转移
癌症研究
透明质酸
紫杉醇
CD44细胞
细胞毒性
车站3
癌细胞
癌症
化学
材料科学
乳腺癌
医学
细胞
体外
细胞凋亡
内科学
生物化学
解剖
作者
Kaipei Luo,Yi Gao,Shaoping Yin,Yawen Yao,Hua Yu,Guangji Wang,Juan Li
标识
DOI:10.1016/j.actbio.2021.07.029
摘要
Metastasis is one of the major causes of mortality in patients suffering from breast cancer. The signal transducer and activator of transcription 3 (STAT3) is closely related to cancer metastasis. Herein, a multifunctional nanocomplex was developed to simultaneously deliver paclitaxel (PTX) and STAT3 siRNA (siSTAT3) to inhibit tumor growth and prevent metastasis of breast cancer cells. PTX was encapsulated into the synthesized polyethyleneimine-polylactic acid-lipoic acid (PPL) micelle through hydrophobic interaction, while siSTAT3 was condensed onto polyethyleneimine through electrostatic interaction. The surface charge of the drug-loaded nanocomplex (siSTAT3PPLPTX) was then converted to negative by coating with hyaluronic acid (HA). The multifunctional nanocomplex (HA/siSTAT3PPLPTX) effectively entered CD44-overexpressed 4T1 cells via an active targeting mechanism. HA shell was degraded by the concentrated hyaluronidase in the endo/lysosome and the rapid drug release was triggered by the redox micro-environment of cytoplasm. Moreover, HA/siSTAT3PPLPTX showed enhanced cytotoxicity against tumor cells due to a synergistic effect of PTX and siSTAT3. The effective inhibition of tumor metastasis was confirmed by in vitro cell migration and invasion in 4T1 cells. More importantly, a superior antitumor efficacy was observed in orthotopic 4T1 tumor-bearing mice, with no side effects in major organs, and the lung metastasis was strongly inhibited in 4T1 metastasis model. In conclusion, the multifunctional nanocomplex provides a versatile platform for efficient treatment of metastatic cancer through tumor-targeted chemo-gene combined therapy. STATEMENT OF SIGNIFICANCE: Metastasis is one of the major causes of mortality in patients suffering from breast cancer. The signal transducer and activator of transcription 3 (STAT3) is closely related to cancer metastasis. In this study, a multifunctional nanocomplex co-loaded with paclitaxel (PTX) and STAT3 siRNA was constructed and characterized. The co-delivery system exhibited active tumor targeting, effective endo/lysosomal escape, and rapid intracellular drug release. Both in vitro and in vivo studies indicated that the nanocomplex could lead to superior tumor growth inhibition, as well as metastasis suppression by silencing expression of STAT3 and p-STAT3. This present study implies that the nanocomplex could be a potential platform for targeted treatment of metastatic cancer through chemo-gene combined therapy.
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