SFB 1066:  Nano-Dimensional Polymer Therapeutics for Tumour Therapy

• Subject Area: Chemistry ; Biology ; Medicine
• Term: since 2013
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213555243

The Collaborative Research Center (CRC)1066 investigates the use of nanoparticulate drug carriers (NP) in tumor immunotherapy. Novel polymer- and lipid-based NP are being synthesized, chemically characterized and their application in complex biological systems is being investigated from bench to bedside. The aim is to activate the immune system of tumor patients in such a way that tumors can effectively be recognized and destroyed by the body's own immune defense. Besides a tumor-specific immune response by vaccina-tion, we aim at reactivation of suppressed immune reactions and a targeted modulation of the tumor microen-vironment. Since both the selectivity and the type of a desired immune response must be precisely control-lable, there are requirements for therapeutic interventions in the immune system that cannot be met by con-ventional small molecules therapeutics, antibodies or their derivatives. This is precisely where the potential of nanoparticular drug carriers lies, because they can be used to precisely tune the immune system due to their complex, but chemically modifiable, structure to(1) encapsulate active ingredients in such a way that they are protected against unintended release or early destruction, thus enabling the use of fragile or even toxic active ingredients (e.g. RNA, immunomodula-tors), (2) transport several active ingredients simultaneously, which is often essential for therapeutic interventions in the immune system, and(3) they can be modified by surface functionalization in such a way that they bind specifically to certain structures on cells or tissues and only there they unfold their pharmacological effect, thus enabling tar-geted drug delivery. The CRC1066 reflects the growing importance of two modern fields of research by applying the increasing efficiency of nanomedicine to urgent problems of the highly dynamic field of tumor immunotherapy. Central areas of research are:• Synthesis, complex functionalization and loading of nanoparticulate drug carriers• Investigation of the mechanisms of NP interaction with biological media (blood, cell surfaces) and of their distribution in the body• Analysis of the effect of multi-functionalized NP on different leukocyte populations and on the immune system as a whole• Investigation of the general applicability of NP as tumor immunotherapeutics, including first clinical stud-ies in humans.This task can only be accomplished by the highly interdisciplinary setup of the CRC1066. Over two success-ful funding periods, our focus has developed systematically from NP synthesis to its characterization, func-tionalization and application in living organisms. Building on this, we will now comprehensively test NP-based tumor immunotherapies in vivo and evaluate them with respect to their clinical applicability.

• DFG Programme: Collaborative Research Centres

Current projects

• B03 - Therapy of primary and secondary liver tumors by addressing tolerance-inducing M2 macrophages using immunomodulating nanoparticles (Project Heads Nuhn, Lutz ;  Schuppan, Detlef ;  Tüttenberg, Andrea Renate ;  Zentel, Rudolf )
• B04 - Polymer-mediated tumor immunotherapy via in situ activation of antigen-presenting cells (Project Heads Grabbe, Stephan ;  Nuhn, Lutz ;  Schild, Hansjörg )
• B06 - Modulation of IL-10- and/or STAT3-mediated tumor-associated tolerance-mechanisms with the help of functionalized nanoparticles (Project Heads Landfester, Katharina ;  Steinbrink, Kerstin )
• B08 - Development and testing of nanoparticles to eliminate the cAMP-mediated immune-suppression in the malignant melanoma (Project Heads Barz, Matthias ;  Becker, Christian ;  Bopp, Tobias )
• B12 - Nano-particular mRNA-carrier systems to reprogram different immune-cell populations (Project Heads Barz, Matthias ;  Langguth, Peter ;  Sahin, Ugur )
• B13 - Multifunctional nanosized peptide/glycopeptide conjugates as fully-synthetic vaccine for tumor-immunotherapy (Project Heads Besenius, Pol ;  Bopp, Tobias ;  Schmitt, Edgar )
• B14 - Modulation of the tumor microenvironment by addressing inhibitory (immune) cells via time-programmed and self-regulating liposome (Project Heads Helm, Mark ;  Tüttenberg, Andrea Renate ;  Walther, Andreas )
• B15 - Induction of intrahepatic anti-tumor immunity by addressing dendritic cells and reprogramming protolerogenic non-parenchymal cell populations (Project Heads Bros, Matthias ;  Gehring, Stephan ;  Landfester, Katharina )
• B16 - Removal of the acidosis-dependent immune evasion mechanism of the malignant melanoma using pH modulating nanocarrier (Project Heads Bohn, Toszka ;  Miederer, Ph.D., Matthias ;  Weil, Tanja )
• B17 - Targeting of cancer-associated fibroblasts with drug-loaded polymeric nanoparticles to improve im-mune therapy for primary and secondary liver tumors (Project Heads Diken, Mustafa ;  Kaps, Leonard ;  Lammers, Twan )
• B18 - Tumor-specific immunization by transcutaneous vaccination: Preclinical and clinical development of drug forms for adjuvant therapy of Merkel cell carcinoma (Project Heads Grabbe, Stephan ;  Langguth, Peter ;  Radsak, Markus P. )
• Q01 - Complexation and adsorption of nanocarriers with biological components like RNA, serum proteins and other blood components and the influence on stability and interaction with cell membranes (Project Heads Landfester, Katharina ;  Maskos, Michael ;  Schmid, Friederike )
• Q02 - Microscopic characterization of nanocarriers in biological environments - from extracellular behavior to intracellular trafficking and immunomodulator release (Project Heads Koynov, Ph.D., Kaloian ;  Lieberwirth, Ingo ;  Mailänder, Volker )
• Q04 - Evaluation of systemic mRNA/peptide-based nanoparticle vaccines in melanoma tumor models (Project Heads Diken, Mustafa ;  Schild, Hansjörg )
• Q05 - Targeting and immunomodulator structures and their coupling to therapeutic nanosystems for onco-logical application (Project Heads Opatz, Till ;  Schirmeister, Tanja ;  Weil, Tanja )
• Q06 - From nanomaterial surface to function - multifunctional PEGylation, targeting and in vivo proteomics (Project Heads Frey, Holger ;  Mailänder, Volker ;  Tenzer, Stefan )
• Z - Central tasks (Project Heads Grabbe, Stephan ;  Zentel, Rudolf )
• Z02 - Integrated Research Training Group (Project Heads Grabbe, Stephan ;  Zentel, Rudolf )

