Abstract
Purpose: In this study, we independently synthesised and labelled a novel bidentate bifunctional chelating agent, 177Lu-3,4-HOPO-Cetuximab, that achieved tight binding between targeting and radioactivity, and evaluated its targeted killing ability of cells in vitro and in vivo.Method: 3,4-HOPO was successfully synthesised through a series of chemical steps using malt phenol as the raw material, which was then coupled with Cetuximab labelled with 177Lu. 177Lu-3,4-HOPO-Cetuximab and 177Lu-DOTA-Cetuximab was tested for its cell viability and cell-binding rate after different times and at different doses by CCK-8 and cell-binding experiments. 177Lu-3,4-HOPO-Cetuximab (~500 μCi) and 177Lu-DOTA-Cetuximab (~500 μCi) were injected into the tail vein of a subcutaneous metastasis mouse model of triple-negative breast cancer with a single injection, and tumour volume growth and body weight changes were regularly monitored for 20 days. The radioactivity distribution in nude mice was analysed after sacrifice, and the treated and untreated tumour tissues were analysed by HE staining.Result: The cell viability of 177Lu-3,4-HOPO-Cetuximab declined exponentially after treatment for 48 h at 50 Bq/mL to 500 kBq/mL, respectively; the cell activity was slowed down from 8 to 96 h at a dose of 500 kBq; while the binding rate of 4T1 cells in 177Lu-3,4-HOPO-Cetuximab from 1 to 24 h, respectively, increased logarithmically, which was similar with 177Lu-DOTA-Cetuximab. After 20 days of treatment, the body weight of nude mice with 177Lu-3,4-HOPO-Cetuximab and 177Lu-DOTA-Cetuximab were hardly changed, while the body weight with physiological saline decreased significantly. The tumour inhibition rate of the 177Lu-3,4-HOPO-Cetuximab and 177Lu-DOTA-Cetuximab were (37.03 ± 11.16)% and (38.7 ± 5.1)%; HE staining showed that tumour cells were affected by the action of 177Lu causing necrosis.Conclusion: The experiments showed that 177Lu-3,4-HOPO-Cetuximab has a certain targeted therapeutic ability for triple-negative breast cancer, and it is expected to become a potential targeted nuclear medicine treatment for triple-negative breast cancer.
Highlights
The Transitional Breast Cancer Research Consortium (TBCRC) conducted a clinical trial (Cleere, 2010; Lisa et al, 2012; Fatima et al, 2015; Chen et al, 2017; Zimei and Zan, 2017; Pindiprolu et al, 2018) and found that TNBC patients tolerate Cetuximab well with small adverse reactions, its efficacy is limited
The results of UV absorption at 254 nm showed that the HPLC chromatogram of 3,4-HOPO occurred an absorption peak only at 2.2 min with no obvious impurity peaks appeared elsewhere
Mass spectrometry (Figure 2b) shows the LC-MS [M+H+] m/z: 184.00. Since it is the test result in H+ mode, it is inferred that the actual molecular weight is 183.00 Infrared spectrum (Figure 2c) ensured that the structure of 3,4-HOPO is correct
Summary
The Transitional Breast Cancer Research Consortium (TBCRC) conducted a clinical trial (Cleere, 2010; Lisa et al, 2012; Fatima et al, 2015; Chen et al, 2017; Zimei and Zan, 2017; Pindiprolu et al, 2018) and found that TNBC patients tolerate Cetuximab well with small adverse reactions, its efficacy is limited. This suggests that the combination of Cetuximab and EGFR inhibitor therapy is expected to be a development point for TNBC. Several peptides and monoclonal antibodies (mAbs) have been conjugated to bifunctional chelators and the labelled radionuclide 177Lu. Ramli et al (2011) successfully prepared radioimmunoassays based on the anti-HER-2 monoclonal antibody compound 177Lu-DOTA-trastuzumab, which showed potent anticancer effects
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