Design of nano-structured drug delivery devices

Controlled packaging of pharmaceutical agents can be achieved by complexing them with organic polymers or incorporating them into inorganic nanoporous structures. The latter is being explored in the group of Bein by using functionalized nanoporous silica particles and related systems, which offer stable, biocompatible hosts that can be invisible to the immune system. In order to optimize the encapsulation and to design targeted release mechanisms the dynamic behaviour of drugs in nanoporous hosts is being studied by the groups of Bein and Bräuchle. The group of Bein will modify the nanoporous particles for controlled host-guest interactions, targeting, and controlled release of the pharmaceutical agents at the locus of activity. The transport mechanisms of these nanoparticles will be investigated with individual cells using single molecule microscopy in the group of Bräuchle. The group of Wagner investigates the pharmaceutical applicability in cell cultures and finally in in vivo systems. The advantages of inertness of inorganic particles will also be explored in the group of Bausch by building colloidosomes, where silica particles are assembled into a higher ordered structure aimed at additional tuneability of encapsulation and release mechanisms.

Model systems such as collagen solutions or in vitro cytoskeletal networks, as described in the research area H, will be applied for quantification and optimization of the transport mechanisms of the nanoparticles by the groups of Rädler and Bausch. The insights gained here will be tested in the recently introduced single cell - single molecule assays by the group of Bräuchle. In this approach various ultra-sensitive single molecule fluorescence techniques in conjunction with live cell imaging are applied to study the trafficking of drug delivery systems and the controlled release of their cargo within living cells. With these techniques, central questions about the mechanisms of cell interaction, different uptake pathways, motion within the cytoplasm via diffusion and active transport, disassembly of the carrier and drug release will be investigated with unprecedented spatial and temporal precision. Such investigations will increase our understanding of the cellular mechanisms and bottlenecks of drug delivery and will profit from the planned efforts in the research area I and B. Several transport and uptake processes for PEI/DNA complexes serving as a simple model of a ‘synthetic virus’ have already been determined by the groups of Bräuchle and Wagner.

While most targeting approaches rely on biochemical interactions, physical forces such as ultrasound, local exposure to light or magnetic forces can also be used for targeted drug applications, and will be further explored by the groups of Plank and Wagner. One promising approach will be to combine biochemical with magnetic targeting technology by incorporation of magnetic nanoparticles, optionally including microbubbles. Magnetic drug formulations will be selected with suitable characteristics to achieve blood circulation times sufficiently long for magnetic targeting. Drug release and tissue penetration at target sites will be induced by the local application of ultrasound and/or alternating magnetic fields. This combination of molecular and physical targeting is expected to increase the percentage of injected dose in the target tissue, and thus the overall efficiency of the delivery. Formulations will be optimized in in vitro and in vivo studies (Plank, Wagner, Bräuchle, Rädler). The intended medical use will be for tumor malignancies, as well as neurodegenerative and cardiovascular diseases. The active agents to be delivered include apoptosis- or necrosis-inducing or anti-angiogenetic agents for cancer therapy, anti-apoptotic and survival factor agents for neurodegenerative pathologies such as ischemia and stroke, as well as angiogenesis-inducing or restenosis-inhibiting agents for cardiovascular treatments.

Hierarchical functionalities can be introduced by the self-assembly of small organic or inorganic particles or even proteins. This approach can be used to build drug delivery devices with tuneable functionalities on many different levels of complexity. The preparation of hollow, elastic capsules, with sizes ranging from a few micrometers to millimeters and with easily adjusted and highly controllable permeability in the nanometer regime and tuneable elasticity will be achieved by an emulsion technique. The capsule surfaces can be composed of close-packed layers of organic or inorganic colloidal particles, linked together to form a solid shell; the interstices between the particles form an array of uniform pores, whose size controls the permeability of the capsules. These recently-introduced capsules are called “colloidosomes” by analogy with liposomes, which are capsules composed of phospholipid bilayers (Bausch).

A related very promising approach for building new drug delivery devices is the use of recombinant proteins which mimic spider silk proteins and are highly inert with respect to the immune system. The recombinant expression of these new proteins was recently achieved by the group of Thomas Scheibel (Lehrstuhl für Biotechnologie, TUM). The group of Bausch will use the self assembly of these building blocks at liquid interfaces to build thin polymer capsules of spider silk proteins. Unique functionalities on the single protein level can be designed through point mutations, and thus the capsules can be tuned for a wide range of applications and release mechanisms. In both above systems targeting can be achieved by biochemical or physical means (Wagner, Plank). The transport properties and release mechanisms of these microsized containers will be studied in vitro and after optimization in in vivo studies (Wagner, Rädler, Bausch).