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 111In-3BP-227, we investigated the
therapeutic effect of its 177Lu-labeled analog on the
tumor growth of NTR1-positive HT29 colon
carcinoma xenografts. Methods: 3BP-227 was labeled with 177Lu. To assess its biodistribution properties, SPECT and CT scans of HT29-xenografted nude mice injected with 177Lu-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, n = 10) or 110 MBq (82-116 MBq, n = 10), whereas control mice were injected with vehicle (n = 10).
Tumor sizes and
body weights were monitored for up to 49 d. Renal function and histologic morphology were evaluated. Results: 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 of 177Lu-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 177Lu-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% (P = 0.034) in the 110-MBq and by 88% (P < 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. Conclusion: 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.