Out-of-equilibrium routes toward drug delivery vehicles

Polymeric nanoparticles have shown great potential as drug delivery vehicles for a wide variety of pharmaceutical cargos. Encapsulating the cargo in such vehicles leads to enhanced drug efficacy by prolonged in vivo circulation times, targeted delivery, controlled drug release, and cargo protection. A vast majority of the polymeric delivery vehicles are based on amphiphilic block-copolymers. These polymers comprise two distinct segments of which one is solvophobic and the other solvophilic. The incompatibility of the solvophobic segments with the dispersing medium drives the assembly of the polymer chains into micellar structures. The solvophobic interior can be used to load non-soluble drugs into the interior of these supra-polymeric constructs. Relying on the modularity and flexibility of today’s polymer chemistry toolbox, the resulting micelles can be tailored for specific drugs and/or targets. However, a persistent bottleneck in the full-scale application of these polymeric nanoparticles is their limited formation efficiency. A potential route to overcome this hurdle it to perform the assembly and block copolymer formation in one single step in highly concentrated systems. These so-called polymerization-induced self-assembly (PISA) routes can yield well-defined micellar structures with controllable morphology at very high yields. By performing detailed studies into the formation mechanism, stability and drug loading ability, we aim to mature the use of PISA for pharmaceutical purposes

Super-selective drug delivery vehicles. How selective can we get?

A long-standing challenge in drug delivery is the selective targeting of sick cells or tissues only. Leaving healthy cells untouched by the often toxic cargo is crucial to prevent adverse side-effects of the supplied treatment. One approach for delivery vehicles to differentiate sick from healthy cells is by looking at the concentration of certain receptors that are expressed on the surface of cells. For many diseases, sick cells overexpress these receptors, providing a possibility for differentiating healthy from sick cells. Recent theoretical models predict that the selectivity of a drug delivery vehicle that needs to dock on receptor coated surfaces is determined by the number of possible binding conformation between the vehicle and the surface. The more binding modes a vehicle has, the higher the probability for binding. From a theoretical perspective, a high number of binding modes and hence sensitivity to the surface receptor concentration, can be realized by using multi-valent drug delivery vehicles with flexible linkers. Optimizing these design parameters can yield to vehicles that basically only bind to sick cells that overexpress the receptors, while healthy cells remain untouched. In this research project, we would like to take these physical chemical design criteria underlying super-selective binding and translate them to pharmaceutically relevant drug delivery systems.