Beyond the Dilemmas: Design of PLA-PEG Assemblies Based on pH-Reversible Boronic Ester for the Synchronous PEG De-Shielding and Ligand Presentation to Hepatocytes

Abstract

A new polymeric construct is proposed as a starting material for a liver-targeted delivery system in the present communication. The polymeric material has been designed to be sensitive to pH variations and potentially loaded with hydrophobic antitumoral agents. It is based on one of the most used copolymers in the field of nanomedicine: PEG-PLA. The latter, usually obtained by polymerization of lactic acid on the hydroxyl-terminated polyether, is assembled by the pH-reversible condensation between a phenylboronic acid-ended methoxy PEG 2000 (MeO-PEG2000-PBA) and a galactose-capped PLA of 1–10 kDa (PLA-Gal). Our approach is based on the strategic assumption that would allow a new ligand presentation strategy in which Gal is both a structural element for the stimulus-responsive PEG de-shielding and the targeting moiety. Indeed, Gal has a vicinal diol able to form a reversible boronate ester with a B(OH) 2 residue, which is cleavable at the acidic pH of the tumor microenvironment, and it is also recognized by the asialoglycoprotein receptor, which is hyper-expressed on the membrane of hepatocytes. The functionalization of the two blocks is presented here, and they are characterized using NMR, FTIR, and GPC. The analytical evaluation of the ability of the boronated PEG and Gal to condense in a pH sensible way completes the study.

Keywords

• active targeting
• ligand presentation
• galactose
• PEG-PLA
• hepatocarcinoma
• pH-responsive