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

• 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
• 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

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向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，以改进现有的肿瘤术中检测方法。双标记策略通常基于尚未翻译的修饰放射性示踪剂，因此缺乏临床数据来基准双标记对应物的性能。因此，尽管靶向杂交剂具有增强手术疗效的明显潜力，但尚未通过临床前试验。为了克服这一点，临床验证的生长抑素靶向肽，奥曲肽，将作为杂交剂开发的模型。镓-68标记的奥曲肽（68 Ga-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），并且与当前的临床标准Octreoscan相比具有上级成像特性。为了实现试剂设计的多功能性，而商业螯合剂如DOTA无法实现，将螯合剂和NIRF染料结合成单一实体的新型多模态螯合（MMC）支架将用于奥曲肽的简易双标记。 通过使用MMC，预计68 Ga-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灭术并减少残留疾病的发生率。这将减少对额外手术的需求，并且是核和NIRF成像的重要一步，因为这两种模式将能够将其精致的检测灵敏度转化为治疗设置，直接影响患者的结果。初步研究表明，有效的双重标记和细胞结合的原型MMC-奥曲肽杂合剂，因此提出了策略，以证明术中效用。该提案的具体目标集中在：1。开发一种高比活度配方，允许微量给药并保留荧光特性。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.建立一种术中成像方法，与传统方法（如目视检查和触诊）相比，可改善肿瘤检测，并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，从而实现快速试剂验证并指导可用于更普遍肿瘤的试剂的开发策略。