title: G3-C12 Peptide Reverses Galectin-3 from Foe to Friend for Active Targeting Cancer Treatment.
abstract: 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-Dox) could internalize into galectin-3 overexpressed PC-3 cells via a highly specific ligand-receptor pathway (2.2 times higher cellular internalization than HPMA-Dox). The internalized Dox stimulated the translocation of galectin-3 to the mitochondria to prevent from apoptosis. In turn, this caused G3-C12-HPMA-Dox 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.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P. R. China.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P. R. China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shan
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P. R. China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, P. R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D037502:Galectin 3; D010446:Peptide Fragments; D011108:Polymers; D017382:Reactive Oxygen Species; D004317:Doxorubicin
keywords: G3-C12 peptide; active targeting; cell metastasis; galectin-3; mitochondrial apoptosis-inducing factors