RT Journal Article
SR Electronic
T1 A radiotheranostic study for strategic treatment of ovarian cancer peritoneal metastases using the all-in-one multimeric radiopeptide <sup>64</sup>Cu-cyclam-RAFT-c(-RGDfK-)<sub>4</sub>
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1215
OP 1215
VO 62
IS supplement 1
A1 Zhao-Hui Jin
A1 Atsushi B. Tsuji
A1 Melissa Degardin
A1 Aya Sugyo
A1 Satoshi Obara
A1 Hidekatsu Wakizaka
A1 Kotaro Nagatsu
A1 Kuan Hu
A1 Ming-Rong Zhang
A1 Pascal Dumy
A1 Didier Boturyn
A1 Tatsuya Higashi
YR 2021
UL http://jnm.snmjournals.org/content/62/supplement_1/1215.abstract
AB 1215Objectives: We have successfully developed 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD) as a multimeric RGD-based radiopeptide for specifically targeting the transmembrane cell adhesion receptor, αVβ3 integrin (αVβ3). Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors. Despite advances in surgical cytoreduction and drug development, the 5-year survival rate for OCPM patients remains as low as &lt;30%. The αVβ3 is overexpressed on tumoral neovessels and also on ovarian cancer cells and the radioisotope 64Cu has a suitable half-life (12.7 h) and multiple decay modes for both PET imaging and therapeutic irradiation. Hence, the present study aimed to evaluate the radiotheranostic potential of 64Cu-RaftRGD in clinically relevant αVβ3-positive OCPM small animal models. Methods: Athymic BALB/c nude mice with intraperitoneally inoculated ovarian carcinoma IGR-OV1 and NIH:OVCAR-3 cells were used as the OCPM small animal models, and their corresponding subcutaneous xenografts were used as a reference. 64Cu-RaftRGD was administered either intravenously or intraperitoneally to determine the optimal injection route. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies. Results: Intraperitoneal administration (i.p.) was shown to be the efficient route for targeting 64Cu-RaftRGD to OCPMs with excellent tumor penetration. The fluorescent surrogate Cy5.5-labeled RaftRGD and high-resolution multifluorescence imaging found that the ITD of 64Cu-RaftRGD was colocalized with CD31-stained microvessels and spatially distinct from but complementary to that of pimonidazole-stained hypoxia. 64Cu-RaftRGD (i.p.) PET visualized multiple OCPM deposits and ascites. The biodistribution study demonstrated an inverse correlation between the tumor size (1.2-17.2 mm) and tumor uptake levels (also absorbed doses). 64Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol, i.p.) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis detected on day 3 after therapy, and significantly prolonged the survival of mice. The toxicity evaluation of 148 MBq/0.357 nmol i.p. 64Cu-RaftRGD in normal mice for 60 days after administration demonstrated negligible toxicity in hematology and hepatorenal functions. Conclusion: Our results demonstrate the all-in-one potential of the i.p. 64Cu-RaftRGD as a tumor penetrating radiodrug for PET imaging-guided radiotherapy of OCPMs by targeting both tumoral neovessels and cancerous cells, with negligible toxicity. We propose that further study of intra- and intertumoral heterogeneity of the radiodrug in relation to the tumor microenvironment may provide a basis for understanding the treatment limitation and facilitate a rational combination therapy design.