Development of Novel Activatable Theranostic Nanoparticles for combined Cancer MR

描述（由申请人提供）：本研究是对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（“具有改进的靶向、生物相容性和成像对比能力的癌症治疗诊断学”）的使命的响应。当前癌症治疗的主要问题是对非癌组织和器官的不期望的剂量限制活性的普遍存在。体内监测药物递送、药效学和治疗反应的能力有限进一步加剧了这一问题。为了解决对选择性靶向治疗肿瘤的新方法的迫切需求，我们提出开发和测试新的可活化的“治疗诊断”（组合治疗和诊断）纳米颗粒，其在被特定肿瘤酶（基质金属蛋白酶，MMP-14）裂解后释放有效的治疗药物azademethylcolchicine，从而导致MMP-14表达肿瘤中的选择性毒性作用，而不是内脏器官。此外，纳米颗粒的氧化铁核可以用MR成像检测，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肿瘤酶可激活的治疗诊断纳米颗粒（TNP），其在表达MMP-14的肿瘤中而不是正常器官中发挥选择性毒性作用，并且能够利用磁共振（MR）成像实时监测肿瘤中的药物积累和定位。实现这一目标将大大提高癌症治疗的疗效，并允许通过直接体内药物跟踪和MR成像的治疗反应监测来指导个性化治疗方案。该方法依赖于MMP-14在多种乳腺癌和其他癌症中的高患病率，一种经证实的MMP-14可激活的前药策略，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TNP将在表达MMP-14的肿瘤中从无毒转化为活性治疗剂，释放有效的治疗药物氮杂去甲基秋水仙碱，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用MR成像实时监测药物在肿瘤处的积聚和定位。如果成功的话，所提出的新型多功能TNP具有显著提高治疗效果和监测的潜力，同时减少剂量限制性毒性，从而增加治疗指数。我们的研究原则上可以很容易地转化为临床应用，可能直接影响临床决策，并最终帮助改善和定制个性化的治疗方案。所提出的概念将具有广泛的应用，并可扩展到各种其他癌症类型。

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.