Maleic acid amide derivatives as pH-sensitive linkers for therapeutic peptide conjugation

Abstract

Therapeutic peptides are gaining popularity in the biopharmaceutical industry due to their higher tissue penetration and lower immunogenicity than traditional anticancer drugs. However, therapeutic peptides require carriers to reach the tumour site, as they are rapidly cleared from the bloodstream. The advancement of nanomedicine allows us to solve this challenge by entrapping the peptide inside polymeric micelles. Passive targeting, using the Enhanced Permeability and Retention effect (EPR) and selective release of cargo from the nanocarrier in response to stimuli endogenous to tumour tissue (such as reduced pH), are envisioned to be implemented in the delivery approach. This work exam-ines three maleic anhydride derivatives as possible substrates for pH-sensitive linker synthesis on a model therapeutic peptide. The novel aspect of this study is binding a model peptide into polymeric micelles using a maleic acid amide-based linker. Although these maleic anhydrides have been previously employed for pH-sensitive drug delivery applications, in this study, side product formation significantly decreased the effectiveness of the investigated tool. The results presented in this work raise questions towards the employment of maleic amide derivatives in such systems as side product interference could not be avoided.