Chemotherapy priming of the Pancreatic Tumor Microenvironment Promotes Delivery and Anti-Metastasis Efficacy of Intravenous Low-Molecular-Weight Heparin-Coated Lipid-siRNA Complex
Chemotherapy priming of the Pancreatic Tumor Microenvironment Promotes Delivery and Anti-Metastasis Efficacy of Intravenous Low-Molecular-Weight Heparin-Coated Lipid-siRNA Complex
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DOI：
10.7150/thno.29137
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发表时间：
2019-01
期刊：
影响因子：
12.4
通讯作者：
Qianwen Yu;Yue Qiu;Xiaoxiao Chen;Xuhui Wang;Ling Mei;Haiyao Wu;Kai Liu;Yayuan Liu;Man Li;Zhirong Zhang;Qin He
中科院分区：
文献类型：
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作者：
Qianwen Yu;Yue Qiu;Xiaoxiao Chen;Xuhui Wang;Ling Mei;Haiyao Wu;Kai Liu;Yayuan Liu;Man Li;Zhirong Zhang;Qin He
胰腺导管腺癌（PDAC）是一种致死率很高的恶性肿瘤。其高肿瘤细胞密度和多种细胞外基质（ECM）成分构成了药物输送的主要障碍。方法：使用负载紫杉醇的聚乙二醇化脂质体（PTX-Lip）作为肿瘤引发剂，诱导肿瘤细胞凋亡并降低ECM的丰度，从而促进纳米药物的细胞摄取和肿瘤递送。紫杉醇具有抗癌作用，但矛盾的是，紫杉醇通过增加凋亡 B 细胞淋巴瘤 2 蛋白 (BCL-2) 的表达而加剧癌症转移和耐药性。因此，构建了低分子量肝素包被的脂质-siRNA复合物（LH-Lip/siBCL-2）以抑制癌症转移并通过BCL-2 siRNA（siBCL-2）沉默BCL-2。结果：具有显着的肿瘤生长抑制功效，并伴有明显的体内癌症转移抑制作用。结论：这些结果表明我们顺序递送 PTX-Lip 和 LH-Lip/siBCL-2 可能为 PDAC 或其他富含 ECM 的肿瘤提供实用的方法。
Pancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with high lethality. Its high tumor cell-density and large variety of extracellular matrix (ECM) components present major barriers for drug delivery. Methods: Paclitaxel-loaded PEGylated liposomes (PTX-Lip) were used as a tumor-priming agent to induce tumor cell apoptosis and decrease the abundance of ECM to promote cellular uptake and tumor delivery of nanodrugs. Paclitaxel exerts anti-cancer effects but, paradoxically, exacerbates cancer metastasis and drug resistance by increasing the expression of apoptotic B-cell lymphoma-2 protein (BCL-2). Thus, low-molecular-weight heparin-coated lipid-siRNA complex (LH-Lip/siBCL-2) was constructed to inhibit cancer metastasis and silence BCL-2 by BCL-2 siRNA (siBCL-2). Results: Significant tumor growth inhibition efficacy was observed, accompanied by obvious inhibition of cancer metastasis in vivo. Conclusion: These results suggested our sequential delivery of PTX-Lip and LH-Lip/siBCL-2 might provide a practical approach for PDAC or other ECM-rich tumors.