间质细胞
吉西他滨
胰腺癌
基质
药物输送
癌症研究
材料科学
一氧化氮
纳米医学
脂质体
咬合
纳米颗粒
医学
癌症
病理
内科学
纳米技术
免疫组织化学
计算机图形学(图像)
计算机科学
作者
Xiaohui Chen,Fan Jia,Yongzhou Li,Yongyan Deng,Yue Huang,Weifeng Liu,Qiao Jin,Jian Ji
出处
期刊:Biomaterials
[Elsevier]
日期:2020-07-01
卷期号:246: 119999-119999
被引量:75
标识
DOI:10.1016/j.biomaterials.2020.119999
摘要
Abundant desmoplastic stroma, which typically exists in pancreatic ductal adenocarcinoma (PDAC), can act as a natural protective physical barrier rendering insufficient drug delivery and penetration. To address this issue, we herein report a two-step sequential delivery strategy for enhanced pancreatic cancer therapy. In this sequential strategy, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) loaded liposomes (Lip-SNAP) were firstly delivered to pancreatic stellate cells (PSCs) in tumor tissue to inhibit the production of dense stroma, by inhibiting the expression of TGF-β1 and its downstream profibrotic signal transduction. Therefore, the PSC-mediated desmoplastic reaction could be suppressed by inhibiting the expression of fibronectin, α-SMA and collagen. The gemcitabine (GEM) loaded liposomes (Lip-GEM) were administrated subsequently. The enhanced intratumoral penetration of Lip-GEM was then achieved due to the stromal disruption in consequence of NO treatment, thus significantly improving the drug delivery efficiency. The tumor growth inhibition of the two-step sequential delivery of Lip-SNAP and Lip-GEM was investigated on both subcutaneous and orthotopic tumor mouse models, to show the remarkably improved therapeutic efficacy of GEM. Such NO-induced stromal depletion provides a general strategy to overcome the blockage of desmoplastic stroma on other therapeutic agents.
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