺癌的对卡铂有反应的PDX， 选择学习。将通过三周给药方案监测肿瘤大小，并监测Pt和Pt的量 肿瘤中的Fe将通过质谱法测量。将Pt的Fe（III）笼载体与Pt的Fe（III）笼载体进行比较。 给药时未使用笼。

Abstract Image-guided drug delivery is a promising approach to improve tumor uptake and to prevent the accumulation of toxic chemotherapeutic agents in healthy tissue. The imaging agent serves to provide information about biodistribution and drug delivery to better inform treatment. Most examples of image guided drug delivery have liposomes or nanoparticles as drug and imaging carriers. Our approach involves innovative Fe(III) self- assembled cages that are effective T1 MRI contrast agents. The four Fe(III) ions are tightly connected in a tetrahedral shape to form a robust complex that is highly soluble in water and has an interior cavity for encapsulation of metal ion complexes. One of our Fe(III) cages binds to serum albumin and accumulates in murine tumor models as shown by MRI studies. Such tumor uptake and accumulation suggests that the cage will be an effective agent for MRI guided drug delivery. Our overall goals are to develop methods for the delivery of Pt(II) and Pt(IV) anti-cancer agents to murine tumor models to determine the feasibility of this approach. Specific aims include the preparation of different Fe(III) cage derivatives that have varying overall charge and binding affinity to serum albumin. This aim will test our hypothesis that albumin binding is key to tumor uptake of the cages. The Fe(III) cage biodistribution and pharmacokinetic clearance will be studied in healthy mice and, subsequently in mice containing subcutaneous tumors from patient derived xenografts (PDX). The second aim involves the encapsulation of Pt(II) or Pt(IV) drugs, primarily carboplatin derivatives, in the Fe(III) cages. Release of the Pt drugs from the cages will be studied in solution and will be tested for cytotoxicity in cancer cell lines in order to gain insight into cellular uptake and release of the Pt drug. The third aim entails study of the uptake of the Fe(III) caged Pt drugs in NSG (NOD scid gamma) mice with subcutaneous PDX models. A PDX from squamous non-small cell lung cancer that is carboplatin responsive is chosen for study. Tumor size will be monitored with a three-week dosing schedule, and the amount of Pt and Fe in tumors will be measured by mass spectrometry. Fe(III) cage carriers of Pt will be compared to the Pt drug administered without cage.