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The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy

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Summary

A new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft models. Our results showed that Caba-780 was efficiently absorbed by DU145 and PC-3 cells and that the cytotoxicity of Caba-780 was significantly stronger than that of IR-780 and cabazitaxel. In addition, Caba-780 inhibited the migration and invasion of DU145 and PC-3 cells and promoted apoptosis by prolonging the G2 phase of the cell cycle. Further analysis indicated that Caba-780 could be used to effectively image tumor xenografts. At the same time, this drug inhibited the growth of tumors in vivo. Therefore, the new synthetic drug Caba-780 has potential applications in the diagnosis and treatment of CRPC.

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Funding

This work was supported by the Military Medical Innovation Project (16CXZ023) and the Key Science and Technology Program of Shaanxi Province (2014k11‑03-05-01).

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Author notes

  1. Yu Zheng, Guangdong Hou, Geng Zhang and Ting Lan contributed equally to this research as co-first authors.

Authors and Affiliations

  1. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Yu Zheng, Guangdong Hou, Geng Zhang, Lei Zhang, Fei Yan, Fuli Wang, Ping Meng, Xinlong Dun, Xi’an Li, Zheng Zhu, Di Wei & Jianlin Yuan

  2. Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, China

    Ting Lan & Wei He

  3. St. George’s University School of Medicine, St. George’s, West Indies, Grenada

    Jiarui Yuan

  4. State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, Fourth Military Medical University, Xi’an, Shaanxi, China

    Guo Chen

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  1. Yu Zheng
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Correspondence to Wei He or Jianlin Yuan.

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ESM 1

Supplementary Fig. 1. Semiquantitative uptake of Caba-780 by cells. (a) Uptake of Caba-780 by WMPY-1 and CRPC cells. Compared with WMPY-1 cells, PC-3 and DU145 cells were more efficient in Caba-780 uptake; all P-values < 0.0001. (b) Uptake of Caba-780 by CRPC cells at different concentrations. As the concentration increased, the uptake of Caba-780 by CRPC cells also increased. The uptake of Caba-780 by CRPC cells was concentration-dependent. The P-value was 0.0298 between the 20 µM and 10 µM PC-3 groups, while all the other P-values were < 0.0001. (c) Uptake of Caba-780 by CRPC cells at different time points. Under the same concentration conditions, Caba-780 uptake by CRPC cells also increased with time. The uptake of Caba-780 by CRPC cells was time-dependent, and all P-values were < 0.0001. (d) Inhibition of Caba-780 uptake. The OATP blockers inhibited the uptake of Caba-780 by CRPC cells to varying degrees. Compared with the control group, all P-values < 0.0001. *P < 0.05, **P < 0.01. Supplementary Fig. 2. In vitro effect of Caba-780 on CRPC cells. (a) Migration assay for DU145 cells. From left to right are the control, IR-780, cabazitaxel, and Caba-780 groups. The first horizontal row is the spacing pattern of the initial scratch wound. The second horizontal row is the pattern indicating cell migration towards the scratch after 12 h (magnification, 100 ×, scale: 100 µm). (b) Statistical analysis of the DU145 migration assay. The migration distance of cells in the Caba-780 group was reduced compared to that of the other groups. (c) Migration assay for PC-3 cells. From left to right are the control, IR-780, cabazitaxel, and Caba-780 groups. The first horizontal row indicates the initial scratch wound. The second horizontal row indicates the migration of cells towards the scratch after 12 h (magnification, 100 ×; scale: 100 µm). (d) Statistical analysis of the PC-3 migration assay. The migration distance of cells in the Caba-780 group was less than that of the other groups. (e) Invasion assay for DU145 (above) and PC-3 cells (below). From left to right are the control, IR-780, cabazitaxel, and Caba-780 groups. In the two CRPC cell lines, the number of invasive cells in the Caba-780 group was significantly less than that in the other groups (magnification, 200 ×; scale: 50 µm). (f) Statistical analysis of the invasion assay for DU145 (above) and PC-3 cells (below). In both DU145 and PC-3 cells, the number of invasive cells in the Caba-780 group was less than that in the other groups. *P < 0.05, **P < 0.01. Supplementary Fig. 3. Apoptosis and cell cycle assays for PC-3 cells. (a) Apoptosis assay for PC-3 cells. From left to right are the control, IR-780, cabazitaxel, and Caba-780 groups. The apoptosis rate was defined as the percentage of Annexin V-FITC-positive and PI-negative cells out of the total number of cells. (b) Cell cycle assay for PC-3 cells. From left to right are the control, IR-780, cabazitaxel, and Caba-780 groups. The red peaks on the left side of each group represent the percentage of cells in the G1 phase, the red peaks on the right represent the percentage of cells in the G2 phase, and the shaded bottoms represent the percentage of cells in the S phase. (c) Statistical analysis of the apoptosis assay (left) and cell cycle assay (right) for PC-3 cells. The apoptotic rate in the Caba-780 group was higher than it was in the other groups. In addition, the proportion of G2 phase cells in the Caba-780 group was higher than it was in the other groups. *P < 0.05, **P < 0.01. (PDF 180 kb)

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Zheng, Y., Hou, G., Zhang, G. et al. The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy. Invest New Drugs 38, 1641–1652 (2020). https://doi.org/10.1007/s10637-020-00934-1

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