A novel theranostic probe [111In]In-DO3A-NHS-nimotuzumab in glioma xenograft

Abstract

Abstract Indium-111 (111In) has an appropriate half-life (T 1/2 = 67 h) and energy characteristics for cancer diagnosis via γ-ray imaging and cancer therapy with Auger electrons. The aim of our study is to evaluate the potential of [111In]In-DO3A-NHS-nimotuzumab as a theranostic agent for radioimmunoimaging (RII) and radioimmunotherapy (RIT) against human glioma xenografts in mice. We explored the chelators DO3A-NHS and DOTA-p-SCN-Bz to optimize 111In radiolabeling efficiency of nimotuzumab. The radiopharmaceuticals were purified by PD-10 mini-column and their in vitro stabilities were assessed. We investigated the biodistribution of [111In]In-DO3A-NHS-nimotuzumab as it had relatively superior labeling efficiency and stability in vitro. We conducted SPECT imaging on mice bearing glioma (U87MG) xenografts, which were injected with ∼3.7 MBq of [111In]In-DO3A-NHS-nimotuzumab. The in vivo radiotherapeutic effects of [111In]In-DO3A-NHS-nimotuzumab was analyzed via injecting a single 37 MBq dose, 2 × 18 MBq doses, or 2 × 37 MBq doses into mice bearing U87MG xenografts. The control groups were administered either 30 μg nimotuzumab or saline. The radiochemical yields of [111In]In-DO3A-NHS-nimotuzumab and [111In]In-DOTA-p-SCN-Bz-nimotuzumab were > 85% and > 75%, respectively. [111In]In-DO3A-NHS-nimotuzumab had > 95% radiochemical purity and was more stable in vitro than [111In]In-DOTA-p-SCN-Bz-nimotuzumab. Biodistribution study demonstrated that [111In]In-DO3A-NHS-nimotuzumab was highly stable in vivo. SPECT imaging disclosed that [111In]In-DO3A-NHS-nimotuzumab had excellent targeted tumor uptake and retained in tumors for 24 and 72 h. All [111In]In-DO3A-NHS-nimotuzumab treatments substantially inhibited tumor growth over the controls. The 2 × 37 MBq treatment was particularly efficacious, and presented with survival time prolonged by ≤66 days. In contrast, the survival time of the control group was only 30 days. In our study, we developed an optimized synthesis protocol for radiopharmaceutical 111In-DO3A-NHS-nimotuzumab and demonstrated that it is a promising theranostic agent. It could be highly efficacious in RII and RIT against EGFR-expressing glioma.