Search

Purpose: The advancement of heterodimeric tracers, renowned for their high sensitivity, marks a significant trend in the development of radiotracers for cancer diagnosis. Our prior work on [68Ga]Ga-HX01, a heterodimeric tracer targeting CD13 and integrin αvβ3, led to its approval for phase I clinical trials by the China National Medical Production Administration (NMPA). However, its fast clearance and limited tumor retention pose challenges for broader clinical application in cancer treatment. This study aims to develop a new radiopharmaceutical with increased tumor uptake and prolonged retention, rendering it a potential therapeutic candidate. Methods: New albumin binder-conjugated compounds were synthesized based on the structure of HX01. In vitro and in vivo evaluation of these new compounds were performed after labelling with 68Ga. Small-animal PET/CT imaging were conducted at different time points at 0.5–6 h post injection (p.i.) using BxPC-3 xenograft mice models. The one with the best imaging performance was further radiolabeled with 177Lu for small-animal SPECT/CT and ex vivo biodistribution investigation. Results: We have synthesized novel albumin binder-conjugated compounds, building upon the structure of HX01. When radiolabeled with 68Ga, all compounds demonstrated improved pharmacokinetics (PK). Small-animal PET/CT studies revealed that these new albumin binder-conjugated compounds, particularly [68Ga]Ga-L6, exhibited significantly enhanced tumor accumulation and retention compared with [68Ga]Ga-L0 without an albumin binder. [68Ga]Ga-L6 outperformed [68Ga]Ga-L7, a compound developed using a previously reported albumin binder. Furthermore, [177Lu]Lu-L6 demonstrated rapid clearance from normal tissues, high tumor uptake, and prolonged retention in small-animal SPECT/CT and biodistribution studies, positioning it as an ideal candidate for radiotherapeutic applications. Conclusion: A new integrin αvβ3 and CD13 targeting compound was screened out. This compound bears a novel albumin binder and exhibits increased tumor uptake and prolonged tumor retention in BxPC-3 tumors and low background in normal organs, making it a perfect candidate for radiotherapy when radiolabeled with 177Lu. [ABSTRACT FROM AUTHOR]

Purpose: The integrin αvβ3 and aminopeptidase N (APN/CD13) play vital roles in the tumor angiogenesis process. They are highly expressed in a variety of tumor cells and proliferating endothelial cells during angiogenesis, which have been considered as highly promising targets for tumor imaging. Arginine-glycine-aspartic (RGD) and asparagine-glycine-arginine (NGR) are two peptides specifically binding to the integrin αvβ3 and CD13, respectively. In this study, we optimized our previously developed probe and preclinically evaluated the new integrin αvβ3 and CD13 dual-targeted probe, NOTA-RGD-NGR (denoted as HX01) radiolabeled with 68Ga, in 10 different subcutaneous and orthotopic tumor models. Methods: The specific activity and radiochemical purity of [68Ga]Ga-HX01 were identified. The dual-receptor targeting ability was confirmed by a series of blocking studies and partly muted tracers using BxPC-3 xenograft model. The dynamic imaging study and dose escalation study were explored to determine the optimal imaging time point and dosage in the BxPC-3 xenograft model. Next, we established a variety of subcutaneous and orthotopic tumor models including pancreas (BxPC-3), breast (MCF-7), gallbladder (NOZ), lung (HCC827), ovary (SK-OV-3), colorectal (HCT-8), liver (HuH-7), stomach (NUGC-4), and glioma (U87) cancers. All models underwent [68Ga]Ga-HX01 PET/CT imaging about 2 weeks post-inoculation, with a subset of them undergoing [18F]FDG PET/CT scan performed concurrently, and their results were compared. In addition, ex vivo biodistribution studies were also performed for verifying the semi-quantitative results of the non-invasive PET images. Results: [68Ga]Ga-HX01 significantly outperformed single target probes in the BxPC-3 xenograft model. All blocking and single target groups exhibited significantly descending tumor uptake. The high tumor uptakes were found in BxPC-3, MCF-7, and NOZ subcutaneous tumors (%ID/g > 1.1), while middle uptakes were observed in HCC827, SK-OV-3, HCT-8, and HuH-7 subcutaneous tumor (%ID/g 0.7–1.0). Due to the low background, the tumor-to-muscle and tumor-to-blood ratios of [68Ga]Ga-HX01 were higher than that of [18F]FDG. Conclusions: [68Ga]Ga-HX01, as a dual target imaging agent, exhibited superior in vivo performance in different subcutaneous and orthotopic mice models of human tumors over [18F]FDG and its respectively mono-receptor targeted agents, which warrants the future clinical translation for tumor imaging. [ABSTRACT FROM AUTHOR]

