PET nanoreporter image-guided breast cancer therapy

摘要 在西方和工业化国家，乳腺癌影响了大约12%的女性，导致 仅在美国每年新诊断的病例总数就有23万例。尽管 这些妇女中的大多数已经治愈了这种疾病，每年仍有相当大的死亡率为4万， 这有力地推动了更有效的治疗选择的发展。一份详尽的清单 药理活性药物，称为化疗，无论是口服、全身或局部给药，都是 可用于治疗乳腺癌。不幸的是，一些中长期副作用是 与全身化疗有关。 克服化疗严重副作用的一种方法是通过更有效地将药物输送到 癌变的病变。这可以通过纳米颗粒来实现，这种微小的运载工具可以装载 药物，被称为纳米药物。阿霉素的脂质体制剂多西西是第一个纳米药物 将被批准用于临床的配方。自1995年引入以来，纳米医学领域已经 经历了非凡的增长。非侵入性评估纳米药物肿瘤靶向的能力将 通过允许快速调整剂量和/或治疗方案，极大地改善了患者护理。 在这个多PI应用中，它将建立在穆德的纳米医学之间正在进行的合作 西奈山的小组和纪念斯隆·凯特琳癌症中心的莱纳放射化学小组，我们 提出可应用于临床分级的正电子发射断层扫描(PET)纳米报告技术 不需要化学修饰的纳米疗法。 基于强大的初步数据，在本申请中，我们建议1)进一步推进我们的纳米报告 用于临床相关环境的技术，2)使用它来监测肿瘤穿透增强疗法，以及3) 将纳米报告器的概念推广到新的化疗纳米药物。我们的中心假设是 我们的PET纳米报告器技术可以在小鼠癌症模型中预测结果，并可以适应 多种临床相关的抗癌纳米药物。通过广泛的验证成像实验 和影像引导的治疗研究，我们将在不同的乳腺癌小鼠模型上测试我们的假设 以及不同的疾病背景。我们还将用流式细胞术补充非侵入性成像数据 不同纳米制剂的细胞靶向分析。成功完成拟议的科学研究将 为纳米报告技术在获奖后阶段的临床翻译提供有价值的信息。

SUMMARY Breast cancer affects approximately 12% of all women in western and industrialized nations, resulting in a total number of 230,000 newly diagnosed cases each year in the United States alone. Although the majority of these women is cured of the disease, there still is a considerable annual mortality rate of 40,000, which strongly motivates the development of more effective treatment options. An extensive list of pharmacologically active drugs, known as chemotherapy, either given orally, systemically or locally, is available to treat breast cancer. Unfortunately, a number of intermediate- and long-term side effects are associated with systemic chemotherapy. A way to overcome chemotherapy's severe side effects is through more efficient delivery of the drug to cancerous lesions. This can be accomplished by nanoparticles, tiny carrier vehicles that can be loaded with drugs, known as nanomedicines. Doxil, a liposomal formulation of doxorubicin, was the first nanoparticle drug formulation to be approved for clinical use. Since its introduction in 1995, the nanomedicine field has undergone exceptional growth. The ability to non-invasively evaluate nanomedicine tumor targeting would greatly improve patient care by allowing swift adjustments in dosage and/or treatment regimen. In this multi-PI application, which will build on an ongoing collaboration between Mulder's nanomedicine group at Mount Sinai and Reiner's radiochemistry group at Memorial Sloan Kettering Cancer Center, we propose positron emission tomography (PET) nanoreporter technology that can be applied for clinical grade nanotherapeutics without the need for their chemical modification. Based on strong preliminary data, in this application we propose to 1) further advance our nanoreporter technology to clinically relevant settings, 2) use it to monitor tumor penetration enhancing therapies, and 3) generalize the nanoreporter concept to new chemotherapy nanomedicines. Our central hypothesis is that our PET nanoreporter technology allows outcome prediction in mouse models of cancer and can be adapted to a variety of clinically relevant anti-cancer nanomedicines. Through extensive validation imaging experiments and imaging guided therapeutic studies we will test our hypothesis in different mouse models of breast cancer and different disease contexts. We will also complement the non-invasive imaging data with flow cytometric cell targeting analysis for the different nanoformulations. Successful completion of the proposed science will provide valuable information for clinical translation of the nanoreporter technology in the post-award period.