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

用于 MRI 引导化疗药物输送的自组装铁 (III) 宿主

• 批准号: 10405656
• 负责人: Janet Ruth Morrow
• 金额: $ 22.13万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405656
• 关键词: Affinity; Albumins; Antineoplastic Agents; Binding; Biodistribution; Cancer cell line; Carboplatin; Cells; Charge; Complex; Contrast Media; Data; Development; Dose; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Drug usage; Encapsulated; Goals; Hydrophobic Interactions; Image; Inbred BALB C Mice; Inductively Coupled Plasma Mass Spectrometry; Ions; Iron; Lead; Ligands; Liposomes; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Metals; Methods; Modeling; Modification; Monitor; Mus; Nature; Non-Small-Cell Lung Carcinoma; Organ; Pharmaceutical Preparations; Platinum; Preparation; Prodrugs; Property; Schedule; Series; Serum Albumin; Shapes; Specificity; Tail; Testing; Tissues; Veins; Water; base; cancer therapy; chemotherapeutic agent; cytotoxicity; cytotoxicity test; design; drug action; drug development; image-guided drug delivery; imaging agent; imaging study; improved; improved functioning; in vivo; innovation; insight; nanoparticle; patient derived xenograft model; prevent; scaffold; small molecule; subcutaneous; success; therapy outcome; tumor; tumor growth; tumor xenograft; uptake

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.

摘要 图像引导给药是提高肿瘤摄取和防止肿瘤蓄积的一种很有前途的方法 有毒化疗药物在健康组织中的含量。该成像剂用于提供关于 生物分布和药物输送，以更好地告知治疗。大多数图像引导药物递送的例子都有 脂质体或纳米颗粒作为药物和成像载体。我们的方法包括创新的Fe(III)自我 组装的保持架是有效的T1磁共振造影剂。四个Fe(III)离子紧密地连接在一个 四面体形状，形成坚固的络合物，在水中高度溶解，并具有内部空腔 金属离子络合物的包埋。我们的其中一个铁(III)笼与血清白蛋白结合并在 核磁共振研究显示的小鼠肿瘤模型。这种肿瘤的摄取和积聚表明笼子 将是一种有效的核磁共振引导给药方法。我们的总体目标是为 铂(II)和铂(IV)抗癌药物给药小鼠肿瘤模型的可行性研究 接近。具体目标包括制备不同的Fe(III)笼形衍生物，它们具有不同的总体 与血清白蛋白的电荷亲和力和结合亲和力。这一目标将检验我们的假设，即白蛋白结合是 肿瘤对笼的摄取。铁(III)笼的生物分布和药代动力学清除将在#年进行研究。 健康的小鼠，随后在含有患者来源的异种皮下肿瘤的小鼠中 (PDX)。第二个目标涉及将铂(II)或铂(IV)药物，主要是卡铂衍生物，在 铁(III)笼。铂药物从笼子中的释放将在溶液中进行研究，并将进行测试 为了深入了解铂药物在细胞中的摄取和释放，我们将研究铂药物对癌细胞的细胞毒性。第三 目的研究笼养铂类药物在NSG(NOD SCID-γ)小鼠体内的摄取。 皮下PDX模型。一种对卡铂有反应的鳞状非小细胞肺癌的PDX 被选作研究对象。肿瘤大小将通过三周的剂量计划进行监测，铂和 肿瘤中的铁将通过质谱仪进行测量。Fe(III)笼状载体的铂将与铂 在没有笼子的情况下给药。