Tuning the pH sensitivities of orthoester based compounds for drug delivery applications by simple chemical modification

Orthoesters are acid-sensitive moieties that allow substantial structural diversity for biological applications including drug delivery. Here, the pH-sensitivity of a range of novel orthoester based compounds was compared in the range 7.5–4.5 that is characteristic of the increased acidification during endocytosis. We find that simple modifications close to the orthoester had major effects on both the rate and extent of hydrolysis, suggesting this could be exploited for activating drug delivery systems on endocytic pathways.

Graphical abstractSmall chemical modifications influence aqueous pH-sensitivity of orthoester conjugates.Figure optionsDownload full-size imageDownload as PowerPoint slide