Nanoscale Metal-organic Frameworks for Light Triggered and X-ray Induced Photodynamic Therapy of Head and Neck Cancers

 描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是全球第六大最常见的癌症。放化疗是临床上治疗HNSCC最常用的治疗方法，但会产生许多不良反应，并会产生耐药性。光动力疗法(PDT)是一种有效的抗癌治疗方法，但由于治疗前后患者对光的极端敏感性、次佳的活性氧生成效率以及浅层组织对光(1 Cm)的穿透，其临床应用受到限制。纳米粒子光敏剂(PSS)可以选择性地在肿瘤中蓄积，从而缓解光敏问题。近红外触发光动力疗法和X射线诱导光动力疗法(X-PDT)结合了近红外和X射线改善组织穿透深度的优点和光动力疗法治疗深部肿瘤的优点。在此，我们建议开发一种全新的基于纳米级金属有机骨架(NMOF)的纳米PSS，它具有化学成分可调、晶体结构、极高的孔隙率、短期稳定性和长期生物可降解性等理想特性，使近红外触发的光动力疗法适用于浅表肿瘤，X-光动力疗法适用于深层肿瘤。该项目解决了在开发高效和安全的纳米PSS方面尚未得到满足的需求，该PSS可以通过近红外触发的光动力疗法或X-光动力疗法在癌症的临床应用中得到更广泛的应用。我们提出了以下目标：目标1：用于近红外触发和X-PDT的NMOF的合成和表征。我们将优化NMOF的结构、颗粒尺寸和表面特性，以更高的效率实现近红外触发的PDT和X-PDT。还将努力扩大NMOF的合成和表面功能化，以实现更长的血液循环时间。目的2：评价近红外触发光动力疗法治疗鼻咽癌的疗效。我们将在体外评估NMOF对多种HNSCC细胞株的NIR-PDT效应。我们将在细胞水平上研究一种最有效的NMOF对HNSCC皮下移植和原位小鼠模型的毒性和有效性。目的3：评价X射线诱导光动力疗法治疗人非小细胞肺癌的疗效。我们将在体外研究NMOF对HNSCC细胞的X-PDT效应。对于体内研究，我们将首先评估NMOF和X-PDT单独治疗的毒性。体内的抗癌效果将在皮下和原位HNSCC小鼠模型上进行，其中两种最有效的NMOF是在细胞水平上确定的。我们还将应用最先进的小动物图像引导X射线传输技术，使图像引导X-PDT能够转化为临床放射治疗

 DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Clinically used combination of radiation therapy and chemotherapy is the most common curative treatments for HNSCC, but causes many undesirable side effects and will incur resistance. Photodynamic therapy (PDT) is an effective anticancer procedure but its clinical application is limited due to the extreme light sensitivity o patients before and after treatment, the suboptimal reactive oxygen species generation efficiency, and the shallow tissue penetration of light (< 1 cm). Nanoparticle photosensitizers (PSs) can selectively accumulate in tumors and thus alleviate the light sensitivity issue. NIR triggered PDT and X-ray induced PDT (X-PDT) have the ability to combine the strengths of the improved tissue penetration depth of NIR and X-ray and the advantages of PDT for deep tumor treatment. We herein propose to develop an entirely new class of nanoparticle PSs based on nanoscale metal-organic frameworks (NMOFs) that have the ideal characteristics of tunable chemical compositions, crystalline structures, extremely high porosity, short-term stability, and long-term bio- degradability to enable NIR triggered PDT for superficial tumors and X-PDT for deep tumors. This project addresses the unmet needs in developing highly efficient and safe nanoparticle PSs that can have much broader clinical applications for cancer by NIR-triggered PDT or X-PDT. We propose the following aims: AIM 1: Synthesis and characterization of NMOFs for NIR triggered and X-PDT. We will optimize NMOF structures, particle sizes, and surface characteristics to achieve NIR-triggered PDT and X-PDT with improved efficiency. Efforts will also be made for scaled-up NMOF synthesis and surface functionalization to achieve long blood circulation times. AIM 2: Evaluation of NIR triggered PDT efficacy for HNSCC. The NIR-PDT efficacy of NMOFs will be evaluated against multiple HNSCC cell lines in vitro. We will investigate the in vivo toxicity and efficacy of one most potent NMOF identified at cellular level against HNSCC subcutaneous xenograft and orthotopic mouse models. AIM 3: Evaluation of X-ray induced PDT efficacy for HNSCC. The X-PDT efficacy of NMOFs will be investigated against HNSCC cells in vitro. For the in vivo studies, we will first evaluate the toxicity of the NMOFs and the X-PDT treatment alone. The in vivo anticancer efficacy will be carried out on both subcutaneous and orthotopic HNSCC mouse models with the two most potent NMOFs identified at cellular level. We will also apply state-of-the-art small-animal image-guided X-Ray delivery technology to enable image-guided X-PDT, toward translation to clinical radiotherapy