Proof of Therapeutic Efficacy of a ¹⁷⁷Lu-Labeled Neurotensin Receptor 1 Antagonist in a Colon Carcinoma Xenograft Model

Abstract

Increased expression of neurotensin receptor 1 (NTR1) has been shown in a large number of tumor entities such as pancreatic or colon carcinoma. Hence, this receptor is a promising target for diagnostic imaging and radioligand therapy. Using the favorable biodistribution data of the NTR1-targeting agent In-3BP-227, we investigated the therapeutic effect of itsLu-labeled analog on the tumor growth of NTR1-positive HT29 colon carcinoma xenografts. 3BP-227 was labeled withLu. To assess its biodistribution properties, SPECT and CT scans of HT29-xenografted nude mice injected with Lu-3BP-227 were acquired, and ex vivo tissue activity was determined. To evaluate therapeutic efficacy, 2 groups of mice received the radiopharmaceutical in a median dose of either 165 MBq (129-232 MBq, = 10) or 110 MBq (82-116 MBq, = 10), whereas control mice were injected with vehicle ( = 10). Tumor sizes and body weights were monitored for up to 49 d. Renal function and histologic morphology were evaluated. Whole-body SPECT/CT images allowed clear tumor visualization with low background activity and high tumor-to-kidney and -liver ratios. Ex vivo biodistribution data confirmed high and persistent uptake ofLu-3BP-227 in HT29 tumors (19.0 ± 3.6 vs. 2.7 ± 1.6 percentage injected dose per gram at 3 and 69 h after injection, respectively). The application of Lu-3BP-227 resulted in a distinct delay of tumor growth. Median tumor doubling time for controls was 5.5 d (interquartile range [IQR], 2.8-7.0), compared with 17.5 d (IQR, 5.5-22.5 d) for the 110-MBq and 41.0 d (IQR, 27.5-55.0) for the 165-MBg group. Compared with controls, median relative tumor volume at day 23 after injection was reduced by 55% ( = 0.034) in the 110-MBq and by 88% ( < 0.01) in the 165-MBq group. Renal histology and clinical chemistry results did not differ between radiotherapy groups and controls, suggesting absence of therapy-induced acute renal damage. These data demonstrate that the novel NTR1-targeting theranostic agent 3BP-227 is an effective and promising candidate for radioligand therapy, with a favorable preliminary safety profile and high potential for clinical translation.

Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor‐positive tumors

“…Although the metabolic stability of the probe in vitro was high (90% intact tracer after 6 hours), the determination of its stability in vivo is still pending. 52 A series of 68 Ga-and 18 F-labeled NT analogs bearing the same amino acid sequence, Nlys-Lys-Pro-Tyr-Tle-Leu, was reported by Maschauer et al (entries 5-8, Table 4). [53][54][55] This sequence is one of the few reported thus far that is stable not only in vitro but also in vivo.…”

“…The applicability in vivo, however, was limited by the high uptake in excretion organs (kidneys, liver, and spleen), where the radiotracer displayed only slow washout. Nevertheless, 68 Ga-TRAP(NT4) 3 showed 2-fold higher tumor uptake (1.7%ID/g, 60 minutes p.i.) than the corresponding monomer.…”

“…Therefore, radiolabeling with Ga-68 and further biodistribution studies were only performed with the NT-20.3 and LB119 analogs. 39 In HT29 tumor-bearing nude mice, the 68 Ga-NT-20.3 derivative exhibited significantly higher tumor uptake at 1 hour p.i. than the 68 Ga-LB119 derivative (4.7%ID/g vs 2.7%ID/g, respectively), but higher renal uptake was also observed, resulting in lower tumor-to-kidney ratios (0.46% for 68 Ga-NT-20.3 vs 0.79% for 68 Ga-LB119).…”

“…56 The most recent approach for a multimeric NT peptide was reported by Maschauer et al in 2017, 58 who employed the new chelator TRAP (1,4,7-triazacyclononane-1,4,7-tris[(2carboxyethyl)methylenephosphinic acid]) for the synthesis of a trimeric NT analog. The trimeric analog 68 Ga-TRAP(NT4) 3 (entry 15, Table 4) displayed subnanomolar NTS1 affinity (K i = 0.12 nM), and additional promising in vitro characteristics, such as high and fast internalization in HT29 cells and moderate efflux from cells. The applicability in vivo, however, was limited by the high uptake in excretion organs (kidneys, liver, and spleen), where the radiotracer displayed only slow washout.…”

“…that decreased to 8.5%ID/g at 20 hours p.i. in HT29 tumor‐bearing nude mice . Applying high activities of 110 to 165 MBq per animal lead to 55% to 88% growth inhibition of the HT29 tumors in these animals without any acute renal damage .…”