Image-guided doxorubicin delivery for pediatric sarcomas

 描述（由申请人提供）：该项目的重点是改善儿科肉瘤的治疗，这是一种发生在软组织和骨骼中的恶性肿瘤，约占所有儿童癌症的15%。这些肿瘤通常在手术切除前用多药化疗治疗，多柔比星（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损伤，这在儿童中是特别关注的。最近，已经开发了含有DOX的热敏脂质体（TSL），用于将药物引导至体内的特定部位。当脂质体通过组织的加热区域时，它们非常迅速地释放DOX，导致药物的局部递送。与此同时，已经开发了一种使用磁共振成像引导的高强度聚焦超声治疗（称为MR-HIFU）来精确加热体内组织区域的技术。MR-HIFU非常适合儿童，因为它是非侵入性的，不利用电离辐射。我们假设MR-HIFU产生的温和加热可以安全地传递到骨和软组织中，并且当与含有DOX的热敏脂质体组合时，将提高DOX的治疗指数。该项目分为四个目标，将评估重要的临床问题，包括毒性，安全性和局部肿瘤控制。在目标1中，将使用临床MR-HIFU系统进行图像引导药物递送，并将评价加热持续时间对DOX治疗指数的影响。在目标2中，将量化使用该图像引导的药物递送方法在心脏和其他重要器官内实现的DOX浓度的降低。在目标3中，将在人类儿科肉瘤的啮齿动物模型中进行肿瘤生长延迟实验，以评价使用MR-HIFU和TSL的局部控制。最后，在目标4中，将评价使用临床MR-HIFU系统安全加热骨和软组织目标的能力。一个综合性的多学科团队已经组建起来，由MR-HIFU专家、儿科肿瘤学家和放射学家、制药科学家、成像物理学家、兽医病理学家和生物统计学家组成。此外，还与MR-HIFU系统制造商Philips Healthcare和Thermodox制造商Celsion Corporation建立了研究伙伴关系。研究小组将获得提供热疗和TSL所需的软件、硬件和药物。这种创新技术应该能够在手术或放射治疗之前安全地向儿科肉瘤提供高剂量化疗，这代表了这种疾病管理的重大进步。如果成功，该项目将导致开发一个“第一个在 儿童的MR-HIFU靶向阿霉素输送治疗儿童肉瘤的临床试验。

 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.