Page 128 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Chapter 6
Abstract
Currently, radiolabeled DOTA-[Tyr3]-octreotate (DOTA-TATE) is most commonly used in the clinic to image and treat neuroendocrine tumors. To further improve tumor uptake, and thus treatment, the amount of radiotracer that can accumulate in the tumor might be increased by prolonging blood circulation time of the radiotracer. To achieve this, we attached an albumin binding domain to DOTA-TATE resulting in the Albutate-1. The aim of this study was to determine the characteristics of the novel radiotracer Albutate-1. A competition binding assay was performed using of [111In]In-DOTA-TATE on fresh-frozen SSTR2+ tumor sections. In vitro cell-uptake and internalization rate of [111In]In-Albutate-1 and [111In]In-DOTA-TATE were determined. Stability of [177Lu]Lu-Albutate-1 was tested. A biodistribution study was performed to provide tumor and organ uptake of [177Lu]Lu-Albutate-1. The biodistribution data was used to determine time-activity curves and the radiation dose for each organ and the tumor. The in vitro IC50 value of [111In]In-Albutate-1 was 1.2 nM. A higher amount of the tracer was found in the intracellular fraction than in the membrane fraction ([111In]In-Albutate-1 14.0 vs 1.9% of added amount; [111In]In-DOTA-TATE 11.0 vs 1.5% of added amount). After radiolabeling [111In] In-Albutate-1 was stable up to 3 days (93.1-88.9%) in labeling solution and very stable in mouse serum (90-94 %) for at least 24 h. In vivo, [177Lu]Lu-Albutate-1 was cleared slowly from the circulation (1 h p.i. 58%ID/g, 168h p.i. 2%ID/g). Addition of an albumin binding domain to DOTA-TATE extended the blood circulation to T1/2= 27.5h. The tumor absorbed dose was raised to 1455 mGy/ MBq. Bone marrow, the dose limiting organ, in the mouse spine, unfortunately received 765 mGy/MBq. All other organs also received a high radiation dose, reducing the therapeutic index.
Keywords: DOTA-TATE; Albutate-1; albumin binding domain; biodistribution; dosimetry
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