title: Treatment of prostate carcinoma with (galectin-3)-targeted HPMA copolymer-(G3-C12)-5-Fluorouracil conjugates.
abstract: Galectin-3 (Gal-3), over-expressed on a variety of human tumor cells, is a potential binding site for targeted metastatic prostate cancer therapy. The aim of this study was to develop a G3-C12-mediated drug delivery system based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers targeting to Gal-3-expressed human PC-3 prostate carcinoma cells. 5-Fluorouracil (5-Fu), an anti-tumor agent, was selected as a model drug. G3-C12, a binding peptide, which specifically binds to the carbohydrate-recognition domain (CRD) of Gal-3, was attached to HPMA copolymers as a targeting moiety. Compared with non-targeted conjugates (P-Fu), Gal-3-targeted HPMA copolymer-(G3-C12)-5-Fu conjugates (P-(G3-C12)-Fu) displayed a superior intracellular internalization followed by enhanced cytotoxicity and apoptosis-induction. Subsequently, the in vitro migration study on PC-3 cells indicated that P-(G3-C12)-Fu was able to efficiently inhibit the cell migration ability after wounding. On PC-3 tumor-bearing mice model, G3-C12-modified copolymers showed a higher tumor accumulation coupled with a faster clearance from blood circulation than non-modified ones. Finally, Gal-3-targeted conjugates significantly improved the anti-tumor activity of 5-Fu in nude mice bearing PC-3 tumor xenografts. Consequently, G3-C12 would be a promising targeting moiety for cell-specific prostate cancer therapy in future.
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, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Shuang
authors.initials: S
authors.lastname: He
authors.forename: Tingting
authors.initials: T
authors.lastname: Fan
authors.forename: Yun
authors.initials: Y
authors.lastname: Jin
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.forename: Chunhui
authors.initials: C
authors.lastname: Chen
authors.forename: Zhi-rong
authors.initials: ZR
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000502:physiology; D005472:Fluorouracil / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008422:Materials Testing; D008689:Methacrylates / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D037502:Galectin 3; D008689:Methacrylates; D011108:Polymers; D005472:Fluorouracil; C032802:hydroxypropyl methacrylate