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.

Radionuclide therapy using 131I-labeled anti-epidermal growth factor receptor-targeted nanoparticles suppresses cancer cell growth caused by EGFR overexpression

“…Liposomes, which are spherical vesicles formed by lipid bilayers, have been widely investigated as carriers of tumor-targeting therapeutic agents. Some specific ligands have been conjugated to nanoparticles that serve as carriers for a therapeutic agent and have been used to increase the specific toxicity of tumor therapy by specific delivery to target cells, including folic acid (Pinhassi et al 2010), Arg-Gly-Asp peptides (Su et al 2012), vitamins (Chen et al 2010), aptamers (Neff et al 2011), and antibodies (Mamot et al 2003). In particular, immunoliposomes directed against EGFR ligands can increase the targeting therapeutic efficacy in vivo and may be of important clinical significance as a novel treatment for cancer (Mamot et al 2005).…”

Sweet Fairytale: Carbohydrates as Backbones for Glyconanomedicine

“…Arabinogalactan is extracted mainly from the Larix tree and is available at 99.9 % purity, with reproducible molecular weight (Mw) and physicochemical properties. [54] The unusual water solubility (70 % w/w in water), biocompatibility, biodegradability, and ease of drug conjugation in aqueous media makes arabinogalactan attractive as a potential drug carrier. [54] …”

“…[54] The unusual water solubility (70 % w/w in water), biocompatibility, biodegradability, and ease of drug conjugation in aqueous media makes arabinogalactan attractive as a potential drug carrier. [54] …”

“…Recently, Arabinogalactan-folic acid-drug conjugates for targeted delivery and activated drug release were prepared and characterized. [54] The targeted nanovehicle was formed by conjugation of folic acid and the anti-cancer drug methotrexate to arabinogalactan. The use of folic acid as a targeting ligand derives from the fact that cancer cells overexpress receptors for nutrients in order to maintain their fast-growing metabolism.…”

Nanomedicine in GI

“…Polysaccharides, in particular, have additional advantages in that they are degraded by bacteria and hence can be used as a colonic delivery system (81,91). The monosaccharide subunit (galactose, glucose, acid derivatives, or N-acetyl) degradation products are easily eliminated or assimilated by the body.…”