Visual Universitätsmedizin Mainz

Drug Delivery & Development

The "Drug Delivery" program was recently established to address the often unmet medical need of insufficient biodistribution and / or intracellular uptake of promising drugs or vaccines. This initiative was substantially promoted by the excellent expertise within the Mainz Max-Planck-Institute for Polymer Research (MPIP) and its close association with the UCT Mainz. Innovative treatment concepts such as tumor-specific transfer of small interfering RNAs (siRNA) mediating gene knockdown or induction of immune responses are hampered by rapid degradation in the bloodstream or minor passage of the cell membrane. Shifting the biodistribution towards the desired cell population by targeting moieties represents a major goal of nanocarrier design. Nanocarriers provide unprecedented protection in blood and outside target cells with the ability for endosomal / phagosomal uptake route, thereby altering the pharmacokinetics of drugs. 

Achievements

  • This program not only links excellent expertise located at the Institute of Chemistry, the Institute of Pharmacology, the MPIP and the UCT Mainz; it has culminated in the Collaborative Research Consortium “Nanodimensional polymeric therapeutics for cancer therapy” (SFB1066 funded by the DFG).
     
  • To improve drug delivery by nanocarriers, new molecules with stabilized shielding effect have been produced by the groups of R. Zentel, T. Opatz and H. Frey (Zentel R. Macromol Rapid Commu. 2010; Frey H. Biomacromolecules 2015; Opatz T. Chem Soc Rev. 2015).
     
  • The Landfester group has generated biodegradable polymers like hydroxyl ethyl starch and albumin to produce clinically relevant and transferable nanocarriers (Landfester F.R. Angew Chem Int Ed Engl. 2015; Landfester F.R. Biomaterials 2015).
     
  • The group of V. Mailänder at the UCT analyzed the routes of biodistribution and intracellular fate as well as the interaction of nanocarriers with proteins (BMBF; Mailänder V. Acs Nano, 2014). Label-free snapshot proteomics was used to obtain quantitative time-resolved profiles of human plasma coronas formed on silica and polystyrene nanoparticles and was found to affect hemolysis, platelet activation, nanoparticle uptake and endothelial cell death (Tenzer S. Nature Nanotechnology 2013).
     
  • Liposomal formulations like micelles or aggregates like lipoplexes as potential delivery systems are investigated by the groups of U. Sahin, D. Schuppan and M. Helm (Diken M. Prog Tumor Res. 2015; Schuppan D. Hepatology 2015; Helm M. Biomacromolecules 2014).
     
  • The Stauber group designs biodegradable immune-nanoparticles loaded with patented Survivin small molecule export inhibitors (European Patent EP 2431364A1) providing a link to the “Genetic Instability and Resistance” program.
     
  • These combined efforts resulted in a first-in-man-study aiming at systemic nanoparticle targeted delivery of a RNA-vaccine. Robust and reproducible vaccine-induced immune responses were recorded upon intravenous application of the liposomal RNA formulation in patients with metastasized melanoma (S. Grabbe; U. Sahin). Obviously this approach holds further promises to optimize the specific anti-tumor effect especially in the era of checkpoint inhibitors to specifically guide the immune responses.

Aims

After performing proof-of-concept studies using the lipoplex approach, it is essential to establish additional platforms to enable the delivery of a variety of active molecules. As these molecules range from very hydrophilic to hydrophobic and from small molecule like chemotherapeutic agents to high molecular constructs, such as mRNA, the development of novel nanocarriers will be necessary to successfully translate these concepts into the clinic. To strengthen the UCT Research Program “Drug Delivery”, the Center for Translational Nanomedicine (CTN) has been founded including a new interdisciplinary W2 professorship for translational nanomedicine (accepted by V. Mailänder).

Most significant publications since 2013

  • Hofmann, D., S. Tenzer, M.B. Bannwarth, C. Messerschmidt, S.-F. Glaser, H. Schild, K. Landfester, and V. Mailänder. 2015 Mass Spectrometry and Imaging Analysis of Nanoparticle-Containing Vesicles Provide a Mechanistic Insight into Cellular Trafficking, Acs Nano. 8 (2014) 10077-10088.
     
  • Kang, B., P. Okwieka, S. Schöttler, O. Seifert, R. Kontermann, K. Pfizenmaier, A. Musyanovych, R. Meyer, M. Diken, U. Sahin, V. Mailänder, F.R. Wurm, and K. Landfester. 2015 Tailoring the stealth properties of biocompatible polysaccharide nanocontainers. Biomaterials. 49:125-134.
     
  • Calvente, C.J., A. Sehgal, Y. Popov, Y.O. Kim, V. Zevallos, U. Sahin, M. Diken, and D. Schuppan. 2015. Specific hepatic delivery of procollagen 1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis. Hepatology. 62:1285-1297
     
  • Docter, D., U. Distler, W. Storck, J. Kuharev, D. Wunsch, A. Hahlbrock, S.K. Knauer, S. Tenzer, and R.H. Stauber. 2014. Quantitative profiling of the protein coronas that form around nanoparticles. Nature Protocols. 9:2030-2044.
     
  • Tenzer, S., D. Docter, J. Kuharev, A. Musyanovych, V. Fetz, R. Hecht, F. Schlenk, D. Fischer, K. Kiouptsi, C. Reinhardt, K. Landfester, H. Schild, M. Maskos, S.K. Knauer, and R.H. Stauber. 2013. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat Nanotechnol. 8:772-U1000.

 
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