Arabinogalactan-folic acid-drug conjugate for targeted delivery and target-activated release of anticancer drugs to folate receptor-overexpressing cells

Roy I. Pinhassi, Yehuda G. Assaraf, Shimon Farber, Michal Stark, Diana Ickowicz, Stavit Drori, Abraham J. Domb, Yoav D. Livney

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Folic acid (FA) is a high affinity ligand (Kd = 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.

Original languageEnglish
Pages (from-to)294-303
Number of pages10
JournalBiomacromolecules
Volume11
Issue number1
DOIs
StatePublished - 11 Jan 2010
Externally publishedYes

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