G3-C12 Peptide Reverses Galectin-3 from Foe to Friend for Active Targeting Cancer Treatment

详细信息    查看全文

• 作者：Wei Sun ; Lian Li ; Qingqing Yang ; Wei Shan ; Zhirong Zhang ; Yuan Huang
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：November 2, 2015
• 年：2015
• 卷：12
• 期：11
• 页码：4124-4136
• 全文大小：734K
• ISSN：1543-8392

文摘

Galectin-3 is overexpressed by numerous carcinomas and is a potential target for active tumor treatments. On the other hand, galectin-3 also plays a key role in cancer progression and prevents cells from undergoing apoptosis, thereby offsetting the benefits of active targeting drugs. However, the relative contribution of the protective antiapoptotic effects of galectin-3 and the proapoptotic effects of galectin-3-targeted therapies has remained yet unrevealed. Here, we show that a galectin-3-binding peptide G3-C12 could reverse galectin-3 from foe to friend for active targeting delivery system. Results showed G3-C12 modified N-(2-hydroxypropyl)methacrylamide copolymer doxorubicin conjugates (G3-C12-HPMA鈥揇ox) could internalize into galectin-3 overexpressed PC-3 cells via a highly specific ligand鈥搑eceptor pathway (2.2 times higher cellular internalization than HPMA鈥揇ox). The internalized Dox stimulated the translocation of galectin-3 to the mitochondria to prevent from apoptosis. In turn, this caused G3-C12-HPMA鈥揇ox to concentrate into the mitochondria after binding to galectin-3 intracellularly. Initially, mitochondrial galectin-3 weakened Dox-induced mitochondrial damage; however, as time progressed, G3-C12 active-mediation allowed increasing amounts of Dox to be delivered to the mitochondria, which eventually induced higher level of apoptosis than nontargeted copolymers. In addition, G3-C12 downregulates galectin-3 expression, 0.43 times lower than control cells, which could possibly be responsible for the suppressed cell migration. Thus, G3-C12 peptide exerts sequential targeting to both cell membrane and mitochondria via regulating galectin-3, and eventually reverses and overcomes the protective effects of galectin-3; therefore, it could be a promising agent for the treatment of galectin-3-overexpressing cancers.