Evaluation of the best pH-sensitive linker using norbornene-derived polymers

Abstract

pH-responsive drug delivery systems that are bearing with acid-sensitive linkages between therapeutic molecules and polymers have been extensively explored in cancer treatment. But there is no systematic study to choose the best acid-sensitive linker in literature. In this report, three polymer-drug conjugates were synthesized with different pH-sensitive linkers such as ester, amide, and hydrazone with the anticancer drug doxorubicin with the same polymer backbone and the same molecular weights. We believe that this study will provide useful decision-making information to choose the best linker for the stimuli-responsive delivery system. First, we synthesized three different norbornene monomers with ester linker (mono 1), amide linker (mono 2), and hydrazone linker (mono 3). Next, the homopolymerization of mono 1 (HP-DOXE), mono 2 (HP-DOXA), and mono 3 (HP-DOXH) were carried out to obtain same molecular weight of homopolymers by using second generation Grubbs’ catalyst. In vitro drug release profile indicated the importance of having the hydrazone linker that helps the drug at the mildly acidic conditions resembling the pH of the cancerous cells, compared to amide and ester linkers with the same polymer backbone and the same molecular weights of polymers. The cell viability experiments in cancerous cell lines demonstrate that the hydrazone linker kills more cells compared to ester and amide linkers up to 500 µg/mL concentration.