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Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer
Fuqiang Shao1,2,3,4, Zhidi Pan5, Yu Long1,2,4
1Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Ave, Wuhan, 430022, China.
Background:
Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth.
Methods:
Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated.
Results:
Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity.
Conclusion:
mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.
Insights
This study introduces a novel theranostic approach targeting Nectin-4 for triple-negative breast cancer (TNBC). The Nectin-4 antibody-based system enables accurate diagnosis via radioimmunoimaging and effective treatment through photothermal therapy, offering a promising platform for TNBC management.
Area of Science:
- Oncology
- Molecular Imaging
- Theranostics
Background:
- Triple-negative breast cancer (TNBC) presents poor prognosis and limited treatment options due to high metastasis rates and resistance to targeted therapies.
- Nectin-4 is identified as a highly expressed target in TNBC, presenting an opportunity for novel diagnostic and therapeutic strategies.
- Current challenges in TNBC diagnosis and treatment necessitate innovative theranostic approaches.
Purpose of the Study:
- To develop and evaluate an anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair for TNBC.
- To utilize 99mTc-HYNIC-mAbNectin-4 for immuno-single photon emission computed tomography (SPECT) imaging for TNBC diagnosis and classification.
- To employ mAbNectin-4-ICG for Nectin-4-targeted photothermal therapy (PTT) to inhibit TNBC tumor growth.
Main Methods:
- Nectin-4 expression was validated in TNBC cells (MDA-MB-468) versus non-TNBC cells (MCF-7) using western blot, flow cytometry, and immunofluorescence.
- 99mTc-HYNIC-mAbNectin-4 targeting was assessed via cell uptake, SPECT imaging, and biodistribution studies.
- mAbNectin-4-ICG was generated, characterized, and evaluated for in vitro PTT efficacy, in vivo fluorescence imaging, and in vivo PTT treatment effects and toxicity.
Main Results:
- Overexpression of Nectin-4 in TNBC cells confirmed specific uptake of 99mTc-HYNIC-mAbNectin-4, enabling accurate TNBC diagnosis and classification via immunoSPECT.
- mAbNectin-4-ICG demonstrated good biocompatibility, potent photothermal effects, and excellent tumor targeting and retention in vivo, visualized by FL imaging.
- mAbNectin-4-ICG-mediated PTT achieved significant TNBC tumor destruction with minimal systemic toxicity.
Conclusions:
- mAbNectin-4-based radioimmunoimaging offers effective visualization for TNBC stratification and diagnosis.
- mAbNectin-4-mediated PTT demonstrated potent anti-tumor activity against TNBC.
- The developed Nectin-4 targeting strategy provides a simplified and effective theranostic platform for TNBC.
