Hyaluronic Acid Based Nanoparticles for Targeted Image-Guided Tumor Surgery

用于靶向图像引导肿瘤手术的透明质酸纳米颗粒

• 批准号: 9071684
• 负责人: Aaron M. Mohs
• 金额: $ 33.19万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071684
• 关键词: Acute; Address; Animals; Award; Biodistribution; Biosensor; Blood; Buffers; CD44 gene; Cancer Detection; Cancerous; Cell Line; Cell Surface Receptors; Cells; Chemistry; Colon; Contrast Media; Drug Formulations; Drug Kinetics; Dyes; Enzymes; Ethylene Glycols; Evaluation; Excision; Fluorescence; Fluorescence Microscopy; Fluorescence Spectroscopy; Fluorescent Dyes; Goals; Grant; Health; Healthcare Systems; Hepatic; Human; Hyaluronan; Hyaluronic Acid; Hyaluronidase; Image; Image-Guided Surgery; Immune system; In Vitro; Indocyanine Green; Inflammatory; Kidney; Ligands; Malignant Neoplasms; Mammary Neoplasms; Modification; Molecular Weight; Mus; Operative Surgical Procedures; Organ; Outcome; Patients; Plasma; Polymers; Property; Prostate; Protein Binding; Public Health; Rattus; Recurrent disease; Recurrent tumor; Regimen; Residual Tumors; Rodent; Safety; Series; Serum Proteins; Social Welfare; Specificity; Spectrum Analysis; System; Techniques; Therapeutic; Time; Tissues; Toxic effect; base; controlled release; cost; crosslink; cytotoxicity; density; design; detector; ethylene glycol; fluorescence imaging; fluorophore; image guided; imaging agent; imaging system; improved; in vivo; infiltrating duct carcinoma; innovation; innovative technologies; instrumentation; intraoperative imaging; malignant breast neoplasm; mouse model; nanoparticle; novel; outcome forecast; overexpression; psychologic; targeted imaging; tumor; tumor microenvironment; tumor xenograft; zeta potential

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to develop novel fluorescence contrast agents that can enhance tumors intraoperatively to guide surgical tumor removal. Nanoparticles used in this proposal will be derived from modifications to hyaluronic acid (HLA). These nanoparticles have the ability entrap near infrared (NIR) fluorescent dyes. Upon entrapment, these NIR fluorescent dyes are quenched. In addition, HLA is a ligand for the cell surface receptor CD44 and is degraded by hyaluronidases. Ideally, specific degradation of HLA-based nanoparticles by hyaluronidases will release free dye that is again fluorescent. Both hyaluronidases and CD44 are overexpressed in a variety of tumors, including invasive ductal carcinoma, which is investigated in this proposal. The HLA-based nanoparticles would comprise a new class of nanoparticle biosensors that specifically identify diseased cells. A key innovative step is that these NIR biosensors can be readily detected by new image-guided surgical instrumentation to provide real-time image-guidance on tumor status. Indeed, an image-guided surgery system has been designed that excites NIR fluorophores with a directed excitation beam. NIR emission is detected spectrally and by CCD detectors in an overhead multicamera detector. The combination of NIR biosensors and intraoperative imaging addresses a key public health concern, the inability to exact complete surgical removal during the first surgery, which can result in a high rate of recurrent tumors. Recurrent tumors, can decrease patient prognosis, change therapeutic regimens, and have severe psychological consequences in addition to the overall costs of additional surgery to health care system. The integration of highly innovative technology to improve patient welfare for those undergoing tumor removal is addressed in four aims: (1) optimize the loading of NIR dye and colloidal properties of NIR dyes through modifying HLA molecular weight, introducing crosslinking chemistry, and coating nanoparticles with poly(ethylene glycol), (2) determine the mechanism for fluorescence activation and CD44 targeting, (3) perform in vivo tumor contrast studies, including image-guided surgery efficacy, and (4) an overall safety evaluation of the agents that includes detailed biodistribution studies, inflammatory and immune system activation in vitro, and blood pharmacokinetics. All in vivo studies will be performed in rodents; mice bearing human breast tumor xenografts, healthy mice, and rats. It's hypothesized that image-guided tumor removal will decrease recurrent disease, while nanoparticle entrapped dye will specifically enhance tumors and their margins resulting in more sensitive cancer detection compared to controls.

描述（由申请人提供）：该提案的总体目标是开发新型荧光造影剂，可以在术中增强肿瘤以指导手术肿瘤切除。该提案中使用的纳米颗粒将源自透明质酸（HLA）的修饰。这些纳米颗粒能够捕获近红外 (NIR) 荧光染料。一旦被捕获，这些近红外荧光染料就会被猝灭。此外，HLA 是细胞表面受体 CD44 的配体，可被透明质酸酶降解。理想情况下，透明质酸酶对基于 HLA 的纳米颗粒的特异性降解将释放出再次发出荧光的游离染料。透明质酸酶和 CD44 在多种肿瘤中均过度表达，包括本提案中研究的浸润性导管癌。基于 HLA 的纳米颗粒将构成一类新型纳米颗粒生物传感器，专门识别患病细胞。一个关键的创新步骤是，这些近红外生物传感器可以很容易地被新的图像引导手术器械检测到，以提供有关肿瘤状态的实时图像引导。事实上，已经设计了一种图像引导手术系统，可以用定向激发光束激发近红外荧光团。 NIR 发射通过光谱和高架多相机探测器中的 CCD 探测器进行检测。近红外生物传感器和术中成像的结合解决了一个关键的公共健康问题，即在第一次手术期间无法精确完成手术切除，这可能导致肿瘤复发率很高。肿瘤复发会降低患者预后，改变治疗方案，除了增加医疗保健系统额外手术的总成本外，还会产生严重的心理后果。整合高度创新的技术来改善接受肿瘤切除的患者的福利，有四个目标：(1) 通过修改 HLA 分子量、引入交联化学和用纳米粒子包覆纳米粒子，优化近红外染料的负载和近红外染料的胶体特性聚乙二醇，(2) 确定荧光激活和 CD44 靶向的机制，(3) 进行体内肿瘤对比研究，包括图像引导手术疗效，以及 (4) 对药物进行总体安全性评估，包括详细信息生物分布研究、体外炎症和免疫系统激活以及血液药代动力学。所有体内研究都将在啮齿类动物中进行；携带人类乳腺肿瘤异种移植物的小鼠、健康小鼠和大鼠。据推测，图像引导的肿瘤切除将减少复发性疾病，而纳米颗粒捕获的染料将特异性增强肿瘤及其边缘，从而与对照相比，使癌症检测更加灵敏。