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.

中文翻译：

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亚洲酸通过减少肿瘤基质胶原蛋白来增强肿瘤内递送和聚乙二醇化脂质体阿霉素的抗肿瘤作用。

肿瘤靶向药物递送系统（Tt-DDSs）被提出作为一种有前途的癌症治疗策略。然而，肿瘤基质中的致密胶原网络显着降低了Tt-DDS的渗透和功效。为了研究积雪草酸（AA）通过减弱基质胶原蛋白对聚乙二醇化脂质体阿霉素（PLD）的抗肿瘤作用，分别采用PLD，AA或联合方案治疗结肠癌异种移植小鼠（SW620细胞系）；通过天狼星红/快绿双重染色和免疫组化（IHC）染色来评估胶原蛋白水平；通过离体荧光成像观察阿霉素的肿瘤内暴露并通过HPLC / MS分析定量。此外，体外研究了AA对成纤维细胞（HFL-1）胶原合成的影响以及PLD和阿霉素对癌细胞（SW620）的细胞毒性作用。在AA（4 mg / kg）存在的情况下，体内和体外均限制了肿瘤内胶原水平（降低了22％，从4.14％±0.30％降低到3.24％±0.25％，P = 0.051）。随后，阿霉素水平增加了约30％。AA组合可显着改善PLD的抗肿瘤活性（抑制57.3％的肿瘤生长，减少44％的肿瘤重量）。另外，没有观察到AA诱导的PLD或阿霉素的细胞毒性作用有显着改善。总之，通过通过基质重塑增强肿瘤内药物暴露，AA是用于肿瘤治疗的有希望的敏化剂。体内的肿瘤内胶原水平受到限制（从22％，从4.14％±0.30％降低到3.24％±0.25％，P = 0.051）。随后，阿霉素水平增加了约30％。AA组合可显着改善PLD的抗肿瘤活性（抑制57.3％的肿瘤生长，减少44％的肿瘤重量）。另外，没有观察到AA诱导的PLD或阿霉素的细胞毒性作用有显着改善。总之，通过通过基质重塑增强肿瘤内药物暴露，AA是用于肿瘤治疗的有希望的敏化剂。体内的肿瘤内胶原水平受到限制（从22％，从4.14％±0.30％降低到3.24％±0.25％，P = 0.051）。随后，阿霉素水平增加了约30％。AA组合可显着改善PLD的抗肿瘤活性（抑制57.3％的肿瘤生长，减少44％的肿瘤重量）。另外，没有观察到AA诱导的PLD或阿霉素的细胞毒性作用有显着改善。总之，通过通过基质重塑增强肿瘤内药物暴露，AA是用于肿瘤治疗的有希望的敏化剂。另外，没有观察到AA诱导的PLD或阿霉素的细胞毒性作用有显着改善。总之，通过通过基质重塑增强肿瘤内药物暴露，AA是用于肿瘤治疗的有希望的敏化剂。另外，没有观察到AA诱导的PLD或阿霉素的细胞毒性作用有显着改善。总之，通过通过基质重塑增强肿瘤内药物暴露，AA是用于肿瘤治疗的有希望的敏化剂。