Page 174 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis
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                                Chapter 8
analogue. Both DOTA-TATE and Albutate-1 showed a comparable high binding affinity for SST2 and a similar uptake and internalization rate of the tracers. After radiolabelling [111In]In-Albutate-1 was stable for up to 3 days in labelling solution and at least for 24h in mouse serum. When tested in vivo, the circulation time of [177Lu]Lu-Albutate-1 was T1/2 = 27.5 h. We determined that for the dose tested a tumor absorbed dose per administered activity of 1455 mGy/MBq. This absorbed dose is 5 times higher than with [177Lu]Lu-DOTA-TATE (unpublished data) and is the result of an extended exposure time to radiation. Normal organs however also encountered a higher absorbed dose, especially bone marrow. We calculated that the spine, which has a cellular fraction of 52%, received a total absorbed dose of 765 mGy/MBq. We conclude that addition of an albumin binding domain to [177Lu]Lu-DOTA-TATE extended the blood circulation time and raised the tumor uptake. However, bone marrow, kidneys and all other organs received a high radiation dose, reducing the therapeutic index. Other groups also searched for the best balance between high tumor dose and limited organ dose using an albumin binding domain or Evans blue as albumin binder. In search for the best biodistribution profiles the structure of the tracer can be modified by varying the binding strength to albumin, and the spacer length. Preferred are a weaker binding strength and a shorter spacer length which both result in a shorter dissociation constant with a sub sequentially shorter circulation time (58-61). According to our results and other studies by other groups, attachment of albumin-binding domains to tracers can improve circulation time and increase tumor uptake. However, if the plasma protein-binding results in long dissociation times, the blood circulation time becomes extended to a level where all other organs also receive a high radiation dose, reducing the therapeutic index dramatically. Future perspectives are to create a tracer with more optimal pharmacokinetics, applying adaptations in albumin binding strength and spacer length.
Macrophage imaging during osteoarthritis development
As described in Chapters 5 and 6 tumor cells can be visualised using peptide radionuclide receptor imaging, but other cell populations that over- express receptors can be visualised the same way. Inflammatory cells, like macrophages, are of high interest, because they play a prominent role in the pathogenesis and progression of many different diseases and therefore form an interesting therapeutic target (62, 63).
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