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Co-delivery of paclitaxel and STAT3 siRNA by a multifunctional nanocomplex for targeted treatment of metastatic breast cancer
Luo, Kaipei1,2; Gao, Yi1,2; Yin, Shaoping1,2; Yao, Yawen1,2; Yu, Hua3; Wang, Guangji4; Li, Juan1,2
2021-10-15
Source PublicationActa Biomaterialia
ISSN1742-7061
Volume134Pages:649-663
AbstractMetastasis 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 (PPL) was then converted to negative by coating with hyaluronic acid (HA). The multifunctional nanocomplex (HA/PPL) 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/PPL 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.
KeywordAntimetastasis Chemo-gene therapy Co-delivery and co-rapid release Combinative antitumor efficacy Multifunctional nanocomplex
DOI10.1016/j.actbio.2021.07.029
URLView the original
Language英語English
Scopus ID2-s2.0-85111304652
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Cited Times [WOS]:6   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 24 Tong Jia Xiang, 210009, China
2.NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing, 210009, China
3.Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, Macao
4.Center of Pharmacokinetics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, China
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GB/T 7714
Luo, Kaipei,Gao, Yi,Yin, Shaoping,et al. Co-delivery of paclitaxel and STAT3 siRNA by a multifunctional nanocomplex for targeted treatment of metastatic breast cancer[J]. Acta Biomaterialia,2021,134:649-663.
APA Luo, Kaipei,Gao, Yi,Yin, Shaoping,Yao, Yawen,Yu, Hua,Wang, Guangji,&Li, Juan.(2021).Co-delivery of paclitaxel and STAT3 siRNA by a multifunctional nanocomplex for targeted treatment of metastatic breast cancer.Acta Biomaterialia,134,649-663.
MLA Luo, Kaipei,et al."Co-delivery of paclitaxel and STAT3 siRNA by a multifunctional nanocomplex for targeted treatment of metastatic breast cancer".Acta Biomaterialia 134(2021):649-663.
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