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Anti-tumor effect of integrin targeted (177)Lu-3PRGD2 and combined therapy with Endostar.

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 ?v?3 targeting. Given the promising results of (99m)Tc-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 ?v?3 mediated therapeutic effect of (177)Lu-3PRGD2 in the animal model. EXPERIMENTAL DESIGN: Biodistribution, gamma imaging and maximum tolerated dose (MTD) studies of (177)Lu-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 (177)Lu-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 (177)Lu-3PRGD2 in nude mice (>111 MBq) was twice to that of (90)Y-3PRGD2 (55.5 MBq). U87MG tumor growth was significantly delayed by (177)Lu-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.

SUBMITTER: Shi J

PROVIDER: S-EPMC3915089 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Anti-tumor effect of integrin targeted (177)Lu-3PRGD2 and combined therapy with Endostar.

Shi Jiyun J Fan Di D Dong Chengyan C Liu Hao H Jia Bing B Zhao Huiyun H Jin Xiaona X Liu Zhaofei Z Li Fang F Wang Fan F

Theranostics 20140118 3

<h4>Purpose</h4>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 αvβ3 targeting. Given the promising results of (99m)Tc-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 αvβ3 mediated therapeutic effect o ...[more]

PMID: 24505234

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Project description:PurposeProstate-specific membrane antigen (PSMA) continues to be the hallmark biomarker for prostate cancer as it is expressed on nearly all prostatic tumors. In addition, increased PSMA expression correlates with castration resistance and progression to the metastatic stage of the disease. Recently, we combined both an albumin-binding motif and an irreversible PSMA inhibitor to develop the novel PSMA-targeted radiotherapeutic agent, CTT1403. This molecule was novel in the field of PSMA-targeted agents as its key motifs resulted in extended blood circulation time and tumor uptake, rapid and extensive internalization into PSMA+ cells, and promising therapeutic efficacy. The objective of this study was to perform IND-enabling translational studies on CTT1403 in rodent models.ProceduresA dose optimization study was performed in PC3-PIP (PSMA+) tumor-bearing mice. Treatment groups were randomly selected to receive one to three 14-MBq injections of CTT1403. Control groups included (1) saline, (2) non-radioactive [175Lu]CTT1403, or (3) two injections of 14 MBq CTT1751, a Lu-177-labeled non-targeted albumin-binding moiety. Tumor growth was monitored up to 120 days. Small-animal single photon emission tomography/X-ray computed tomography imaging was performed with CTT1403 and CTT1751 in PC3-PIP tumor-bearing mice to visualize infiltration of the Lu-177-labeled agent into the tumor. In preparation for a first-in-human study, human absorbed doses were estimated based on rat biodistribution out to 5 weeks to determine a safe CTT1403 therapy dose in humans.ResultsTwo to 3 injections of 14 MBq CTT1403 yielded significant tumor growth inhibition and increased survival compared with all control groups and mice receiving 1 injection of 14 MBq CTT1403. Five of 12 mice receiving 2 or 3 injections of CTT1403 survived to the 120-day post-treatment study endpoint. Dosimetry identified the kidneys as the dose-limiting organ, with an equivalent dose of 5.18 mSv/MBq, resulting in a planned maximum dose of 4.4 GBq for phase 1 clinical trials.ConclusionsThe preclinical efficacy and dosimetry of CTT1403 suggest that this agent has significant potential to be safe and effective in humans.

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Anti-tumor effect of integrin targeted (177)Lu-3PRGD2 and combined therapy with Endostar.

Publications

Anti-tumor effect of integrin targeted (177)Lu-3PRGD2 and combined therapy with Endostar.

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