Asiatic acid enhances intratumor delivery and the antitumor effect of pegylated liposomal doxorubicin by reducing tumor-stroma collagen

Abstract

Tumor-targeted drug delivery systems (Tt-DDSs) are proposed as a promising strategy for cancer care. However, the dense collagen network in tumors stroma significantly reduces the penetration and efficacy of Tt-DDS. In order to investigate the effect of asiatic acid (AA) on antitumor effect of pegylated liposomal doxorubicin (PLD) by attenuating stroma-collagen, colon cancer xenograft mice (SW620 cell line) were treated by PLD, AA, or combined regimes, respectively; the collagen levels were estimated by Sirius red/fast green dual staining and immunohistochemistry (IHC) staining; the intratumor exposure of doxorubicin was visualized by ex vivo fluorescence imaging and quantified by HPLC/MS analysis. In addition, the impact of AA on collagen synthesis of fibroblast cell (HFL-1) and cytotoxic effect of PLD and doxorubicin to cancer cell (SW620) were studied in vitro. In the presence of AA (4 mg/kg), the intratumor collagen level was restricted in vivo (reduced by 22%, from 4.14% ± 0.30% to 3.24% ± 0.25%, P = 0.051) and in vitro. Subsequently, doxorubicin level was increased by ~30%. The antitumor activity of PLD was significantly improved (57.3% inhibition of tumor growth and 44% reduction in tumor weight) by AA combination. Additionally, no significant improvement in cytotoxic effect of PLD or doxorubicin induced by AA was observed. In conclusion, AA is a promising sensitizer for tumor treatment by enhancing intratumor drug exposure via stromal remodeling.

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Acknowledgements

The authors thank Dr. Qin-jie Weng and Dr. Xiao-yang Dai at the Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, China, for xenograft-model building; Dr. Xiao-dan Wu and Dr. Zhi-wei Ge at the Center of Analysis and Measurement, Zhejiang University, China, for HPLC-MS/MS analysis of doxorubicin; and Dr. Tian-yuan Zhang at the Institute of Pharmaceutics, Zhejiang University, China, for ex vivo fluorescence imaging of doxorubicin. This work was supported by the National Natural Science Foundation of China (81301873 and 81773819), the Natural Science Foundation of Zhejiang Province (LY16H160038 and LQ17H300001), the Science and Technology in Zhejiang Province Chinese Medicine Program (2015ZA036), the Scientific Research Key Program of the Health Bureau of Zhejiang Province (WKJ-ZJ-1504), the Medical Science Research Foundation of Zhejiang Province (2015ZDA006), the Zhejiang Provincial Program for the Cultivation of 151 Talents (PH and LF), the Zhejiang Provincial Program for the Cultivation of High-level Innovative Heath Talents (Ping Huang), and the Zhejiang Cancer Hospital Program for the Cultivation of 1022 Talents (LF).

Author contributions

F-zL, PH, and LF designed the research. LF, S-sK, L-kZ, Y-jL, C-mW, and JS performed the research. LF, S-sK, and H-yD analyzed the data. LF, Y-jL, and Y-wZ wrote the paper. All authors approved the final manuscript.

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Correspondence to Fan-zhu Li or Ping Huang.

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The authors declare no competing interests.

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Fang, L., Kong, S., Zhong, L. et al. Asiatic acid enhances intratumor delivery and the antitumor effect of pegylated liposomal doxorubicin by reducing tumor-stroma collagen. Acta Pharmacol Sin 40, 539–545 (2019). https://doi.org/10.1038/s41401-018-0038-2

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Keywords

  • colon cancer
  • asiatic acid
  • pegylated liposomal doxorubicin
  • stromal collagen
  • intratumor drug delivery