期刊
JOURNAL OF CONTROLLED RELEASE
卷 161, 期 3, 页码 875-883出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2012.05.015
关键词
siRNA delivery; Breast cancer therapy; DNA methyltransferases; Single-chain antibody fragment
资金
- National Basic Research Program of China (973 Programs) [2010CB934001, 2009CB930301]
- National Natural Science Foundation of China [51125012, 81172526]
- Specialized Research Fund for the Doctoral Program of Higher Education from the Ministry of Education of China [SRFDP 20113402130008]
- Fundamental Research Funds for the Central Universities [WK2070000008]
- Open Project of State Key Laboratory of Supramolecular Structure and Materials [SKLSSM201201]
The targeted delivery of small interfering RNA (siRNA) to specific tumor tissues and tumor cells remains as one of the key challenges in the development of RNA interference as a therapeutic application. To target breast cancer, we developed a therapeutic delivery system using a fusion protein of an anti-Her2 single-chain antibody fragment with a positively charged protamine, namely F5-P, as the carrier to specifically deliver siRNA-targeting DNA methyltransferases 1 and/or 3b genes (siDNMTs) into Her2-expressing breast tumor cells. The carrier F5-P, expressed by the Escherichia coli system, was able to bind siRNA molecules and specifically deliver the siRNA to Her2-expressing BT474 breast cancer cells but not Her2-nonexpressing MDA-MB-231 breast cancer cells, while delivery of siDNMTs to BT474 cells successfully silenced the expression of targeted DNA methyltransferases (DNMTs) and facilitated the de-methylation of the RASSF1A tumor suppressor gene promoter, leading to the suppression of tumor cell proliferation. Moreover, as demonstrated in the BT474 xenograft murine model, F5-P successfully delivered siRNA into a Her2-expressing breast tumor, and tumor growth inhibition was mediated by an intravenous injection of F5-P/siDNMTs complex by down-regulating the expression of DNMTs and restoring tumor suppressor gene expression. These data suggest that the delivery of siDNMTs by F5-P could be used to treat Her2-expressing breast cancer. (c) 2012 Elsevier B.V. All rights reserved.
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