Completed projects

• A01 - Development of strategies for radiolabeling of nanodimensional carriers and the incorporation of targeting vectors (Project Heads Ross, Tobias Ludwig ;  Rösch, Frank ;  Zentel, Rudolf )
• A02 - Synthesis of carbohydrate based nanocapsules and their functionalization with glycomimet-ics for cell-specific targeting (Project Heads Landfester, Katharina ;  Opatz, Till )
• A03 - Multifunctional magnetic nanoparticles for transport and tracking of active compounds (Project Heads Blümler, Peter ;  Tremel, Wolfgang )
• A04 - Cleavable cationic nanohydrogel-particles as carrier systems for oligonucleotides (Project Heads Waldvogel, Siegfried R. ;  Zentel, Rudolf )
• A06 - Synthetic control of morphology and function in peptide based carrier systems (Project Heads Barz, Matthias ;  Weil, Tanja )
• A07 - Liposomes and polymersomes with multifunctional endgroups: targeting and controlled release (Project Heads Frey, Holger ;  Helm, Mark ;  Zentel, Rudolf )
• B01 - Targeted inflammation - improving migration of leucocytes to the tumor through polymer-assisted activating of tumor endothelial tissue (Project Heads Sahin, Ugur ;  Schmitt, Edgar )
• B05 - Transcriptional addressing of dendritic cells (DCs) with the help of an hPFscn1 derived promotor using DC-addressing polymers for tumortherapy (Project Heads Bros, Matthias ;  Wagner, Ernst ;  Zentel, Rudolf )
• B07 - RNA-loaded functionalized nanoparticles for inhibition of tumour-associated regulatory T cells and antigen loading of human dendritic cells (Project Heads Helm, Mark ;  Jonuleit, Helmut )
• B09 - Transfection of tumor-reactive T cells using RNA loaded nanocapsules (Project Heads Mailänder, Volker ;  Wölfel, Thomas Johann )
• B11 - Proteins on nanocarriers: from the stealth effect to active targeting in vivo (Project Heads Mailänder, Volker ;  Tenzer, Stefan ;  Weil, Tanja )
• MGK - Integrated research training group (Project Head Zentel, Rudolf )
• Q03 - Multimodale and multiscalar in-vivo imaging of biodistribution and the efficiency of immunotherapy (Project Heads Lammers, Twan ;  Miederer, Ph.D., Matthias ;  Rösch, Frank )
• Z01 - Central tasks (Project Head Zentel, Rudolf )

• Applicant Institution: Johannes Gutenberg-Universität Mainz
• Participating University: Julius-Maximilians-Universität Würzburg, since 4/2022; Rheinisch-Westfälische Technische Hochschule Aachen; Universität Münster
• Participating Institution: Max-Planck-Institut für Polymerforschung
• Spokesperson: Professor Dr. Stephan Grabbe