On the uncertainty of the correlation between nanoparticle avidity and biodistribution

The specific delivery of a drug to its site of action also known as targeted drug delivery is a topic in the field of pharmaceutics studied for decades. One approach extensively investigated in this context is the use ligand functionalized nanoparticles. These particles are modified to carry receptor specific ligands, enabling them to accumulate at a desired target site. However, while this concept initially appears straightforward to implement, in-depth research has revealed several challenges hindering target site specific particle accumulation - some of which remain unresolved to this day. One of these challenges consists in the still incomplete understanding of how nanoparticles interact with biological systems. This knowledge gap significantly compromises the predictability of particle distribution in biological systems, which is critical for therapeutic efficacy. One of the most crucial steps in delivery is the attachment of nanoparticles to cells at the target site. This attachment occurs via the formation of multiple ligand receptor bonds. A process also referred to as multivalent interaction. While multivalency has been described extensively for individual molecules and macromolecules respectively, little is known on the multivalent binding of nanoparticles to cells. Here, we will specifically introduce the concept of avidity as a measure for favorable particle membrane interactions. Also, an overview about nanoparticle and membrane properties affecting avidity will be given. Thereafter, we provide a thorough review on literature investigating the correlation between nanoparticle avidity and success in targeted particle delivery. In particular, we want to analyze the currently uncertain data on the existence and nature of the correlation between particle avidity and biodistribution.