Development of Novel Activatable Theranostic Nanoparticles for combined Cancer MR

描述(申请人提供)：本研究是为了响应国家生物医学成像和生物工程研究所(“生物医学成像纳米级技术的研究和开发”)和国家癌症研究所(“具有更好的靶向性、生物兼容性和成像对比度能力的癌症治疗”)的使命。当前癌症治疗的一个主要问题是在非癌症组织和器官上普遍存在不受欢迎的剂量限制活动。在体内监测药物输送、药效学和治疗反应的能力有限，进一步加剧了这一点。为了解决对选择性靶向治疗肿瘤的新方法的迫切需求，我们建议开发和测试新的、可激活的、(联合治疗和诊断)纳米颗粒，该纳米颗粒在被特定的肿瘤酶(基质金属蛋白酶，MMP-14)切割后释放有效的治疗药物氮甲基秋水仙碱，从而导致对表达MMP-14的肿瘤(但不是内脏器官)产生选择性毒性作用。此外，纳米粒子的氧化铁核心可以通过磁共振成像进行检测，从而实现体内药物跟踪。因此，我们项目的主要目标是开发新型的肿瘤酶可激活的治疗纳米粒(TNPs)，它可以在表达MMP-14的肿瘤中发挥选择性毒性作用，而不是正常器官，并能够通过磁共振成像实时监测药物在肿瘤中的累积和定位。实现这一目标将大大提高癌症治疗的效率，并通过直接体内药物跟踪和磁共振成像监测治疗反应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中基质金属蛋白酶-14的高流行率，经过验证的基质金属蛋白酶-14可激活前药策略，以及基于FDA批准的超顺磁性氧化铁纳米颗粒的纳米载体平台。我们假设我们的TNPs将在表达肿瘤的基质金属蛋白酶-14中从无毒转化为活性治疗剂，释放出有效的治疗药物氮甲基秋水仙碱，并诱导显著的抗肿瘤作用，同时避免对正常组织的毒副作用。此外，我们假设氧化铁 纳米颗粒部分将允许通过磁共振成像实时监测药物在肿瘤中的积聚和定位。如果成功，所提出的新型多功能TNPs有可能显著提高治疗效果和监测，同时减少剂量限制毒性，从而提高治疗指数。原则上，我们的研究可以很容易地转化为临床应用，可能直接影响临床决策，最终有助于改进和定制个性化的治疗方案。拟议的概念将有广泛的应用，并可能扩展到各种其他类型的癌症。

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.