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Journal of Integrative Medicine ›› 2021, Vol. 19 ›› Issue (5): 408-417.doi: 10.1016/j.joim.2021.05.001

• Original Experimental Research • Previous Articles     Next Articles

Design of dual targeting immunomicelles loaded with bufalin and study of their anti-tumor effect on liver cancer

Hao Goua, Ruo-chen Huangb, Yong-hua Suc,d, Wei Lie #br#   

  1. a. Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai 200433, China
    b. Teaching Office of Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201900, China
    c. Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
    d. Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai 201203, China
    e. International Joint Cancer Institute, Naval Medical University, Shanghai 200433, China
  • Online:2021-09-15 Published:2021-09-30
  • Contact: Yong-hua Su; E-mail address: suyh2001@126.com. Wei Li; E-mail address: liwei@smmu.edu.cn.

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Objective

Bufalin is an effective drug for the treatment of liver cancer. But its high toxicity, poor water-solubility, fast metabolism and short elimination half-life limit its use in tumor treatment. How to make the drug accumulate in the tumor and reduce side effects while maintaining its efficacy are urgent problems to be solved. The goal of this study is to solve these problems.

Methods

A copolymer with tunable poly-N-isopropylacrylamide and polylactic acid was designed and synthesized. The corresponding dual targeting immunomicelles (DTIs) loaded with bufalin (DTIs-BF) were synthesized by copolymer self-assembly in an aqueous solution. The size and structure of DTIs-BF were determined by ZetaSizer Nano-ZS and transmission electron microscopy. Then, its temperature sensitivity, serum stability, critical micelle concentration (CMC), entrapment efficiency (EE), drug release and non-cytotoxicity of blank block copolymer micelles (BCMs) were evaluated. Next, the effects of DTIs-BF on cellular uptake, cytotoxicity, and tumor cell inhibition were evaluated. Finally, the accumulation of DTIs-fluorescein isothiocyanate (FITC) and the in vivo anti-tumor effect were observed using an interactive video information system. 

Results

DTIs-BF had a small size, spherical shape, good temperature sensitivity, high serum stability, low CMC, high EE, and slow drug release. The blank BCMs had very low cytotoxicity. Compared with free bufalin, the in vitro cellular internalization and cytotoxicity of DTIs-BF against SMMC-7721 cells were significantly enhanced, and the effects were obviously better at 40 ℃ than 37 ℃. In addition, the therapeutic effect on SMMC-7721 cells was further enhanced by the programmed cell death specifically caused by bufalin. When DTIs-FITC were injected intravenously in BALB/c nude mice bearing liver cancer, the accumulation of FITC was significantly increased in tumors.

Conclusion

DTIs-BF is a potentially effective nano-formulation and has broad prospects in the clinical treatment of liver cancer.


Key words: Bufalin, Liver cancer, Epidermal growth factor receptor, Immunomicelles

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