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Theranostics 2014; 4(3):256-266. doi:10.7150/thno.7781 This issue Cite

Research Paper

Anti-tumor Effect of Integrin Targeted ¹⁷⁷Lu-3PRGD₂ and Combined Therapy with Endostar

Jiyun Shi^1,2, Di Fan^1,3, Chengyan Dong^1,3, Hao Liu^1,3, Bing Jia^1,3, Huiyun Zhao^1,2, Xiaona Jin⁴, Zhaofei Liu^1,3, Fang Li⁴, Fan Wang^1,3✉

1. Medical Isotopes Research Center, Peking University, Beijing 100191, China;
2. Medical and Healthy Analytical Center, Peking University, Beijing 100191, China;
3. Department of Radiation Medicine, Basic Medical Sciences, Peking University, Beijing 100191, China;
4. Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing 100857, China.

✉ Corresponding author: Fan Wang, Ph.D., Medical Isotopes Research Center, Peking University, 38 Xueyuan Rd, Beijing 100191, China. Tel.: 86-10-82802871 & Fax: 86-10-82801145. E-mail: wangfanedu.cn.

Abstract

Purpose: Targeted radiotherapy (TRT) is an emerging approach for tumor treatment. Previously, 3PRGD₂ (a dimeric RGD peptide with 3 PEG₄ linkers) has been demonstrated to be of advantage for integrin α_vβ₃ targeting. Given the promising results of ^99mTc-3PRGD₂ for lung cancer detection in human beings, we are encouraged to investigate the radiotherapeutic efficacy of radiolabeled 3PRGD₂. The goal of this study was to investigate and optimize the integrin α_vβ₃ mediated therapeutic effect of ¹⁷⁷Lu-3PRGD₂ in the animal model.

Experimental Design: Biodistribution, gamma imaging and maximum tolerated dose (MTD) studies of ¹⁷⁷Lu-3PRGD₂ 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 ¹⁷⁷Lu-3PRGD₂ 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 ¹⁷⁷Lu-3PRGD₂ in nude mice (>111 MBq) was twice to that of ⁹⁰Y-3PRGD₂ (55.5 MBq). U87MG tumor growth was significantly delayed by ¹⁷⁷Lu-3PRGD₂ 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.

Keywords: Integrin α_vβ₃, Arg-Gly-Asp (RGD), ¹⁷⁷Lu, radionuclide therapy, combination therapy.

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