Development of hybrid somatostatin analogs for surgical guidance

描述(申请人提供)：这项建议的目标是开发一种混合成像方法，通过在放射示踪剂中添加近红外荧光(NIRF)染料来改进现有的术中肿瘤检测方法。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对双标记对应物的性能进行基准测试。因此，靶向杂交药物没有通过临床前测试，尽管有明显的潜力提高手术疗效。为了克服这一点，临床验证的生长抑素靶向多肽奥曲肽将作为杂交药物开发的模型。~(68)Ga标记的奥曲肽(68Ga-DOTA-TOC)用于临床正电子发射断层扫描检测神经内分泌肿瘤(Nets)，与目前的临床标准Octreoscan相比具有更好的成像性能。为了在试剂设计上实现DOTA等商业螯合剂所不能达到的多功能性，一种将螯合剂和NIRF染料结合成单一实体的新型多模络合(MMC)支架将被用于轻松地对奥曲肽进行双重标记。 通过MMC的使用，预计68Ga-DOTA-TOC转化为杂交剂将为外科医生提供最先进的工具，以便有效地进行细胞减少手术，并减少残留疾病的发生率。这将减少对额外手术的需要，并在核和NIRF成像方面向前迈出重要的一步，因为这两种方式都将能够将其精致的检测灵敏度转化为治疗环境，直接影响患者的结果。初步研究表明，一种原型MMC-奥曲肽杂交剂具有有效的双重标记和细胞结合，因此提出了展示术中实用性的策略。这项提议的具体目标集中在：1.开发一种允许微剂量并保持荧光特性的高比活性配方。2.用体外实验证明结合特性的保留。3.在小鼠体内进行成像，以显示对肿瘤检测的有效性并评估成像性能。4.建立一种术中成像方法，与传统的视觉检查和触诊方法相比，该方法提高了肿瘤的检测能力，并导致更有效的肿瘤切除。建议的混合成像方法建立在SSTR靶向成像试剂的发展和已建立的网络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的肿瘤的药物的开发战略。

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.