ausblenden:
Schlagwörter:
-
Zusammenfassung:
Introduction: Currently used MRI contrast agents are unspecific towards the identification of diseased tissues. Targeted MRI-contrast agents are therefore of interest. The most frequently used radio-peptides in the clinic are somatostatin analogs for neuroendocrine tumor imaging and radiotherapy. Higher accumulation in the target is needed for contrast enhanced MRI but also in targeted radiotherapy and can be obtained by grafting several Gd(III)/111In/90Y chelates onto the peptide carrier.
Aim: We synthesized Tyr3-Thr8-Octreotide (TATE) carrying multiple DOTA chelators allowing higher targeted doses to tumors and studied the pharmacologic properties of these molecules.
Results: Internalization studies (AR4-2J tumor cells) showed no significant difference after 4h between [111In-DOTA]-TATE and the tree-like compounds [111In-DOTA]4-Apg3-Sar5-TATE and [153Gd-DOTA]4-Apg3-Sar5-TATE. After 4 h the internalization of the comb-like compound [111In-DOTA]4-linLys3-Sar5-TATE decreased significantly by a factor of 2. The internalization results highly correlate with the IC50 values from binding assays.
The biodistribution studies (rat tumor AR4–2J model) showed a high and specific uptake in tumor and receptor positive tissue. [111In-DOTA]-TATE showed a tumor uptake of 4.1%id/g and a tumor-to-kidney ratio of 1.7:1, whereas [111In-DOTA]4-Apg3-Sar5-TATE showed a tumor uptake of only 1.9%id/g but no significantly different uptake into the somatostatin receptor positive organs. Compared to Gd(DOTA)−(r1=3.83 mM−1s−1/20 MHz/37°C), the relaxivity of [Gd-DOTA]4-Apg3-Sar5-TATE (r1=8.9 mM−1s−1/20 MHz/37°C/per Gd) increased by a factor of 2.3 which is due to its increased rotational correlation time of 490 ps (vs. 177 ps for Gd(DOTA)−).
Conclusion: Despite major modifications at the N-terminus of the octapeptide and the complexation with different (radio-)metals, the internalization rate was not highly influenced. [111In-DOTA]4-Apg3-Sar5-TATE showed a high uptake in somatostatin receptor positive tissue but somewhat lower uptake in the tumor compared with the parent peptide. This also holds for the Gd(III) modified peptides and encourages the future use of these molecules in animal models for targeted MRI diagnosis.
