|Title: Development of “smart” amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of inflammatory and autoimmune diseases, cancer and myeloablation.|
|Programme: FETOPEN-01-2018-2019-2020 – FET-Open Challenging Current Thinking||Start: 01.01.2020
|Coordinated by Friedrich-Alexander-University of Erlangen-Nürnberg||RIE: Research and Innovation Action|
FRIEDRICH-ALEXANDER-UNIVERSITY OF ERLANGEN-NÜRNBERG, Germany,
|UNIVERSITATSKLINIKUM ERLANGEN, Germany (DE)||PD Dr. Markus Hoffmann; Prof. Dr. Martin Herrmann; Prof. Dr. Georg Schett|
|UNIVERSITY OF SURREY, United Kingdom (UK)||Prof. Dr. Helen Griffiths|
|LVIVSKYI NATIONALNYI MEDYCHNYI UNIVERSYTET IMENI DANYLA HALYTSKOHO, Ukraine (UA)||Prof. Dr. Rostyslav Bilyy|
|CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.), Spain (ES)||Dr. Andres Hidalgo Alonso|
|REDOXIS AB, Sweden (SE)||Dr. Malin Hultqvist|
|INSTITUT GUSTAVE ROUSSY, France (FR)||Prof. Dr. Guido Kroemer|
Publications (since 2020, *: corresponding author)
1.Xu, H.; Schikora, M.; Sisa, M.; Daum, S.; Klemt, I.; Janko, C.; Alexiou, C.; Bila, G.; Bilyy, R.; Gong, W.; Schmitt, M.; Sellner, L.; Mokhir, A.* An endoplasmic reticulum – specific pro-amplifier of reactive oxygen species in cancer cells. Angew. Chem. Int. Ed., 2021, under revision.
2. R. Bilyy, G. Bila, O. Vishchur, V. Vovk, M. Herrmann, Neutrophils as main players of immune response towards nondegradable nanoparticles. Nanomaterials 2020, 10, 1273; doi:10.3390/nano10071273.
3. K. Borah, O. J. Rickman, N. Voutsina, E. L. Baple, I. HK Dias, A. H. Crosby, H. R. Griffiths, Datasets of whole cell and mitochondrial oxysterols derived from THP-1, SH-SY5Y and human peripheral blood mononuclear cells using targeted metabolomics. Data in Brief 2020, 106382; doi: 10.1016/j.redox.2020.101595.
4. K. Borah, O. J. Rickman, N. Voutsina, I. Ampong, D. Gao, E. L. Baple, I. HK Dias, A. H. Crosby, H. R. Griffiths, A quantitative LC-MS/MS method for analysis of mitochondrial-specific oxysterol metabolism. Redox Biology 2020, 36, 101595; doi.org/10.1016/j.redox.2020.101595.
5. S. Lind, C. Dahlgren, R. Holmdahl, P. Olofsson, H. Forsman, Functional selective FPR1 signalling in favor of an activation of the neutrophil superoxide generating NOX2 complex. J. Leukoc. Biol. 2020, 1-16; doi.org/10.1002/ JLB.2HI0520-317R.
Reactive oxygen species (ROS) have key functions in healthy organism such as redox signaling for regulation of cell growth, triggering formation of neutrophil extracellular traps (NETs), and modulation of inflammation. Since in high concentration ROS are damaging to tissues, nature has evolved precise mechanisms to control their generation at the required time, concentration and space, proximal to their target. Disturbance of these mechanisms leads to aberrant ROS production that causes uncontrolled inflammation, occurs in myeloablation caused by radio- or chemotherapy and is a crucial feature of cancer cell phenotype as well as autoimmunity. Despite the damaging properties of ROS it is a paradox that pharmaceutical ROS amplifiers can reverse (“cure”) many pathologic features.
For example, ROS-induced cancer cell killing inhibits cancer growth, ROS-induced deactivation of T-cells and NETs generation contributes to resolution of inflammation, and ROS-induced boosting of haematopoiesis can relieve myeloablation. These exciting possibilities have not been realized in clinical settings yet, since the high level of temporal and spatial control of ROS generation, required to allow for safe patient treatment, has yet not been achieved for any known drug.
NeutroCure will be the first attempt to achieve a breakthrough solution to this problem. Using an innovative approach based on the multiple-trigger prodrug activation, this consortium will develop safe ROS amplifiers capable of boosting ROS specifically in abnormal polymorphonuclear neutrophils associated with cancer, uncontrolled inflammation and relevant for myeloablation without affecting normal cells.
NeutroCure consists of 6 European academic partners and an SME who will promote commercialization of the new drugs. We expect that this project will have a great positive impact on the Society by providing previously unexplored treatment solutions for severe pathological conditions caused by dysregulated ROS-production.
Imaging of distribution of drugs in mice delivers accurate information for confirmation that the mechanism of action elaborated in cell-based assays is also operative in vivo. These data are critical for the transfer of drug discovery process from pre-clinical to clinical phase. To enable the imaging, drugs should be labeled with easily detectable moieties, e.g. radioactive markers and fluorescent dyes. Ideally, the markers should not affect in vivo properties of the drugs that can be better achieved with radioactive markers, since they can be selected to be small: e.g. a single atom marker 18F applied in positron emission tomography.
Despite this intrinsic advantage, PET suffers from safety issues, since radioactivity is harmful to humans and environment. In terms of safety optical imaging is much better and, therefore, in future can replace PET. However, fluorescent dyes compatible with the optical imaging are usually extended pi-systems carrying overall positive or negative charge. Their conjugation strongly affects properties of the majority of medium sized and low molecular weight drugs that limits the applicability of this method in drug discovery. The interdisciplinary and intersectoral consortium NoBiasFluors consisting of 4 academic and 2 industrial teams aims at achieving a breakthrough solution of this problem. We will develop non-biased red and near infrared fluorescent dyes, which are compatible with in vivo optical imaging and do not affect properties of drugs upon their conjugation.
This goal will be achieved by the careful optimization of dye structure, polarity and charge. We will confirm the functionality of the developed dyes for labeling of representative drugs (anticancer N-alkylaminoferrocene-based prodrugs, D-peptides targeting Alzheimer’s disease) and binders of biomolecules (nucleopeptides and lectins) and monitoring their distribution both in cellulo and in vivo (for a selected labeled drug).