Journal
JOURNAL OF CONTROLLED RELEASE
Volume 161, Issue 3, Pages 893-902Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2012.05.002
Keywords
TMTP1; Peptide; Targeting; NF-kappa B; Metastasis
Funding
- National Science Foundation of China [81001151, 81001006, 81101971, 30973148, 30973472, 81172468]
- 973 Program of China [2009CB521808]
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Micromolecular agents that block tumor development and metastasis hold great promise as cancer-targeted therapies. Tumor molecular targeted peptide 1 (TMTP1) was previously shown to target primary tumors and metastatic foci specifically. In this study, a group of composite peptides were incorporated to TMPT1. The NF-kappa B essential modulator-binding domain (NBD), and the trans-activator of transcription (TAT) peptide, were synthesized to enhance the targeted anti-tumor effects of TMTP1. TMTP1-NBD did not exhibit strong affinity to tumor cells as we had expected. Conjugating TAT with TMTP1-NBD ameliorated the poor hydrophilicity and negative charge of TMTP1-NBD. Therefore TMTP1-TAT-NBD displayed strong affinity and anti-tumor effects as we expected in vivo and in vitro. Interestingly cytoplasmic glycogen accumulation as well as apoptosis was observed in TMTP1-TAT-NBD treated PC-3M-1E8 cells. The downstream signaling pathways including AKT, GSK-3 beta, I kappa B alpha and NF-kappa B activity were verified to decrease by TMTP1-TAT-NBD. The pharmacokinetics and distribution of TMTP1-TAT-NBD in MDA-MB-231 tumor-bearing mice model provided some evidence for safety of the composite peptide, which showed the fluorescence of the peptide peaked in the tumor 6 h after injection, with little fluorescence detected in normal organs except for very weak fluorescence in kidney. In conclusion, TMTP1-TAT-NBD may be a promising targeted anti-tumor agent for primary tumor and metastatic foci, which enhances the anticancer effects through inhibiting the AKT/GSK-3 beta/NF-kappa B pathway comparing with TMTP1. (c) 2012 Elsevier B.V. All rights reserved.
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