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

用于光触发和 X 射线诱导光动力治疗头颈癌的纳米级金属有机框架

基本信息

批准号：
9150514
负责人：
Wenbin Lin
金额：
$ 57.58万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9150514
关键词：
Accounting Address Adverse effects Aftercare Blood Circulation Time Cell Line Cells Characteristics Chemicals Clinical Disease Dose Energy Transfer Evaluation Generations Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Health In Vitro Injection of therapeutic agent Lanthanoid Series Elements Lead Light Lighting Malignant Epithelial Cell Malignant Neoplasms Metals Modality Normal tissue morphology Operative Surgical Procedures PUVA Photochemotherapy Particle Size Patients Penetration Photophobia Porosity Porphyrins Procedures Radiation Radiation therapy Reactive Oxygen Species Resistance Roentgen Rays Structure Surface Technology Therapeutic Tissues Toxic effect Translations Treatment Efficacy Xenograft procedure absorption animal imaging antitumor effect base cancer cell cancer recurrence cancer therapy cancer type chemotherapy clinical application curative treatments image guided improved in vivo irradiation killings mortality mouse model nanoparticle nanoscale neoplastic cell novel particle scale up subcutaneous treatment strategy tumor

项目摘要

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

描述（由申请人提供）：头颈鳞状细胞癌（HNSCC）是全球第六大常见癌症，临床上使用的放射治疗和化疗组合是治疗 HNSCC 最常见的治疗方法，但会引起许多不良副作用。光动力疗法（PDT）是一种有效的抗癌方法，但由于患者治疗前后的光敏感性极高、活性氧生成效率欠佳以及组织穿透浅，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，从而缓解近红外触发的PDT和X射线诱导的PDT（X-PDT）的优点。 NIR 和 X 射线的组织穿透深度以及 PDT 用于深层肿瘤治疗的优势，我们在此建议开发一种基于纳米级金属有机框架 (NMOF) 的全新纳米颗粒 PS，该框架具有以下特点：可调节的化学成分、晶体结构、极高的孔隙率、短期稳定性和长期生物降解性的理想特性，使 NIR 触发的 PDT 用于浅表肿瘤，X-PDT 用于深层肿瘤。该项目解决了开发中未满足的需求。通过近红外触发的 PDT 或 X-PDT，高效且安全的纳米粒子 PS 可以在癌症方面具有更广泛的临床应用。我们提出以下目标：AIM 1：NMOF 的合成和表征。 NIR触发和X-PDT。我们将优化NMOF结构、粒径和表面特性，以提高NIR触发PDT和X-PDT的效率，还将努力扩大NMOF合成和表面功能化，以实现长寿命。目标 2：评估 NMOF 对 HNSCC 的 NIR-PDT 功效我们将在体外研究多种 HNSCC 细胞系的 NIR-PDT 功效。在细胞水平上鉴定的一种最有效的 NMOF 对 HNSCC 皮下异种移植和原位小鼠模型的体内毒性和功效 AIM 3：评估 X 射线诱导的 HNSCC PDT 功效将在 HNSCC 细胞中研究 NMOF 的 X-PDT 功效。对于体内研究，我们将首先评估 NMOF 和单独 X-PDT 治疗的毒性，体内抗癌效果将在皮下和皮下进行。我们还将应用最先进的小动物图像引导 X 射线传输技术来实现图像引导 X-PDT，从而转化为临床。放射治疗