title: Two birds, one stone: dual targeting of the cancer cell surface and subcellular mitochondria by the galectin-3-binding peptide G3-C12.
abstract: Active tumor-targeting approaches using specific ligands have drawn considerable attention over the years. However, a single ligand often fails to simultaneously target the cancer cell surface and subcellular organelles, which limits the maximum therapeutic efficacy of delivered drugs. We describe a polymeric delivery system modified with the G3-C12 peptide for sequential dual targeting. In this study, galectin-3-targeted G3-C12 peptide was conjugated onto the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer for the delivery ofD(KLAKLAK)2(KLA) peptide. G3-C12-HPMA-KLA exhibited increased receptor-mediated internalization into galectin-3-overexpressing PC-3 cells. Furthermore, G3-C12 peptide also directed HPMA-KLA conjugates to mitochondria. This occurred because the apoptosis signal triggered the accumulation of galectin-3 in mitochondria, and the G3-C12 peptide that specifically bound to galectin-3 was trafficked along with its receptor intracellularly. As a result, G3-C12-HPMA-KLA disrupted the mitochondrial membrane, increased the generation of reactive oxygen species (ROS) and induced cytochrome c release, which ultimately resulted in enhanced cytotoxicity. An in vivo study revealed that the G3-C12 peptide significantly enhanced the tumor accumulation of the KLA conjugate. In addition, G3-C12-HPMA-KLA exhibited the best therapeutic efficacy and greatly improved the animal survival rate. Our work demonstrates that G3-C12 is a promising ligand with dual-targeting functionality.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.|Therapeutic Proteins Key Laboratory of Sichuan Province, Kang Hong Pharmaceutical Group, Chengdu 610036, 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, Chengdu 610041, 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, Chengdu 610041, China.
authors.forename: Li-Jia
authors.initials: LJ
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001798:Blood Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D037502:Galectin 3 / Q000096:biosynthesis / Q000378:metabolism*; D037161:Galectins; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; D008024:Ligands; D010455:Peptides; C032976:N-(2-hydroxypropyl)methacrylamide