Nowadays, pancreatic cancer is still a formidable disease to diagnose. The CXC chemokine receptor 4 (CXCR4) and integrin αvβ3 play important roles in tumor development, progression, invasion, and metastasis, which are overexpressed in many types of human cancers. In this study, we developed a heterodimeric tracer 68Ga-yG5-RGD targeting both CXCR4 and integrin αvβ3, and evaluated its feasibility and utility in PET imaging of pancreatic cancer. The 68Ga-yG5-RGD could accumulate in CXCR4/integrin αvβ3 positive BxPC3 tumors in a high concentration and was much higher than that of 68Ga-yG5 (p < 0.001) and 68Ga-RGD (p < 0.001). No increased uptake of 68Ga-yG5-RGD was found in MX-1 tumors (CXCR4/integrin αvβ3, negative). In addition, the uptake of 68Ga-yG5-RGD in BxPC3 was significantly blocked by excess amounts of AMD3100 (an FDA-approved CXCR4 antagonist) and/or unlabeled RGD (p < 0.001), confirming its dual-receptor targeting properties. The ex vivo biodistribution and immunohistochemical results were consistent with the in vivo imaging results. The dual-receptor targeting strategy achieved improved tumor-targeting efficiency and prolonged tumor retention in BxPC3 tumors, suggesting 68Ga-yG5-RGD is a promising tracer for the noninvasive detection of tumors that express either CXCR4 or integrin αvβ3 or both, and therefore may have good prospects for clinical translation. [ABSTRACT FROM AUTHOR]

Ovarian cancer has the highest mortality rate of gynecologic malignancy. 18F-FDG positron emission tomography (PET) adds an important superiority over traditional anatomic imaging modalities in oncological imaging but has drawbacks including false negative results at the early stage of ovarian cancer, and false positives when inflammatory comorbidities are present. Aminopeptidase N (APN, also known as CD13) and integrin αvβ3 are two important targets overexpressed on tumor neo-vessels and frequently on ovarian cancerous cells. In this study, we used subcutaneous and metastatic models of ovarian cancer and muscular inflammation models to identify 68Ga-NGR-RGD, a heterodimeric tracer consisting of NGR and RGD peptides targeting CD13 and integrin αvβ3, respectively, and compared it with 18F-FDG. We found that 68Ga-NGR-RGD showed greater contrast in SKOV3 and ES-2 tumors than 18F-FDG. Low accumulation of 68Ga-NGR-RGD but avid uptake of 18F-FDG were observed in inflammatory muscle. In abdominal metastasis models, PET imaging with 68Ga-NGR-RGD allowed for rapid and clear delineation of both peritoneal and liver metastases (3-6 mm), whereas, 18F-FDG could not distinguish the metastasis lesions due to the relatively low metabolic activity in tumors and the interference of intestinal physiological 18F-FDG uptake. Due to the high tumor-targeting efficacy, low inflammatory uptake, and higher tumor-to-background ratios compared to that of 18F-FDG, 68Ga-NGR-RGD presents a promising imaging agent for diagnosis, staging, and follow-up of ovarian tumors. [ABSTRACT FROM AUTHOR]