The use of HA oligosaccharide-loaded nanoparticles to breach the endogenous hyaluronan glycocalyx for breast cancer therapy.
The use of HA oligosaccharide-loaded nanoparticles to breach the endogenous hyaluronan glycocalyx for breast cancer therapy.
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DOI：
10.1016/j.biomaterials.2013.05.036
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发表时间：
2013-09
期刊：
影响因子：
14
通讯作者：
Cuixia Yang;Yi-wen Liu;Yi-qing He;Yan Du;Wen-juan Wang;Xiaoxin Shi;F. Gao
中科院分区：
文献类型：
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作者：
Cuixia Yang;Yi-wen Liu;Yi-qing He;Yan Du;Wen-juan Wang;Xiaoxin Shi;F. Gao
乳腺癌的特征是由高度丰富的透明质酸(HA)组成的间质微环境。透明质酸大衣作为一座“堡垒”，将肿瘤细胞与循环中应用的药物隔离开来，这一作用在很大程度上被以前的研究工作忽视了。在这项研究中，我们证明了异常丰富的透明质酸分泌与乳腺癌的耐药性有关。然而，低聚透明质酸(OHA)治疗打乱了细胞相关的透明质酸外壳，使乳腺癌细胞对紫杉醇非常脆弱。其次，对自组装的羟基磷灰石纳米粒的抗肿瘤活性进行了评价。结果表明，纳米粒在体外和体内都诱导了抗肿瘤反应。在荷乳腺肿瘤的小鼠模型中，全身应用纳米粒显著提高了化疗的活性，并减少了肿瘤的生长，这可能是由于减少了HA在异种移植瘤周围细胞外基质中的积聚。我们提供的直接证据表明，OHA具有理想的药物载体和药物靶向性的优势，负载OHA的纳米颗粒在克服HA相关的化疗耐药和提高肿瘤治疗方面具有巨大的潜力。
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.