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Targeted delivery of nuclear targeting probe for bladder cancer using cyclic pentapeptide c(RGDfK) and acridine orange

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Abstract

Purpose

Both cyclic pentapeptide c(RGDfK) and acridine orange (AO) exhibit antitumor effects and cell permeability. This study aimed to evaluate the nuclear targeting efficiency and safety of the nuclear targeting probe for bladder cancer (BCa) synthesized by c(RGDfK) and AO.

Methods

The nuclear targeting probe AO-(cRGDfK)2 was synthesized from AO hydrochloride, azided c(RGDfK), and a near-infrared skeleton synthesized via click chemistry reactions. The effect of the AO-(cRGDfK)2 probe on cell viability was assessed in BCa 5637 cells. The tumor cell targeting efficacy of the AO-(cRGDfK)2 probe was evaluated in BCa cells in vitro and in tumor-bearing mice in vivo. Nuclear-specific accumulation of fluorescence probe in BCa tumor cells was evaluated using laser scanning confocal microscopy (LSCM). Hematoxylin and eosin staining was performed to detect histopathological changes in the spleen, heart, liver, and kidney.

Results

The AO-(cRGDfK)2 probe did not cause a significant reduction in cell viability. LSCM analysis showed that AO-(cRGDfK)2 exhibited nuclear-specific ambulation in BCa cells and was not accumulated in 293T cells. Also, this probe efficiently targeted tumor cells in the serum and urine samples. In vivo imaging system of tumor-bearing mice showed that ~ 80% percent of fluorescence signal was accumulated in the tumor sites. The probe did not change histopathology in the heart, liver, spleen, and kidney in tumor-bearing mice after the 21-day treatment.

Conclusions

The AO-(cRGDfK)2 probe exhibited nuclear-specific accumulation in BCa cells without cytotoxicity, which provides an innovative alternative to improve anticancer therapy for BCa.

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Funding

This work was supported by the National Natural Science Foundation of China (82004110), the Jiangsu Province Key Research and Development Program (BE2020758, BE2019637); the Xuzhou Medical Outstanding Talents (Xuzhou Health Education Research [2017] No.22); the Jiangsu Medical Innovation Team (CXTDA2017048); the Key Projects of Xuzhou Science and Technology Plan (KC19075, KC21184) and the Xuzhou clinical medicine expert team project(2018TD004); the Jiangxi Province Health Commission Science and technology project (202120104).

Author information

Author notes

  1. Jiaxin Qin, Qing Liang and Guangyue Wang have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Urology, Xuzhou Clinical College of Xuzhou Medical University, Jiefang South Road, No. 199, Xuzhou, Jiangsu, China

    Jiaxin Qin, Qing Liang, Lin Hao, Xing Liu, Xinlei Wang, Liang Xue, Yan Zhao, Conghui Han & Zhenduo Shi

  2. Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu, China

    Jiaxin Qin, Qing Liang, Lin Hao, Xing Liu, Xinlei Wang, Liang Xue, Yan Zhao, Conghui Han & Zhenduo Shi

  3. Graduate School of Bengbu Medical College, Anhui, China

    Guangyue Wang

  4. Graduate School of Jinzhou Medical College, Liaoning, China

    Zhengxiang Hu

  5. School of Life Sciences, Jiangsu Normal University, Jiangsu, China

    Gaochuan Fang, Conghui Han & Zhenduo Shi

  6. Central Laboratory, Xuzhou Central Hospital, Xuzhou, Jiangsu, China

    Rui Li & Qian Lv

  7. Department of Urology, Shanghai East Hospital Ji’an Hospital, Jiangxi, People’s Republic of China

    Jiling Wen & Guosheng Yang

  8. Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China

    Jiling Wen & Guosheng Yang

  9. Department of Urology, Heilongjiang Provincial Hospital, Heilongjiang, China

    Conghui Han

Authors
  1. Jiaxin Qin
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  2. Qing Liang
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  4. Lin Hao
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  5. Xing Liu
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  8. Gaochuan Fang
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  10. Yan Zhao
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  13. Jiling Wen
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  14. Guosheng Yang
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  15. Conghui Han
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  16. Zhenduo Shi
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Contributions

JQ, QL, GW, CH and ZS are responsible for the conception or design of the work. JQ, QL, GW, LH, XL, XW, ZH, GF, LX, YZ, RL, QL, JW, GY, CH and ZS contribute to the acquisition, analysis, or interpretation of data for the work. LH, XL, XW and ZH prepare the tissue samples. QL, JW and GY help in the experiments. All authors finally approved the manuscript version to be published. QZ is the guarantor of the article.

Corresponding authors

Correspondence to Conghui Han or Zhenduo Shi.

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The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Ethical Committee of Xuzhou Clinical College of Xuzhou Medical University and conducted in accordance with ethical standards.

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Qin, J., Liang, Q., Wang, G. et al. Targeted delivery of nuclear targeting probe for bladder cancer using cyclic pentapeptide c(RGDfK) and acridine orange. Clin Transl Oncol 25, 375–383 (2023). https://doi.org/10.1007/s12094-022-02938-0

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  • DOI: https://doi.org/10.1007/s12094-022-02938-0

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