A radiotherapeutic for breast cancer brain metastases

乳腺癌脑转移的放射治疗

基本信息

批准号：
8755494
负责人：
Santosh Kesari
金额：
$ 20.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8755494
关键词：
Address Affect Aluminum Antineoplastic Agents Area Biodistribution Biological Assay Blood - brain barrier anatomy Blood Cell Count Blood Chemical Analysis Blood Circulation Blood Vessels Body Weights and Measures Brain Brain Neoplasms Breast Cancer Cell Bypass Cancer cell line Cardiac Cardiotoxicity Cells Characteristics Charge Chemicals Chronic Clinical Clinical Trials Complex Complication Development Disease Dose Dose-Limiting Doxorubicin Doxorubicin Hydrochloride Liposome Drug Kinetics Feasibility Studies Fostering Funding Funding Mechanisms Goals Half-Life Hand Human Immunocompetent Immunocompromised Host In Vitro Inflammation Inhibitory Concentration 50 Injection of therapeutic agent Label Lead Letters Life Light Link Liposomes Literature Low Dose Radiation Malignant Neoplasms Mammary Neoplasms Measures Metastatic Mass Metastatic malignant neoplasm to brain Mission Modeling Morphology Mus Neoplasm Metastasis Normal tissue morphology Organ Parents Patients Pharmaceutical Preparations Photons Physiological Polyethylene Glycols Pre-Clinical Model Primary Brain Neoplasms Primary Neoplasm Prodrugs Public Health Radiation Radiation therapy Resistance SCID Mice Serum Site Staging Streptavidin Surface System Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Tumor Burden Tumor Cell Line United States National Institutes of Health Validation Work Yttrium base cancer type cell killing design high reward high risk improved in vivo indexing intravenous injection irradiation malignant breast neoplasm nano nanocrystal nanoparticle nanoscale neoplastic cell novel pre-clinical research preclinical study public health relevance resistance mechanism response translational study tumor yttria

项目摘要

DESCRIPTION (provided by applicant): This application is intended to address the significant clinical problem of breast cancer metastasis to the brain via localized activation of high drug doses in these metastases, thereby potentially overcoming their notorious resistance, and minimizing normal tissue toxicity. Our concept is novel and the work is at an early stage, making it suitable for the R21 high risk high reward concept validation funding mechanism. The strategy is to concentrate toxic drug effects at breast cancer brain metastases via selective concentration at the tumor of a nontoxic, inactive complex consisting of a nanoparticle linked to doxorubicin (Dox). Dox in sufficient doses potently suppresses breast tumor cells in culture and in preclinical models, but in free form is constrained by various toxicities throughout the body. A localized, external low dose radiation beam aimed only at the tumor will activate the radiation scintillator crystal part of the nanoparticle, which will emit light to break a photosensitive linkr. Hence Dox attached to the linker will be released only at the tumor site in the active, toxic form. We feel this new strategy is feasible for three reasons (1) breast tumor brain metastases do not infiltrate the brain beyond 1mm past the primary metastatic site and so are potentially controllable, (2) these metastases retain the blood vessel morphology of the parent tumor, which is malformed, porous and leaky, and without a blood brain barrier, and (3) the literature and our own work indicates that intravenous injection of 100-150 nm liposomes bearing Dox can result in sufficient accumulation at brain tumors to exert a marked therapeutic effect. Importantly, because the radiation dose will be low and localized, and with non-toxic prodrug primarily in tumor foci, normal tissues will be relatively spared. The present proposal represents an initial feasibility study as part of a long term initiative for preclinical studies culminating clinical trials. The specific aims to determine feasibility are; (1) assemble, physically characterize, and quantify the radiation response of the nanoscintillator - Dox platform, and (2) determine in vitro potency and in vitro efficacy of nanoparticle prodrug. We envisage our overall strategy as not necessarily a complete cure, but rather, a novel way of addressing the clinically difficult resistance of these brain metastases and as a way to significantly reduce patient tumor burden. Very low doses of radiation are well tolerated and may be used repeatedly over months and years to help control these metastases, an approach which realistically aligns with the idea of reducing cancer to a manageable, chronic condition.

描述（由申请人提供）：此应用旨在通过在这些转移酶中局部激活高药剂量来解决乳腺癌转移对大脑的重大临床问题，从而有可能克服其臭名昭著的耐药性，并最大程度地减少正常的组织毒性。我们的概念是新颖的，这项工作正处于早期阶段，使其适合R21高风险高奖励概念验证资金机制。该策略是通过选择性浓度在乳腺癌脑转移酶的肿瘤中浓缩有毒药物的作用，该肿瘤由与阿霉素（DOX）相关的纳米颗粒组成的无毒，无活性复合物。足够剂量的DOX在培养和临床前模型中有效抑制乳腺肿瘤细胞，但自由形式受到整个体内各种毒性的约束。一个仅针对肿瘤的局部外部低剂量辐射束将激活纳米颗粒的辐射闪烁体晶体部分，该部分将发出光线以打破光敏的链接。因此，连接到接头的DOX将仅在活性的有毒形式的肿瘤部位释放。 We feel this new strategy is feasible for three reasons (1) breast tumor brain metastases do not infiltrate the brain beyond 1mm past the primary metastatic site and so are potentially controllable, (2) these metastases retain the blood vessel morphology of the parent tumor, which is malformed, porous and leaky, and without a blood brain barrier, and (3) the literature and our own work indicates that intravenous injection of 100-150 nm携带DOX的脂质体可导致在脑肿瘤上足够积累，从而发挥明显的治疗作用。重要的是，由于辐射剂量将较低且局部化，并且主要在肿瘤灶中的无毒前药将相对幸免。目前的提议代表最初的可行性研究是临床前研究长期倡议的一部分，最终导致临床试验。确定可行性的具体目的是；（1）组装，物理表征和量化纳米尺度拟合器-DOX平台的辐射响应，（2）确定纳米颗粒前药的体外效力和体外功效。我们将整体策略设想为不一定是一种完整的治疗方法，而是一种解决这些脑转移临床困难抗性的新型方法，也可以显着减轻患者肿瘤负担。非常低剂量的辐射的耐受性良好，可以在几个月和几年的时间内反复使用，以帮助控制这些转移，这种方法实际上与将癌症降低到可控制的慢性疾病的想法相结合。