RT Journal Article SR Electronic T1 Cu-64/Cu-67 SAR-bisRGD as a theranostic for cancer JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP P744 OP P744 VO 64 IS supplement 1 A1 van Dam, Ellen A1 Mclnnes, Lachlan A1 Blyth, Benjamin A1 Van Zuylekom, Jessica A1 Rogers, Buck A1 Wieczorek Villas Boas, Cristian A1 Rao, Yi A1 Lewis, Jason A1 Gehlsen, Kurt A1 Norenberg, Jeff A1 Harris, Matt YR 2023 UL http://jnm.snmjournals.org/content/64/supplement_1/P744.abstract AB P744 Introduction: Arginine-Glycine-Aspartate (RGD)-recognizing cell surface integrins are involved in tumor growth, invasiveness/metastases, and angiogenesis, and are therefore an attractive treatment target in cancers. The subtype integrin avb3 is upregulated on endothelial cells during angiogenesis and is expressed on tumors such as glioblastoma, breast cancer, and pancreatic cancer.Theranostics is a stratified approach to medicine allowing selection of patients most likely to respond to therapy and monitoring of patient treatment and response, which ultimately aims to improve patient outcomes. Targeted Copper Theranostics (TCTs) using the radionuclides of copper, 64Cu (t1/2 = 12.7 hours, β+ = 17.5%) for imaging and 67Cu (t1/2 = 61.8 h, β- = 100%, Emax = 562 keV) for therapy, offer significant advantages in the development of next generation theranostics including: (1) centralized production and broad distribution of ready-to-use TCTs for either diagnosis or therapy due to the sufficient physical half-lives; (2) Scalable product supply for 64Cu and 67Cu due to favorable production methods using cyclotrons and accelerators, respectively; (3) 64Cu can be imaged on the same day (as with current patient scheduling) but also offers the ability to collect multiple images from one hour to 72 hours for flexible patient scheduling; and (4) since 64Cu and 67Cu are a "true" matched pair, the radiochemical products will have the same in vitro and in vivo behavior. A TCT agent can be developed using the sarcophagine (SAR) chelator, an ideal choice as they complex copper with fast kinetics, and form extremely stable complexes resistant to transmetalation and metabolism in vivo. To demonstrate the utility of the 64Cu/67Cu radionuclide pair for oncology TCT, a sarcophagine-based chelator conjugated to two cyclic-(RGDfK) peptides was prepared, SAR-bisRGD. The complex was radiolabeled with 64Cu or 67Cu and the tumor targeting and therapeutic efficacy was evaluated in multiple mouse models of cancers to determine the theranostic potential of [64/67Cu]Cu-SAR-bisRGD.Methods: A sarcophagine ligand containing two RGD peptides (SAR-bisRGD) was radiolabeled with 64Cu or 67Cu at either room temperature or 40 °C in up to 30 min to give complexes with >95% radiochemical purity, without the need for further purification.Small animal PET/CT images and/or organ biodistribution data of U87MG (glioblastoma), 66cl4b3 (breast cancer), and FC1245 Ft2AB (pancreatic cancer) tumor-bearing mice were acquired at early (1, 4 hr) and/or late (24, 48 hr) timepoints post-injection following intravenous administration of [64Cu]Cu-SAR-bisRGD. Blocking studies were performed to determine specificity. Efficacy of administrations of 11, 22, or 37 MBq [67Cu]Cu-SAR-bisRGD was determined in a syngeneic xenograft model of pancreatic cancer (FC1245 Ft2AB).Results: [64Cu]Cu-SAR-bisRGD displayed specific tumor uptake in all three models and significant tumor retention over a 48 hour period, with more than 30% of the 1 h value retained at 48 h. Biodistribution studies showed rapid clearance through the kidneys, and low uptake in organs, which peaked at 1 hr for most organs. Therapy with [67Cu]Cu-SAR-bisRGD in the pancreatic cancer model showed that it was well tolerated with no toxicity observed at any dose level as assessed by body weight changes and whole blood analyses. [67Cu]Cu-SAR-bisRGD significantly inhibited tumor growth, and increased survival. These data demonstrate the potential of this agent for clinical assessment in the treatment of pancreatic cancer, glioblastoma and breast cancer, as well as other cancers expressing avb3.Conclusions: Targeted copper theranostics is a versatile platform to develop a range of theranostic products. [64/67Cu]Cu-SAR-bisRGD displayed specific tumor uptake and retention, which was reflected in the significant anti-tumor activity. This study warrants further investigation for this product as a theranostic agent for all cancers expressing avb3.