PET nanoreporter image-guided breast cancer therapy

PET 纳米报告仪图像引导乳腺癌治疗

• 批准号: 10170301
• 负责人: Zahi A. Fayad
• 金额: $ 72.41万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170301
• 关键词: 4T1; Affect; Award; BT 474; Biological Markers; Breast Cancer Model; Breast Cancer therapy; Cancer Model; Cancerous; Cells; Chemicals; Clinical; Collaborations; Companions; Complement; Data; Daunorubicin; Developed Countries; Development; Disease; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Delivery Systems; Drug Formulations; ERBB2 gene; Evaluation; FDA approved; Formulation; Glycolates; Growth; Heterogeneity; Human; Image; Imaging Techniques; Incidence; Individual; Lesion; Liposomes; Malignant Neoplasms; Measurement; Measures; Memorial Sloan-Kettering Cancer Center; Modification; Monitor; Mus; Nature; Newly Diagnosed; Oral; Patient Care; Patient-derived xenograft models of breast cancer; Patients; Penetration; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Polymers; Positron-Emission Tomography; Prediction of Response to Therapy; Predictive Value; Publishing; Radiochemistry; Regional Disease; Science; Specimen; Techniques; Technology; Testing; Therapeutic; Therapeutic Studies; Treatment Efficacy; Treatment Protocols; United States; Validation; Woman; anti-cancer; anti-cancer therapeutic; base; chemotherapy; clinical translation; clinically relevant; controlled release; dosage; effective therapy; experimental study; image guided; imaging approach; imaging modality; improved; inclusion criteria; innovation; malignant breast neoplasm; mortality; mouse model; nanoemulsion; nanoformulation; nanoliposome; nanomedicine; nanoparticle; nanoparticle drug; nanoparticulate; nanotherapeutic; nanotherapy; non-invasive imaging; non-invasive monitor; outcome prediction; personalized medicine; prospective; response; side effect; success; tool; treatment response; triple-negative invasive breast carcinoma; tumor

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.

总结 在西方和工业化国家，乳腺癌影响了大约12%的女性， 仅在美国，每年就有23万例新诊断病例。虽然 这些妇女中的大多数已经治愈，但每年仍有4万人死亡， 这强烈地促进了更有效治疗选择的发展。的广泛列表 口服、全身或局部给药的化疗药物， 可用于治疗乳腺癌。不幸的是，一些中期和长期的副作用是 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 癌性病变这可以通过纳米颗粒来实现，纳米颗粒是可以装载 被称为纳米药物的药物。阿霉素的脂质体制剂Doxil是第一种纳米颗粒药物 拟批准用于临床的制剂。自1995年引入以来，纳米医学领域已经 经历了非凡的增长。非侵入性评估纳米医学肿瘤靶向的能力将 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应用程序，这将建立在一个正在进行的合作穆德的纳米医学 西奈山的放射化学小组和纪念斯隆凯特琳癌症中心的雷纳放射化学小组，我们 提出可应用于临床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治疗剂。 基于强有力的初步数据，在本申请中，我们提出1）进一步推进我们的纳米报告物 技术用于临床相关设置，2）使用它来监测肿瘤渗透增强疗法，以及3） 将nanoreporter概念推广到新的化疗纳米药物。我们的核心假设是， 我们的PET纳米报告技术允许在小鼠癌症模型中预测结果， 各种临床相关的抗癌纳米药物。通过广泛的验证成像实验 和成像引导的治疗研究，我们将在不同的乳腺癌小鼠模型中测试我们的假设。 和不同的疾病背景。我们还将补充非侵入性成像数据与流式细胞仪 不同纳米制剂的细胞靶向分析。成功完成拟议的科学将 为nanoreporter技术在获奖后的临床转化提供有价值的信息。