Anti-tumor Effect of Integrin Targeted (177)Lu-3PRGD(2) and Combined Therapy with Endostar

Purpose: Targeted radiotherapy (TRT) is an emerging approach for tumor treatment. Previously, 3PRGD(2) (a dimeric RGD peptide with 3 PEG(4) linkers) has been demonstrated to be of advantage for integrin α(v)β(3) targeting. Given the promising results of (99m)Tc-3PRGD(2) for lung cancer detection in human beings, we are encouraged to investigate the radiotherapeutic efficacy of radiolabeled 3PRGD(2). The goal of this study was to investigate and optimize the integrin α(v)β(3 )mediated therapeutic effect of (177)Lu-3PRGD(2) in the animal model. Experimental Design: Biodistribution, gamma imaging and maximum tolerated dose (MTD) studies of (177)Lu-3PRGD(2) were performed. The targeted radiotherapy (TRT) with single dose and repeated doses as well as the combined therapy of TRT and the anti-angiogenic therapy (AAT) with Endostar were conducted in U87MG tumor model. The hematoxylin and eosin (H&E) staining and immunochemistry (IHC) were performed post-treatment to evaluate the therapeutic effect. Results: The U87MG tumor uptake of (177)Lu-3PRGD(2) was relatively high (6.03 ± 0.65 %ID/g, 4.62 ± 1.44 %ID/g, 3.55 ± 1.08 %ID/g, and 1.22 ± 0.18 %ID/g at 1 h, 4 h, 24 h, and 72 h postinjection, respectively), and the gamma imaging could visualize the tumors clearly. The MTD of (177)Lu-3PRGD(2) in nude mice (>111 MBq) was twice to that of (90)Y-3PRGD(2) (55.5 MBq). U87MG tumor growth was significantly delayed by (177)Lu-3PRGD(2 )TRT. Significantly increased anti-tumor effects were observed in the two doses or combined treatment groups. Conclusion: The two-dose TRT and combined therapy with Endostar potently enhanced the tumor growth inhibition, but the former does not need to inject daily for weeks, avoiding a lot of unnecessary inconvenience and suffering for patients, which could potentially be rapidly translated into clinical practice in the future.