Two ⁹⁰Y-labeled multimeric RGD peptides RGD4 and 3PRGD2 for integrin targeted radionuclide therapy.
We have recently developed a series of new Arg-Gly-Asp (RGD) dimeric peptides for specific targeting of integrin α(v)β₃ with enhanced tumor uptake and improved pharmacokinetics. In this study, we investigated ⁹⁰Y-labeled RGD tetramer (RGD4) and the new type of RGD dimer (3PRGD2), for the radionuclide therapy of integrin α(v)β₃-positive tumors. Biodistribution and gamma imaging studies of ¹¹¹In labeled RGD4 and 3PRGD2 were performed. Groups of nude mice were used to determine maximum tolerated dose (MTD) of ⁹⁰Y-DOTA-RGD4 and ⁹⁰Y-DOTA-3PRGD2. The radionuclide therapeutic efficacy of ⁹⁰Y-DOTA-RGD4 and ⁹⁰Y-DOTA-3PRGD2 was evaluated in U87MG tumor-bearing nude mice. The U87MG tumor uptake of ¹¹¹In-DOTA-3PRGD2 was slightly lower than that of the ¹¹¹In-DOTA-RGD4 (e.g., 6.13 ± 0.82%ID/g vs 6.43 ± 1.6%ID/g at 4 h postinjection), but the uptake of ¹¹¹In-DOTA-3PRGD2 in normal organs, such as liver and kidneys, was much lower than that of ¹¹¹In-DOTA-RGD4, which resulted in much higher tumor-to-nontumor ratios and lower toxicity. The MTD of ⁹⁰Y-DOTA-RGD4 in nude mice is less than 44.4 MBq, while the MTD of ⁹⁰Y-DOTA-3PRGD2 in mice is more than 55.5 MBq. ⁹⁰Y-DOTA-3PRGD2 administration exhibited a similar tumor inhibition effect as compared with ⁹⁰Y-DOTA-RGD4 at the same dose. The tumor vasculature in the ⁹⁰Y-DOTA-3PRGD2 treatment group was much less than the control groups. Radionuclide therapy studies exhibited that both ⁹⁰Y-DOTA-RGD4 and ⁹⁰Y-DOTA-3PRGD2 caused significant tumor growth delay in the U87MG tumor model. Compared to ⁹⁰Y-DOTA-RGD4, the low accumulation of ⁹⁰Y-DOTA-3PRGD2 in normal organs led to lower toxicity and higher MTD in nude mice, which would make it more suitable for high dose or multiple-dose regimens, in order to achieve maximum therapeutic efficacy.
Medical Isotopes Research Center, Basic Medical Sciences, Peking University, Beijing 100191, China.
Zhaofei
Z
Liu
Jiyun
J
Shi
Bing
B
Jia
Zilin
Z
Yu
Yan
Y
Liu
Huiyun
H
Zhao
Fang
F
Li
Jie
J
Tian
Xiaoyuan
X
Chen
Shuang
S
Liu
Fan
F
Wang
D000818:Animals; D019281:Dimerization; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D013379:Substrate Specificity; D013667:Technetium / Q000627:therapeutic use; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D013667:Technetium; C047981:arginyl-glycyl-aspartic acid