Preclinical Pharmacokinetics and Dosimetry Studies of ¹²⁴I/¹³¹I-CLR1404 for Treatment of Pediatric Solid Tumors in Murine Xenograft Models

Abstract

Cancer is the second leading cause of death for children between the ages of 5 and 14 y. For children diagnosed with metastatic or recurrent solid tumors, for which the utility of external-beam radiotherapy is limited, the prognosis is particularly poor. The availability of tumor-targeting radiopharmaceuticals for molecular radiotherapy (MRT) has demonstrated improved outcomes in these patient populations, but options are nonexistent or limited for most pediatric solid tumors. 18-(p-iodophenyl)octadecylphosphocholine (CLR1404) is a novel antitumor alkyl phospholipid ether analog that broadly targets cancer cells. In this study, we evaluated the in vivo pharmacokinetics of 124 I-CLR1404 (CLR 124) and estimated theranostic dosimetry for 131 I-CLR1404 (CLR 131) MRT in murine xenograft models of the pediatric solid tumors neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Methods: Tumor-bearing mice were imaged with small-animal PET/CT to evaluate the whole-body distribution of CLR 124 and, correcting for differences in radioactive decay, predict that of CLR 131. Image volumes representing CLR 131 provided input for Geant4 Monte Carlo simulations to calculate subject-specific tumor dosimetry for CLR 131 MRT. Pharmacokinetics for CLR 131 were extrapolated to adult and pediatric humans to estimate normal-tissue dosimetry. In neuroblastoma, a direct comparison of CLR 124 with 124 I-metaiodobenzylguanidine ( 124 I-MIBG) in an MIBG-avid model was performed. Results: In vivo pharmacokinetics of CLR 124 showed selective uptake and prolonged retention across all pediatric solid tumor models investigated. Subject-specific tumor dosimetry for CLR 131 MRT presents a correlative relationship with tumor-growth delay after CLR 131 MRT. Peak uptake of CLR 124 was, on average, 22% higher than that of 124 I-MIBG in an MIBG-avid neuroblastoma model. Conclusion: CLR1404 is a suitable theranostic scaffold for dosimetry and therapy with potentially broad applicability in pediatric oncology. Given the ongoing clinical trials for CLR 131 in adults, these data support the development of pediatric clinical trials and provide detailed dosimetry that may lead to improved MRT treatment planning.

Antitumor efficacy of90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

“…Dosimetry estimations were performed as previously reported using a Monte Carlo-based dosimetry assessment platform, Radionuclide Assessment Platform for Internal Dosimetry. [38][39][40] Tumor growth studies Tumors were measured twice weekly via calipers. Tumor volume was calculated as (long axis x short axis 2 )/2.…”

Image-Based Dosimetry in Dogs and Cross-Reactivity with Human Tissues of IGF2R-Targeting Human Antibody

“…As an increase in SUV in both the shoulder and spine ROI is observed over time ( Figure 2 , Figure 3 and Figure 4 ), it can support osteophilic catabolite accumulation as a source for this uptake. The RAPID platform used in this work to perform the image-based dosimetry estimations affords the estimation of absorbed doses, which will be delivered to normal organs and tumors [ 8 , 9 , 10 , 11 ]. Very recently, RAPID was used to calculate the doses of 90 Y-small molecule NM600 for treatment of companion dogs with various advanced cancers [ 12 ].…”

Nanotheranostics for Image-Guided Cancer Treatment

“…Their β- and γ-emitter counterparts can help define the dose and rate at which the radionuclides are delivered to tumor versus normal tissues before α particle therapy due to similar pharmacokinetics. One such example is the use of SPECT/PET imaging with 123 I/ 124 I-labeled agents before 131 I-based radionuclide therapy [ 102 , 103 , 104 ]. These identical diagnostic/therapeutic pairs enable a theranostic regime for reliable delineation of biodistribution, target site accumulation, and prediction of responsive tumors.…”