Pentixafor-based radiopharmaceuticals: A promising route towards CXCR4-targeted theranostics

Objectives As shown in first patients, [68Ga]pentixafor-PET is a powerful tool for high-contrast in vivo imaging of CXCR4-expression. The optimized structure of [68Ga]pentixafor precludes labelling with therapeutic radiometals. To nevertheless exploit the high tumor uptake of [68Ga]pentixafor, Ga-[125I]pentixafor was investigated preclinically as a potential complementary CXCR4-targeted endoradiotherapeutic agent.

Methods CXCR4-affinities were determined using Jurkat T-cell leukemia cells and [125I]FC131 as radioligand. Internalization of [68Ga]pentixafor and Ga-[125I]pentixafor was studied in dual tracer studies in various human cancer cell lines (Jurkat, Daudi and SU-DHL-8 (lymphoma), HT-29 (colon), MCF-7 (breast), SH-SY5Y (neuroblastoma)). Dual tracer biodistribution studies were performed using SU-DHL-8 and Daudi xenografted SCID mice.

Results Compared to [68Ga]pentixafor, Ga-[125I]pentixafor showed an almost 20-fold increase in CXCR4 affinity and 2- to 4-fold uptake in all CXCR4-expressing cancer cell lines (1h). Internalization was significantly enhanced for Ga-[125I]pentixafor at all time points (67.3±12.6% of total cellular activity at 1h vs 36.5±10.2% for [68Ga]pentixafor). In lymphoma-bearing SCID mice, Ga-[125I]pentixafor (logP= -1.56), showed delayed blood clearance (2.0±0.8 vs 0.97±0.34 %iD/g at 1.5h p.i.) compared to [68Ga]pentixafor (logP= -2.90) and accordingly enhanced background uptake in all organs. While renal uptake seemed slightly reduced compared to the 68Ga-compound (1.4±0.3 vs 1.7±0.9%iD/g), Ga-[125I]pentixafor uptake in Daudi (high CXCR4) and SU-DHL-8 (low CXCR4) xenografts was increased (31.0±7.3 and 7.1±3.1%iD/g vs 16.2±3.8 and 3.5±1.9 for [68Ga]pentixafor).

Conclusions The particularly efficient CXCR4-targeting properties of Ga-[125I]pentixafor, the efficient tracer internalization and adequate circulation time in vivo make its 131I-labelled analog a highly promising candidate for future CXCR4-targeted endoradiotherapy.