Development of hybrid somatostatin analogs for surgical guidance

用于手术指导的混合生长抑素类似物的开发

基本信息

批准号：
8697203
负责人：
Ali Azhdarinia
金额：
$ 34.02万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697203
关键词：
Address Affinity Animals Benchmarking Binding Biodistribution Cancer Patient Caring Cells Chelating Agents Clinical Clinical Data Complement Contrast Media Custom Data Detection Development Devices Diagnostic Diagnostic Imaging Drug Formulations Drug Kinetics Dyes Europe Evolution Excision Fluorescence Fluorescent Dyes Foundations Functional Imaging Gallium Goals Hybrids Image Imagery In 111 Pentetreotide Incidence Label Lesion Light Malignant - descriptor Malignant Neoplasms Methods Modality Modeling Modification Mus Neuroendocrine Tumors Nuclear Octreotide Operating Rooms Operative Surgical Procedures Outcome Palpation Patient Care Patients Penetration Peptides Performance Pharmaceutical Preparations Pharmacology Plague Play Positive Lymph Node Positron-Emission Tomography Postoperative Period Preclinical Testing Property Radiolabeled Receiver Operating Characteristics Research Research Infrastructure Residual Neoplasm Residual Tumors Role Sensitivity and Specificity Somatostatin Somatostatin Receptor Structure Surgeon Therapeutic Time Tissue Sample Tissues Tracer Translating Validation Visible Radiation Visual Visual Acuity analog base cancer surgery chelation clinically relevant design fluorescence imaging imaging modality improved in vitro Assay in vivo imaging instrumentation intraoperative imaging multimodality novel prototype public health relevance radiotracer receptor receptor binding response scaffold somatostatin analog tool tumor

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to develop a hybrid imaging approach by adding a near-infrared fluorescent (NIRF) dye to a radiotracer to improve upon existing methods for intraoperative detection of tumors. Dual labeling strategies are typically based on modifying radiotracers that have yet to be translated, thus lacking clinical data to benchmark the performance of a dual-labeled counterpart. As a result, targeted hybrid agents have not advanced past preclinical testing despite clear potential to enhance surgical efficacy. To overcome this, the clinically validated somatostatin targeting peptide, octreotide, wil serve as a model for hybrid agent development. Gallium-68 labeled octreotide (68Ga-DOTA-TOC) is used clinically to detect neuroendocrine tumors (NETs) by Positron Emission Tomography and possesses superior imaging properties compared to the current clinical standard, Octreoscan. To achieve the versatility in agent design not attainable with commercial chelators such as DOTA, a novel multimodality chelation (MMC) scaffold that combines a chelator and NIRF dye into a single entity will be employed for facile dual labeling of octreotide. Through use of the MMC, it is expected that the conversion of 68Ga-DOTA-TOC into a hybrid agent will provide surgeons with state-of-the-art tools to effectively perform cytoreductive surgery and encounter less incidences of residual disease. This would reduce the need for additional surgeries and be a significant step forward in nuclear and NIRF imaging as both modalities will be able to translate their exquisite detection sensitivities into a therapeutic seting to directly impact patient outcomes. Preliminary studies have shown efficient dual labeling and cell binding of a prototype MMC-octreotide hybrid agent, thus strategies to demonstrate intraoperative utility are proposed. The Specific Aims of this proposal focus upon: 1. Developing a high-specific activity formulation that permits microdosing and retains fluorescent properties. 2. Demonstrating retention of binding properties using in vitro assays. 3. In vivo imaging in mice to show efficacy for tumor detection and assess imaging performance. 4. Establishing an intraoperative imaging approach that improves tumor detection compared to conventional methods such as visual inspection and palpation, and results in more effective tumor resection. The proposed hybrid imaging approach builds upon the evolution of SSTR targeted imaging agents and the established NET clinical imaging infrastructure, thereby enabling rapid agent validation and guiding development strategies for agents that can be used for more prevalent tumors.

描述（由申请人提供）：该提案的目的是通过在放射性示例中添加近红外荧光（NIRF）染料来开发混合成像方法，以改善现有的术中检测方法的方法。双重标记策略通常基于修改尚未翻译的放射性示踪剂，因此缺乏临床数据来基于双标签的对应物的性能。结果，尽管有明确的手术功效潜力，但靶向的混合剂尚未进行过去的临床前测试。为了克服这一点，临床验证的生长抑素靶向肽Ocrothotide，将作为混合剂开发的模型。在临床上使用镀膜68标记的奥曲肽（68GA-DOTA-TOC）通过正电子发射断层扫描来检测神经内分泌肿瘤（NETS），并且与当前的临床标准相比，具有出色的成像性能。为了实现代理设计中的多功能性，无法使用诸如DOTA之类的商业螯合剂，这是一种新型的多模式螯合（MMC）支架，将螯合剂和NIRF染料结合到单个实体中，将用于抗霉素的双重标记。通过使用MMC，可以预期将68GA-DOTA-TOC转化为混合剂，将为外科医生提供最先进的工具，以有效地进行细胞减少手术，并遇到残留疾病的发生率较小。这将减少对其他手术的需求，并在核和NIRF成像方面迈出了重要一步，因为这两种方式都可以将其精致的检测灵敏度转化为一种治疗性，以直接影响患者的结果。初步研究表明，有效的双重标记和原型MMC-康复肽杂交药物的细胞结合，因此提出了证明术中效用的策略。该提案的具体目的集中在：1。开发一种高特异性活性公式，允许微剂量和保留荧光性能。 2。证明使用体外测定的结合特性保留。 3。在小鼠中体内成像显示肿瘤检测和评估成像性能的功效。 4。建立一种术中成像方法，该方法与传统方法（例如视觉检查和触诊）相比，可以改善肿瘤检测，并导致更有效的肿瘤切除。提出的混合成像方法建立在SSTR靶向成像剂和已建立的净临床成像基础设施的基础上，从而实现了可以用于更普遍肿瘤的试剂的快速剂验证和指导开发策略。