Multimodality Somatostatin Analog For Fluorescence-Guided Surgery In Cancer

Author

Servando Hernandez Vargas, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0003-1614-7966

Date of Graduation

5-2019

Document Type

Thesis (MS)

Program Affiliation

Experimental Therapeutics

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Ali Azhdarinia, Ph.D.

Committee Member

Kendra S. Carmon, Ph.D.

Committee Member

Laura Smith Callahan, Ph.D.

Committee Member

Jeffrey A. Frost, Ph.D.

Committee Member

John Rasmussen, Ph.D.

Committee Member

Zhen Fan, M.D.

Abstract

Cancer surgery remains the primary curative treatment for most solid cancers and has major therapeutic implications for patients with neuroendocrine tumors (NETs). Anatomical and functional imaging technologies are widely used during the pre- and postoperative stages, but intraoperative disease recognition relies on direct visual inspection and the hands of surgeons. The limited number of clinical tools for real-time intraoperative visual feedback restricts the ability to remove the complete cancer source and is partially responsible for the high rate of disease recurrence in patients. Intraoperative imaging with fluorescent contrast agents has the potential to improve the ability of surgeons to detect tumors when compared to visual inspection and hands alone. Growing clinical evidence highlights the utility of fluorescence-guided surgery (FGS) in cancer. However, the translation of fluorescently labeled imaging agents has been limited by the semi-quantitative nature of the optical signal. Strategies to combine radioactive and fluorescent contrast have been developed to enable cross-validation of fluorescent agents with nuclear imaging and quantitative analysis. While several methods for dual labeling have been proposed, the selection of a clinical radiotracer as a model system provides a proven targeting approach. Since adding a fluorophore to a radiotracer could adversely affect its imaging properties, we developed a multimodality chelator (MMC) to synthesize a bioactive analog of the NET imaging agent, ⁶⁸Ga-DOTA-TOC. The MMC serves as a “radioactive linker” to bridge the near-infrared fluorescent (NIRF) dye IR800 and targeting moiety Tyr-3-octreotide (TOC), producing MMC(IR800)-TOC. Here, we first examined the radiochemical and pharmacological properties of the dual-labeled analog. Subsequently, we evaluated the ability of the fluorescent somatostatin analog to selectively target tumors that overexpress the somatostatin receptor subtype-2 (SSTR2) and demonstrate utility for FGS. We used ⁶⁷Ga/⁶⁸Ga for quantitative biodistribution studies and cross-validated semi-quantitative findings from fluorescence-based detection methods. The observed receptor-mediated uptake in mice was confirmed via ex vivo analysis at the macro-, meso- and microscopic levels. These results showed the impact of dual labeling on tracer validation and the effectiveness of the MMC technology for developing a novel FGS agent.

Keywords

fluorescence-guided surgery, cancer surgery, somatostatin receptor, dual-labeling, PET, near-infrared fluorescence