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Published on: January 7, 2019
A cutting-edge 68Ga-labeled bicyclic peptide PET molecular probe for noninvasive assessment of Nectin4 expression
Shushan Ge1, Tongtong Jia2, Jinyu Shi2
1Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215006, China; Nuclear Medicine Laboratory of Mianyang Central Hospital, Mianyang 621099, China.
Abstract:
The diagnosis and treatment of triple negative breast cancer (TNBC) are huge challenges due to the lack of identifiable molecular targets. The high expression of Nectin4 in a variety of tumors, including TNBC, is associated with the occurrence, invasion, progression and poor prognosis of tumors. Therefore, Nectin4 is an emerging biomarker for the diagnosis and treatment of TNBC. A PET imaging method to non-invasively quantify Nectin4 expression levels may aid in TNBC diagnosis and classification. In this study, a novel bicyclic peptide molecular probe [68Ga]Ga-DN68 was used to evaluate the expression of Nectin4 in tumors. The radiolabeling rate of [68Ga]Ga-DN68 was over 97 %, while maintaining more than 99 % radiochemical purity. In vitro experiments showed that [68Ga]Ga-DN68 could effectively target Nectin4 in tumor cells, and the cellular uptake of MC38-Nectin4 cells (Nectin4+) was significantly higher than that of MC38 cells (Nectin4-). Biodistribution and PET imaging studies consistently showed that [68Ga]Ga-DN68 was specifically accumulated in MC38-Nectin4 and MDA-MB-468 tumors, which was significantly higher than that of MC38. When co-injected with cold DN68, the specific accumulation could block the tumor uptake of MDA-MB-468. Notably, the signal-to-noise ratio at the tumor site gradually increased over time, reaching a peak at 1 h. These results strongly suggest that [68Ga]Ga-DN68 has broad application prospects as a PET tracer in TNBC imaging.
Insights
Researchers developed a novel PET imaging agent, [68Ga]Ga-DN68, to detect Nectin4, a biomarker for triple-negative breast cancer (TNBC). This agent shows promise for non-invasive TNBC diagnosis and classification.
Area of Science:
- Biomedical imaging
- Molecular oncology
- Radiopharmaceutical chemistry
Background:
- Triple-negative breast cancer (TNBC) lacks specific molecular targets, complicating diagnosis and treatment.
- Nectin4 is highly expressed in TNBC and linked to tumor progression and poor prognosis, making it a potential diagnostic and therapeutic biomarker.
- Non-invasive methods to quantify Nectin4 expression are needed for TNBC management.
Purpose of the Study:
- To develop and evaluate a novel positron emission tomography (PET) imaging probe, [68Ga]Ga-DN68, for non-invasively detecting Nectin4 expression in TNBC.
- To assess the specificity and efficacy of [68Ga]Ga-DN68 for targeting Nectin4-positive tumors.
Main Methods:
- Synthesis and radiolabeling of the bicyclic peptide [68Ga]Ga-DN68, achieving high radiolabeling yield (>97%) and purity (>99%).
- In vitro evaluation of [68Ga]Ga-DN68's targeting ability in Nectin4-positive (MC38-Nectin4) and Nectin4-negative (MC38) cancer cells.
- In vivo studies involving biodistribution and PET imaging in tumor-bearing mice to assess tumor uptake, specificity, and blocking effects.
Main Results:
- [68Ga]Ga-DN68 demonstrated effective targeting of Nectin4 in vitro, with significantly higher uptake in Nectin4+ cells compared to Nectin4- cells.
- PET imaging and biodistribution studies confirmed specific accumulation of [68Ga]Ga-DN68 in tumors expressing Nectin4 (MC38-Nectin4 and MDA-MB-468), with minimal uptake in control tumors (MC38).
- Co-injection with unlabeled DN68 blocked tumor uptake, confirming the specificity of [68Ga]Ga-DN68 for Nectin4, and optimal tumor-to-background signal was observed at 1 hour post-injection.
Conclusions:
- [68Ga]Ga-DN68 is a highly efficient and specific PET tracer for Nectin4.
- This novel probe shows significant potential for non-invasive diagnosis, classification, and monitoring of triple-negative breast cancer.
