Image-guided doxorubicin delivery for pediatric sarcomas

图像引导阿霉素递送治疗儿童肉瘤

• 批准号: 9107831
• 负责人: Rajiv Chopra
• 金额: $ 55.53万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-08 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107831
• 关键词: Address; Adverse effects; Anatomy; Area; Bone Tissue; Cardiotoxicity; Child; Clinical; Clinical Trials; Computer software; Development; Disease Management; Dose; Dose-Limiting; Doxorubicin; Drug Delivery Systems; Drug usage; Excision; Family suidae; Focused Ultrasound Therapy; Goals; Grant; Growth; Health; Healthcare; Heart; Heating; High Dose Chemotherapy; Human; Hyperthermia; Image; International; Investigation; Ionizing radiation; Lead; Liposomes; Location; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Manufacturer Name; Methods; Modeling; Monitor; Myocardial dysfunction; Myocardium; Normal tissue morphology; Oncologist; Operative Surgical Procedures; Organ; Pathologist; Patients; Pediatric Neoplasm; Pediatric Oncologist; Pediatric Oncology; Pediatric Radiologist; Pharmaceutical Preparations; Pharmacologic Substance; Prior Chemotherapy; Radiation therapy; Research; Research Project Grants; Rodent; Rodent Model; Safety; Scientist; Series; Site; Soft tissue sarcoma; System; Technology; Temperature; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Translations; Tumor Volume; bone; chemotherapy; childhood sarcoma; clinically relevant; hyperthermia treatment; image guided; improved; industry partner; innovation; innovative technologies; local drug delivery; new technology; novel; pre-clinical; preclinical study; radiologist; research study; sarcoma; soft tissue; systemic toxicity; tumor; tumor growth

 DESCRIPTION (provided by applicant): This project is focused on improving the treatment of pediatric sarcoma, a malignant neoplasm that arises in soft tissue and bone, comprising approximately 15% of all childhood cancers. These tumors are usually treated with multi-agent chemotherapy prior to surgical resection, and doxorubicin (DOX) is among the most commonly used agents. The cumulative dose limiting toxicity of DOX is irreversible damage to the heart muscle, which is a particular concern in children. Recently, thermosensitive liposomes (TSLs) containing DOX have been developed for directing the drug to a particular site in the body. When the liposomes pass through a heated region of tissue they release DOX very rapidly resulting in a local delivery of the drug. In parallel, a technology has been developed to precisel heat a region of tissue within the body using magnetic resonance imaging-guided high-intensity focused ultrasound therapy (referred to as MR-HIFU). MR-HIFU is well-suited for children because it is non-invasive and does not utilize ionizing radiation. Our hypothesis is that mild heating produced with MR-HIFU can be delivered safely in bone and soft tissue, and when combined with thermosensitive liposomes containing DOX will improve the therapeutic index of DOX. The project is divided into four aims that will evaluate important clinical issues including toxicity, safety, and local tumor control. In Aim 1, image-guided drug delivery will be performed using a clinical MR-HIFU system, and the influence of heating duration on the therapeutic index of DOX will be evaluated. In Aim 2 the reduction in DOX concentration achieved within the heart and other vital organs using this image-guided drug delivery method will be quantified. In Aim 3 a tumor growth delay experiment will be performed in a rodent model of a human pediatric sarcoma to evaluate the local control using MR-HIFU and TSLs. Finally, in Aim 4, the capability to safely heat bone and soft tissue targets using a clinical MR-HIFU system will be evaluated. A comprehensive multi-disciplinary team has been assembled to execute this research project comprised of experts in MR-HIFU, pediatric oncologists and radiologists, pharmaceutical scientists, imaging physicists, veterinary pathologists, and biostatisticians. Further, a research partnership has been formed with Philips Healthcare, a manufacturer of MR-HIFU systems, and Celsion Corporation, the manufacturer of Thermodox(r). The research team will have access to the software, hardware, and drugs necessary for delivering hyperthermia and TSLs. This innovative technology should enable the safe delivery of high-dose chemotherapy to pediatric sarcomas prior to surgical or radiation therapy, representing a significant advance in the management of this disease. If successful, this project will lead to the development of a "first in kids" clinical trial of MR-HIFU targeted doxorubicin delivery for pediatric sarcomas.

 描述（由适用提供）：该项目的重点是改善小儿肉瘤的治疗，这是一种恶性肿瘤，在软组织和骨骼中产生，完成了所有儿童癌症的约15％。这些肿瘤通常在手术切除前用多药化疗治疗，阿霉素（DOX）是最常用的药物之一。 DOX的累积剂量限制毒性是对心肌的不可逆转的损害，这在儿童中特别关注。最近，已经开发了含有DOX的热敏脂质体（TSL），以将药物引导到体内的特定部位。当脂质体穿过加热的组织区域时，它们会非常迅速地释放DOX，从而导致该药物的局部输送。同时，已经开发了一项技术，可以使用磁共振成像引导的高强度聚焦超声疗法（称为MR-HIFU）进行精确加热体内组织区域。 Hifu MR非常适合儿童，因为它是无创的，并且不利用电离辐射。我们的假设是，用MR-HIFU产生的轻度加热可以在骨和软组织中安全地递送，并且与含有DOX的热敏脂质体结合使用时，将改善DOX的治疗指数。该项目分为四个目标，可以评估重要的临床问题，包括毒性，安全性和局部肿瘤控制。在AIM 1中，将使用临床MR-HIFU系统进行图像引导的药物输送，并评估加热持续时间对DOX治疗指数的影响。在AIM 2中，将量化使用此图像引导的药物输送方法在心脏和其他重要器官内实现的DOX浓度的降低。在AIM 3中，将在人类小儿肉瘤的啮齿动物模型中进行肿瘤生长延迟实验，以使用MR-HIFU和TSL评估局部控制。最后，在AIM 4中，将评估使用临床MR-HIFU系统安全加热骨骼和软组织目标的能力。一支综合的多学科团队已经组装，以执行这项研究项目，该研究项目完成了Hifu，儿科肿瘤学家和放射科学家，制药科学家，成像物理学家，兽医病理学家和生物统计学家的专家。此外，已经与热门毒品（R）制造商Celsion Corporation（R）制造商Philips Healthcare建立了研究合作伙伴关系。研究团队将可以访问提供高温和TSL所需的软件，硬件和药物。这种创新的技术应在手术或放射疗法之前安全地将高剂量化学疗法的安全递送到小儿肉瘤中，这代表了该疾病的管理方面的重大进展。如果成功，该项目将导致“首先 儿童” MR-HIFU的临床试验针对小儿肉瘤的阿霉素递送。