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

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.

Comparative Evaluation of the Biodistribution Profiles of a Series of Nonpeptidic Neurotensin Receptor-1 Antagonists Reveals a Promising Candidate for Theranostic Applications.

UNLABELLED: Neurotensin receptor-1 (NTR1) is a promising target for diagnostic imaging and targeted radionuclide therapy. The aim of this study was to evaluate the biodistribution profiles of a series of newly developed diarylpyrazole-based NTR1 antagonists regarding their suitability as diagnostic and potentially radiotherapeutic agents. METHODS: 3BP-227, 3BP-228, and 3BP-483 were labeled with (111)In and injected intravenously into NTR1-positive HT29 xenograft-bearing nude mice. At 3, 6, 12, and 24 h after administration, SPECT/CT images were acquired or mice were sacrificed for ex vivo determination of tissue-associated radioactivity. RESULTS: High-contrast tumor visualization in SPECT/CT images was achieved using the 3 compounds of this study. Ex vivo biodistribution studies confirmed a high and persistent tumor uptake, peaking at 6 h after injection for (111)In-3BP-227 (8.4 ± 3.1 percentage injected dose per gram [%ID/g]) and at 3 h after injection for (111)In-3BP-228 (10.2 ± 5.3 %ID/g) and (111)In-3BP-483 (1.9 ± 0.8 %ID/g). Tumor-to-normal-tissue ratios obtained with (111)In-3BP-227 and (111)In-3BP-228 were consistently greater than 1. CONCLUSION: On the basis of the superior biodistribution profile compared with previously reported radiolabeled NTR1 ligands, (111)In-3BP-227 is an ideal candidate for further development as a theranostic tracer.

Predictive value of intratumoral 99mTc-macroaggregated albumin uptake in patients with colorectal liver metastases scheduled for radioembolization with 90Y-microspheres.

UNLABELLED: (90)Y radioembolization is a promising therapy for patients with primary and secondary liver malignancies. Pretherapeutic assessment consists of hepatic angiography and (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) perfusion scintigraphy to estimate the liver-to-lung shunt and exclude extrahepatic (99m)Tc-MAA deposition. However, the predictive value of intratumoral (99m)Tc-MAA uptake remains unclear. METHODS: One hundred four patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer were treated with (90)Y radioembolization between December 2006 and December 2010. All of the patients underwent angiographic assessment and perfusion scintigraphy with (99m)Tc-MAA before lobar (90)Y radioembolization. For inclusion, patients must have undergone pretherapeutic and follow-up MR imaging (6 wk and 3 mo after radioembolization, respectively). The degree of intratumoral (99m)Tc-MAA uptake was rated, and liver metastases were classified according to changes in tumor diameter on both an individual and a patient basis using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response at both time points, MAA uptake, and catheter position were then statistically analyzed in a linear and generalized linear mixed model at a significance level of 0.05 (P value). RESULTS: Sixty-six patients with a total of 435 colorectal liver metastases (mean number of lesions ± SD, 6.6 ± 2.8; mean lesion size ± SD, 33.8 ± 21.2 mm; lesion size range, 10-154 mm) were included in this analysis. According to the patient-based analysis, 3 patients had partial response, 49 stable disease, and 6 progressive disease after 6 wk. After 3 mo, 5 patients showed partial response, 26 stable disease, and 17 progressive disease. There was no association of patient-based tumor response with overall (99m)Tc-MAA uptake (P = 0.172) or with catheter position (P = 0.6456). Furthermore, an interaction effect of (99m)Tc-MAA uptake and catheter position in relation to tumor response was not found (P = 0.512). Moreover, in lesion-based analysis according to RECIST 1.1 there was no association of tumor response with degree of (99m)Tc-MAA uptake, catheter position, or interaction of (99m)Tc-MAA uptake and catheter position (P = 0.339, 0.593, and 0.658, respectively). CONCLUSION: Response to (90)Y radioembolization was found to be independent of the degree of (99m)Tc-MAA uptake. Therefore, therapy should not be withheld from patients with colorectal liver metastases lacking intratumoral (99m)Tc-MAA accumulation.