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.
Surgical outcomes are dependent upon the ability of surgeons to identify tumors intraoperatively and perform complete resections of malignant tissues. Nuclear imaging approaches provide pre- and post-operative tumor detection but lack the device and drug infrastructure to support intraoperative use. Enhancing radiotracers through the addition of fluorescent contrast enables a hybrid imaging strategy that can address the inherent limitations of radiotracers and improve surgical outcomes by reducing the incidences of minimal residual disease and the need for additional surgical intervention. The goal of this research is to employ a custom multimodality chelation scaffold for dual labeling of a clinically validated neuroendocrine tumor (NET) imaging agent, thereby providing a hybrid approach that can guide surgical removal of NETs and also serve as a model for more prevalent cancers that rely on surgical care.