Determining the Number of NH3 Ligands Required on a PAMAM Dendrimer for Lysosome Escape via the Proton Sponge Effect

Drug delivery systems are a necessity for certain life-saving drugs that must be delivered safely and reliably to their target cells. Dendrimers, a large branching polymer that allow for the functionalization of end groups to perform the functions necessary for drug delivery, are one of the main drug delivery systems used today. However, it may take researchers a long time to develop new dendrimers due to their highly customizable nature. Our study focuses on streamlining the dendrimer design process and adding to the scientific discussion regarding the true cause of lysosome lysis through the proton sponge effect.

One of the obstacles that drug delivery systems must overcome is the lysosome degradation pathway. There are a few methods that are used to escape the lysosome, but the mechanism that we selected to study was the proton sponge effect, a process that causes lysosomal lysis through osmotic pressure.

We calculated the number of NH3 ligands (the end groups that cause the proton sponge effect), needed on a single dendrimer. We determined that for a lysosome of 250nm radius, 62,500 dendrimers with 21 NH3 groups each are required to lyse it. We also found that it is mathematically possible to cause lysosome lysis through only osmotic pressure, without any membrane destabilization.

These results will help researchers who develop new dendrimers, providing information on the needed ratio of ligand types on the dendrimer's terminal groups. Additionally, this paper sheds some light on the scientific discussion regarding lysosome lysis.