Department of Molecular Biology Laboratory, Shanghai Sixth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233, China.
Biomaterials. 2013 Sep;34(28):6829-38. doi: 10.1016/j.biomaterials.2013.05.036. Epub 2013 Jun 12.
Breast cancer is characterized by a stromal microenvironment consisting of highly abundant hyaluronan (HA). The role of the HA-coat as a 'fortress' fencing off tumor cells from drugs applied in the circulation has been largely neglected by previous research efforts. In this study we demonstrated that an unusually abundant secreted HA contributed to drug resistance in breast cancer. However, oligosaccharides of HA (oHA) treatment disrupted the cell-associated HA-coat and rendered breast cancer cells profoundly vulnerable to paclitaxel. Next the anti-tumor activity of self-assembled oHA-loaded nanoparticles was evaluated. Results showed that the nanoparticles induced an anti-tumor response both in vitro and in vivo. Systemic application of the nanoparticles dramatically increased the activity of chemotherapies and reduced tumor growth in breast tumor-bearing mouse model, possibly as a result of reduced accumulation of HA in the extracellular matrix surrounding xenografts tumor. We provided direct evidence suggesting that oHA possesses the advantages of ideal drug carrier and drug targeting, and oHA-loaded nanoparticles have great potential to overcome HA associated chemoresistance and improve cancer therapy.
乳腺癌的特征是由富含透明质酸（HA）的基质微环境组成。先前的研究工作在很大程度上忽视了 HA 涂层作为将肿瘤细胞与循环中应用的药物隔离开来的“堡垒”的作用。在这项研究中，我们证明了异常丰富的分泌型 HA 有助于乳腺癌的耐药性。然而，HA 的低聚糖（oHA）处理破坏了细胞相关的 HA 涂层，使乳腺癌细胞对紫杉醇变得非常敏感。接下来，评估了自组装的负载 oHA 的纳米粒子的抗肿瘤活性。结果表明，纳米粒子在体外和体内均诱导了抗肿瘤反应。纳米粒子的系统应用显著增加了化疗药物的活性，并减少了乳腺癌荷瘤小鼠模型中的肿瘤生长，这可能是由于外植体肿瘤周围细胞外基质中 HA 的积累减少所致。我们提供了直接证据表明，oHA 具有理想的药物载体和药物靶向的优势，负载 oHA 的纳米粒子具有克服 HA 相关化疗耐药性和改善癌症治疗的巨大潜力。
