Pentafluorophenyl-based single-chain polymer nanoparticles

Well defined single chain polymer nanoparticles ( SCNPs ) can be formed by intramolecular crosslinking of single polymer chains . These particles have a size of around 10 nm, which is similar to proteins. SCNPs can be equipped with a wide
variety of functionalities, although the functionalization step, and mainly its quantification, is not straightforward. This thesis describes a method for creating SCNPs with easily modifiable surface groups, to sy n thesize and study sets of
functional nanoparticles for biomedical applications. In Chapter 1 , we first describe the current methods available for modifying the surface of SCNPs.
In Chapter 2 , we describe the synthesis of SCNPs with active ester groups (pentafluorophenyl esters, A series of SCNPs is described with increasing incorporation of a protonatable tertiary amine SCNPs with a small amount of tertiary amines exhibited low cellular uptake, with their cellular fate being the lysosome. Particles with a high er amount of tertiary amines showed significantly higher cellular uptake, while simultaneously reaching the cytosol.
Chapter 3 investigates the set of SCNPs with increasing amounts of tertiary amines in a blood brain barrier model. All SCNPs showed a very high degree of transcytosis compared to other nanostructures tested on a similar model. Particles with the highest surface charge also exhibited cytosolic uptake , however at the expense of transcytosis which is slightly reduced
Chapter 4 combines the functionalization strategy from Chapter 2 with controlled drug delivery with an anticancer drug Only SCNPs with 40% tertiary amines (thus reaching the cytosol) on the surface exhibited a decrease in the number of HeLa
cancer cells. This clearly demonstrates the importance of intracellular location for the effectiveness of anticancer drugs.
In Chapter 5 , we expanded the functionalization strategy by combining active ester chemistry with click chemistry . The particles were functionalized with an increasing amount of amino alkynes, which were then conjugated with azido glucose via two different positions. Uptake studies on cancer cells (HeLa) showed no distinction between conjugation positions, but that the density determined the amount of uptake.
Chapter 6 describes ways to scale up SCNP production and explore new potential functionalization methods . Finally, we describe an in vivo study in which the particles from Chapter 2 were investigated in a mouse model. Despite their small
size, the particles were still present in the body after 24 hours. Increasing surface charge led to increased uptake in the liver and spleen, indicating opsonization by macrophages.