Page 135 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

Albutate-1, a novel long-circulating radiotracer
3. Discussion
For optimization of the therapeutic efficacy of the currently used [177Lu]Lu- DOTA-TATE therapy for NETs, we chose to enhance the circulation time of the radiotracer. An albumin binding domain, 4-(p-iodophenyl)butyric acid, was attached to DOTA-TATE, creating Albutate-1. In this study we evaluated the modified version of DOTA-TATE in in vitro and in vivo studies in mice. DOTA- TATE [22, 23] and Albutate-1 showed a comparable binding affinity for SSTR2 in the nanomolar range, so the attachment of an albumin binding domain did not affect SSTR2 receptor binding. The cell uptake and internalization of [111In] In-Albutate-1 and [111In]In-DOTA-TATE were similar as well. Most radioactivity was found in the intracellular fraction (88%) so the addition of the albumin binding moiety did not hamper the internalization of the tracer.
In vivo we found that the half-life of [177Lu]Lu-Albutate-1 was 27.5 ± 2.6 h in blood. Since the radioactive dose to normal organs is of utmost importance during radionuclide therapy we performed extensive dosimetry calculations. We noticed that there was a tumor absorbed dose per administered activity of 1455 mGy/MBq. Normal organs however also encountered a higher absorbed dose, especially bone marrow. We calculated that the spine, which has a cellular fraction 52%, received a total absorbed dose of 765 mGy/MBq. The blood circulation time is extended, compared to [177Lu]Lu-DOTA-TATE [13] and therefore the high normal organ exposure of [177Lu]Lu-DOTA-Albutate-1 is reducing the therapeutic index. At a limiting dose to the bone marrow of 2 Gy only a 14 Gy absorbed dose to the tumor can be reached, together with an absorbed dose to the kidneys of 9 Gy.
Looking at our data we propose to make adjustments to further improve our albumin binding tracer concept. Like us, other groups also tried to prolong the blood circulation time of their tracer. A search for enhancing the tumor uptake and improving the tumor-to-kidney ratio took place [24]. They also searched for the best balance between high tumor dose and limited organ dose. The structure of the tracer can be modified by varying the binding strength to albumin and/or varying the spacer length. Rousseau et al. [25] conjugated two different albumin binders, Lys-Glu-4-(p-iodophenyl)butyric acid or Lys-Asp-4-(p- iodophenyl)butyric acid, to the parent compound DOTA-TATE. The addition of
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