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Effective delivery of p65 shRNA by optimized Tween 85-polyethyleneimine conjugate for inhibition of tumor growth and lymphatic metastasis.

Abstract
To maximize the interference efficacy of pGPU6/Neo-p65 shRNA-expressing pDNA (p65 shRNA) and subsequently more effectively inhibit tumor growth and lymphatic metastasis through blocking the nuclear factor-kappa B (NF-κB) signaling pathway, seven Tween 85-polyethyleneimine (PEI) conjugates (TnPs, n=2, 3, 4, 5, 6, 7 and 8), which differed in the length of the polymethylene [-(CH2)n-] spacer between Tween 85 and PEI, were synthesized and investigated. The results showed that the transfection efficiency and cytotoxicity both increased with the spacer chain length. Then, TnPs with a [-(CH2)6-] spacer (T6P) were chosen to deliver p65 shRNA to a tumor and subsequently inhibit tumor growth and lymphatic metastasis. The T6P/p65 shRNA complex nanoparticles (T6Ns) could significantly down-regulate p65 expression in breast cancer cells, and consequently inhibit cell invasion and disrupt the tube formation. Most importantly, T6Ns accumulated greatly in tumor tissue, and as a result, significantly inhibited the growth and lymphatic metastasis of breast cancer xenograft. All these results indicated that the transfection efficacies of cationic amphiphiles could be significantly modulated by minor structural variations, and that T6P was promising for the effective delivery of p65 shRNA to knock down the expression of the key metastasis-driving genes and inhibit tumor growth and metastasis.
AuthorsJisheng Xiao, Xiaopin Duan, Qingshuo Meng, Qi Yin, Zhiwen Zhang, Haijun Yu, Lingli Chen, Wangwen Gu, Yaping Li
JournalActa biomaterialia (Acta Biomater) Vol. 10 Issue 6 Pg. 2674-83 (Jun 2014) ISSN: 1878-7568 [Electronic] England
PMID24525035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Chemical References
  • Polysorbates
  • RNA, Small Interfering
  • Polyethyleneimine
Topics
  • Animals
  • Cell Line, Tumor
  • Female
  • Humans
  • Lymphatic Metastasis
  • Mice
  • Mice, Nude
  • Neoplasms (metabolism, pathology)
  • Polyethyleneimine (chemistry)
  • Polysorbates (chemistry)
  • RNA, Small Interfering (administration & dosage)

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