title: Arabinogalactan-folic acid-drug conjugate for targeted delivery and target-activated release of anticancer drugs to folate receptor-overexpressing cells.
abstract: Folic acid (FA) is a high affinity ligand (K(d) = 0.1-1 nM) of folate receptors (FRs) responsible for cellular uptake of folates via receptor-mediated endocytosis. FRs are frequently overexpressed in malignant epithelial cells including ovary, brain, kidney, breast, colon, and lung. FR has emerged as a target for the differential-delivery of anticancer chemotherapeutics with several FA-linked therapeutic agents currently undergoing clinical trials. Here we show that by tethering both FA and the anticancer drug methotrexate (MTX) to arabinogalactan (AG), a highly branched natural polysaccharide with unusual water solubility, a targeted biomacromolecular nanovehicle is formed, which can differentially deliver a cytotoxic cargo into FR-overexpressing cells. Moreover, by linking MTX via an endosomally cleavable peptide (GFLG), we demonstrate a target-activated release mechanism. This FA-AG-GFLG-MTX drug conjugate displayed 6.3-fold increased cytotoxic activity to FR-overexpressing cells compared to their FR-lacking counterparts. These findings establish a novel FA-tethered polymeric nanoconjugate for the targeted delivery of antitumor agents into cancer cells overexpressing FR.
authors.affiliation: Laboratory of Biopolymers and Food Nanotechnology, Department of Biotechnology and Food Engineering, The Russell Berrie Nanotechnology Institute, Israel.
authors.forename: Roy I
authors.initials: RI
authors.lastname: Pinhassi
authors.forename: Yehuda G
authors.initials: YG
authors.lastname: Assaraf
authors.forename: Shimon
authors.initials: S
authors.lastname: Farber
authors.forename: Michal
authors.initials: M
authors.lastname: Stark
authors.forename: Diana
authors.initials: D
authors.lastname: Ickowicz
authors.forename: Stavit
authors.initials: S
authors.lastname: Drori
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Domb
authors.forename: Yoav D
authors.initials: YD
authors.lastname: Livney
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism; D005685:Galactans / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D005685:Galactans; D011956:Receptors, Cell Surface; D005492:Folic Acid; C005653:arabinogalactan; D008727:Methotrexate