Article

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

Authors: Luo Fang1,2, Si-si Kong1, Li-ke Zhong1, Can-ming Wang1, Yu-jia Liu1, Hai-ying Ding1, Jiao Sun1, Yi-wen Zhang1, Fan-zhu Li3, Ping Huang1
1 Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou 310022, China
2 Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Hangzhou 310022, China
3 College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310022, China
Correspondence to: Fan-zhu Li: lifanzhu@zcmu.edu.cn, Ping Huang: Huangping1841@zjcc.org.cn,
DOI: 10.1038/s41401-018-0038-2
Received: 4 December 2017
Accepted: 3 May 2018
Advance online: 19 June 2018

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.
Keywords: colon cancer; asiatic acid; pegylated liposomal doxorubicin; stromal collagen; intratumor drug delivery

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