Development of Novel Activatable Theranostic Nanoparticles for combined Cancer MR

开发用于联合癌症 MR 的新型可激活治疗诊断纳米颗粒

基本信息

批准号：
8636819
负责人：
Heike Elizabeth Daldrup-Link
金额：
$ 20.95万
依托单位：
STANFORD UNIVERSITY
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：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8636819
关键词：
Address Adverse effects Antineoplastic Agents Biological Markers Biosensor Blood Vessels Chemotherapy-Oncologic Procedure Cleaved cell Development Diagnostic Dose Dose-Limiting Drug Delivery Systems Drug Monitoring Endothelial Cells Endothelium Enzymes Evaluation Extravasation FDA approved Family Goals Hair High Prevalence Human Image In Vitro Investigation Lead Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Matrix Metalloproteinases Mediating Membrane Mission Monitor Mouse Mammary Tumor Virus National Cancer Institute National Institute of Biomedical Imaging and Bioengineering Nature Nausea Neoplasms in Vascular Tissue Normal tissue morphology Organ Outcome Peptide Hydrolases Peptides Permeability Pharmaceutical Preparations Pharmacodynamics Play Positioning Attribute Prevalence Prodrugs Radiation Regimen Research Role Signal Transduction Site Specificity Starvation System Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Index Time Tissues Toxic effect Transgenic Organisms Translating Treatment Efficacy Tumor Tissue Vascular Permeabilities Visceral Weight base bioimaging biomaterial compatibility cancer cell cancer therapy cancer type cell behavior clinical application clinical decision-making cytotoxic design disability improved in vivo iron oxide killings malignant breast neoplasm mouse model nanocarrier nanoparticle nanoscale neoplastic cell non-invasive monitor novel novel strategies outcome forecast overexpression public health relevance research and development response theranostics therapeutic target tool tumor tumor eradication tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): This study is in response to the mission of the National Institute of Biomedical Imaging and Bioengineering ("Research and development of nano-scale technologies for biomedical imaging") and the National Cancer Institute ("cancer theranostics with improved targeting, biocompatibility and imaging contrast capability"). A major issue with current cancer therapy is the prevalence of undesired dose-limiting activity upon non-cancerous tissues and organs. This is further compounded by limited ability in monitoring drug delivery, pharmacodynamics and therapeutic response in vivo. To address the urgent need for novel approaches to selectively targeting therapeutics to tumor, we propose to develop and test new, activatable, "theranostic" (combined therapeutic and diagnostic) nanoparticles that release the potent therapeutic drug azademethylcolchicine after cleavage by specific tumor enzymes (matrix metalloproteinases, MMP-14), thereby leading to selective toxic effects in MMP-14 expressing tumors, but not visceral organs. In addition, the iron oxide core of the nanoparticles can be detected with MR imaging, thereby enabling in vivo drug tracking. Thus, the major goal of our project is to develop novel tumor-enzyme activatable theranostic nanoparticles (TNPs), which exert selective toxic effects in MMP-14 expressing tumors, but not normal organs, and which enable real-time monitoring of drug accumulation and localization at tumors with Magnetic Resonance (MR) imaging. Realizing this goal will lead to substantially improved efficacy of cancer therapies, and allow guiding personalized therapy regimens via direct in vivo drug tracking and therapeutic response monitoring with MR imaging. The approach relies on the high prevalence of MMP-14 in a large variety of breast cancers and other cancers, a proven MMP-14 activatable prodrug strategy, and a nanocarrier platform based on FDA-approved superparamagnetic iron oxide nanoparticles. We hypothesize that our TNPs will be converted from a non-toxic to an active therapeutic agent within MMP-14 expressing tumors, releasing the potent therapeutic drug azademethylcolchicine, and inducing a significant antitumor effect, whilst avoiding toxic side effects to normal tissues. In addition, we postulate that the iron oxide nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with MR imaging. If successful, the proposed novel, multifunctional TNPs hold the potential to substantially improving therapeutic efficacy and monitoring whilst simultaneously reducing dose-limiting toxicities, thereby increasing the therapeutic index. Our investigations could be in principle readily translated to clinical applications, may directly impact clinical decision-making, and ultimately, help to improve and tailor individualized therapeutic options. The proposed concept would have broad applications and could be extended to a variety of other cancer types.

描述（由申请人提供）：这项研究是对国家生物医学成像和生物工程研究所的使命（“生物医学成像的纳米级技术的研究与开发”）和国家癌症研究所（“具有改善靶向，生物相容性和成像相比能力的癌症疗法学”）。当前癌症治疗的一个主要问题是对非癌组织和器官的不良剂量限制活性的普遍性。在体内监测药物输送，药效学和治疗反应方面的能力有限的能力进一步使这更加复杂。 To address the urgent need for novel approaches to selectively targeting therapeutics to tumor, we propose to develop and test new, activatable, "theranostic" (combined therapeutic and diagnostic) nanoparticles that release the potent therapeutic drug azademethylcolchicine after cleavage by specific tumor enzymes (matrix metalloproteinases, MMP-14), thereby leading to selective toxic在表达肿瘤的MMP-14中的作用，但没有内脏器官。另外，可以通过MR成像检测到纳米颗粒的氧化铁核心，从而实现体内药物跟踪。因此，我们项目的主要目的是开发新型的肿瘤 - 酶活性溶剂含量纳米颗粒（TNP），在MMP-14表达肿瘤的MMP-14中发挥选择性毒性作用，而不是正常的器官，并且可以实时监测具有磁共振（MR）成像的肿瘤药物在肿瘤中的药物积累和定位。意识到这一目标将导致癌症疗法的疗效，并通过直接的体内药物跟踪和MR成像监测治疗反应监测来指导个性化治疗方案。该方法依赖于多种乳腺癌和其他癌症的MMP-14的高流行率，一种经过验证的MMP-14可激活前药策略，以及基于FDA批准的超帕磁铁氧化铁氧化铁纳米颗粒的纳米载体平台。我们假设我们的TNP将从无毒的MMP-14表达肿瘤中的活性治疗剂转化为活性治疗剂，释放出有效的治疗药物阿扎迪甲基甲基甲基甲基氨基氨酸，并诱导显着的抗肿瘤作用，同时避免对正常组织的有毒副作用。此外，我们假设氧化铁纳米颗粒部分将允许用MR成像对药物积累和定位进行实时监测。如果成功，则提出的新型多功能TNP具有实质上提高治疗功效和监测的潜力，同时减少剂量限制毒性，从而增加治疗指数。我们的调查原则上可以很容易地转化为临床应用，可能会直接影响临床决策，并最终有助于改善和量身定制个性化的治疗选择。拟议的概念将具有广泛的应用，可以扩展到其他各种癌症类型。