To develop a novel α_vβ₃-targeted theranostic agent ¹⁷⁷Lu-Evans blue (EB)-Arg-Gly-Asp (RGD) and evaluate its value for SPECT imaging and targeted radionuclide therapy in the non-small cell lung cancer (NSCLC)-patient-derived xenografts (PDX).

The α_vβ₃-targeted molecule RGD was conjugated with the albumin binding moiety EB to obtain EB-RGD, and EB-RGD was further conjugated with the chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) for ¹⁷⁷Lu radiolabeling. NSCLC-PDX mice models (n=68) were established. ¹⁷⁷Lu-EB-RGD SPECT imaging, biodistribution study were performed in 28 PDX mice models after being injected with ¹⁷⁷Lu-EB-RGD or ¹⁷⁷Lu-RGD. Targeted radionuclide therapy were subsequently performed in NSCLC-PDX mice models, saline group (group A), 18.5 MBq ¹⁷⁷Lu-RGD group (group B), 18.5 MBq ¹⁷⁷Lu-EB-RGD group (group C), 29.6 MBq ¹⁷⁷Lu-EB-RGD group (group D), n=10 in each group; tumor volumes of PDX mice models in each group were observed within 50 d. Differences between 2 groups were compared using independent-sample t test.

¹⁷⁷Lu-EB-RGD was radiolabeled at a specific activity of (55±14) GBq/μmol, with a radiochemical yield of more than 95% and a radiochemical purity of more than 95%. Regarding the SPECT imaging, tumors in NSCLC-PDX mice were clearly observed from 4 to 96 h post-injection and the tumor to muscle ratio (T/M) reached 7.34±0.67, 14.63±3.82, 15.69±3.58 and 15.99±5.42 at 4, 24, 72, 96 h post-injection, respectively. Biodistribution study further confirmed the findings from SPECT imaging, and the tumor uptake of ¹⁷⁷Lu-EB-RGD were markedly increased compared to ¹⁷⁷Lu-RGD 4 h post-injection ((10.15±1.17) vs (3.30±1.47) percent injection dose per gram (%ID/g); t=18.60, P<0.05). Regarding targeted radiotherapy, the tumor volumes were quickly increased within 50 d after treatment in group A and B, while the tumor volumes were decreased in group C and D, until the tumors in group C and D disappeared at the 28th day after initial treatment with no sign of recurrence during the observation period.

¹⁷⁷Lu-EB-RGD can target α_vβ₃-positive NSCLC-PDX with intense tumor to background ratio and strong tumor inhibition efficacy. The preclinical data suggests that ¹⁷⁷Lu-EB-RGD may be an effective new treatment option for advanced NSCLC patients with resistance or ineffective results for targeted therapy.

Carcinoma, non-small-cell lung; Xenograft model antitumor assays; Evans blue; Arginine-glycine-aspartic acid; Lutetium; Mice, nude