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）：本提案的目的是通过在放射性示踪剂中添加近红外荧光（NIRF）染料来开发一种混合成像方法，以改进术中检测肿瘤的现有方法。双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衡量双标记对应物的性能。因此，尽管靶向混合药物具有明显提高手术疗效的潜力，但尚未通过临床前测试。为了克服这个问题，经过临床验证的生长抑素靶向肽奥曲肽将作为混合药物开发的模型。镓-68标记的奥曲肽（68Ga-DOTA-TOC）在临床上用于通过正电子发射断层扫描检测神经内分泌肿瘤（NET），与当前的临床标准Octreoscan相比，具有优越的成像特性。为了实现 DOTA 等商业螯合剂无法实现的药物设计多功能性，将采用一种新型多模式螯合 (MMC) 支架，将螯合剂和 NIRF 染料组合成单个实体，从而轻松对奥曲肽进行双重标记。通过使用MMC，预计将68Ga-DOTA-TOC转化为混合制剂将为外科医生提供最先进的工具，以有效地进行细胞减灭术并减少残留疾病的发生率。这将减少额外手术的需求，并成为核和 NIRF 成像领域向前迈出的重要一步，因为这两种成像方式都能够将其精湛的检测灵敏度转化为治疗环境，从而直接影响患者的治疗结果。初步研究表明，原型 MMC-奥曲肽混合剂具有有效的双重标记和细胞结合作用，因此提出了证明术中实用性的策略。该提案的具体目标集中在： 1. 开发一种高比活性制剂，允许微剂量并保留荧光特性。 2. 使用体外测定证明结合特性的保留。 3. 小鼠体内成像，以显示肿瘤检测的功效并评估成像性能。 4. 建立术中成像方法，与目视检查和触诊等传统方法相比，可提高肿瘤检出率，从而实现更有效的肿瘤切除。所提出的混合成像方法建立在 SSTR 靶向成像剂的发展和已建立的 NET 临床成像基础设施的基础上，从而实现快速药物验证并指导可用于更常见肿瘤的药物的开发策略。