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

 描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症。放射治疗和化学治疗是临床上治疗HNSCC最常用的方法，但会引起许多不良反应，并会产生耐药性。光动力疗法（PDT）是一种有效的抗癌方法，但由于治疗前后患者的极端光敏感性、次优的活性氧生成效率以及光的浅组织穿透（<1cm），其临床应用受到限制。纳米颗粒光敏剂（PS）可以选择性地在肿瘤中积累，从而缓解光敏感性问题。近红外触发光动力学疗法和X射线诱导光动力学疗法（X-PDT）具有联合收割机的能力，结合了近红外和X射线提高组织穿透深度的优点和PDT用于深部肿瘤治疗的优点。我们在本文中提出开发基于纳米级金属有机框架（NMOFs）的全新类别的纳米颗粒PS，其具有可调化学组成、晶体结构、极高孔隙率、短期稳定性和长期生物降解性的理想特性，以使得NIR触发的PDT能够用于浅表肿瘤和X-PDT能够用于深部肿瘤。该项目解决了开发高效和安全的纳米颗粒PS的未满足的需求，这些纳米颗粒PS可以通过NIR触发的PDT或X-PDT对癌症进行更广泛的临床应用。我们提出了以下目标：目的1：合成和表征NMOFs的近红外触发和X-PDT。我们将优化NMOF结构，颗粒尺寸和表面特性，以实现NIR触发的PDT和X-PDT，提高效率。还将努力扩大NMOF合成和表面功能化，以实现长的血液循环时间。目的2：评价近红外光动力疗法治疗头颈部鳞癌的疗效。将在体外针对多种HNSCC细胞系评价NMOF的NIR-PDT功效。我们将研究在细胞水平上鉴定的一种最有效的NMOF对HNSCC皮下异种移植物和原位小鼠模型的体内毒性和功效。目的3：评价X线诱导光动力疗法治疗头颈部鳞癌的疗效。将在体外研究NMOF对HNSCC细胞的X-PDT功效。对于体内研究，我们将首先评估NMOFs和单独X-PDT治疗的毒性。将在皮下和原位HNSCC小鼠模型上进行体内抗癌疗效研究，其中在细胞水平上鉴定了两种最有效的NMOF。我们还将应用最先进的小动物图像引导X射线输送技术，以实现图像引导X-PDT，并将其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