The main aim of the project BIOMOLMACS is to establish a multidisciplinary training network
on the emerging topic of molecular machines. In the last decades, great efforts have been
spent on the development of synthetic strategies for the creation of molecular machines, and
these efforts have been acknowledged by the Nobel committee in 2016. The next important
step is to incorporate the molecular machines in devices with application potential. For this
purpose, the machines will be integrated in mesoscopic assemblies by employing welldefined polymeric components with structural and functional control. Sequence controlled
polymers open up greater possibilities in the precise formation of nanoparticles such as
polymersomes, and even support the generation of artificial cells. The combined molecular
toolbox of molecular machines and precisely designed synthetic macromolecules will support
the design of devices with innovative nanomedical application potential. 15 Early Stage
Researchers will be trained on the design, synthesis, and characterization of such complex
(macro)molecular building blocks, their subsequent devices, as well as their utilization in
artificial and living cells. Besides, biophysical understanding of molecular interactions in
living/synthetic systems will bridge the gap between fundamental and applied research.
In particular, ESR13 will be trained under the guidance of Prof. Maria J. Vicent (Polymer
Therapeutics Lab at CIPF) on mitochondria targeted ROS mediated polypeptide-drug
conjugate delivery platforms. The aim is to design bioresponsive polypeptide based
conjugates capable to target mitochondria and delivery the selected cargo under specific
trigger (ROS). Proline-based block copolymers will be synthesized and fully characterized by
NCA polymerization methods. Alternatively star-shaped proline-based polymers with selfassembling properties and crosslinked stabilization possibilities will be also synthesized to
explore different topologies and therefore different cellular trafficking and distribution. Proline
oligomers already target mitochondria but Triphenyl phosphonium (TPP) or other well-known
residues could be added to enhance this effect. Model drugs capable to modulate cell death
(mitochondria mediated apoptosis) such as Apaf-1 inhibitors (antiapoptotic) or bcl-2 inhibitors
(pro-apoptotic) will be conjugated through ROS-sensitive linkers following well-established
post-polymerization modifications. Conjugates and polymers will be
labeled with fluorescence probes through non-biodegradable linkers to allow cell trafficking
studies.
Selected conjugates will be evaluated in adequate cell models regarding cytotoxicity as well
as pharmacological activity. Once demonstrated the mitochondrial targeting, the synthesized
proline-rich polymers will be also utilized to coat molecular motors synthesized by ESR1 and
to evaluate their intracellular localization. The expected outcome of this project is the design
and creation of polypeptide-based drug delivery systems with the ability to selectively release
the drug in selected intracellular organelles, such as mitochondria. This would be a key drug
delivery platform for many unmet clinical needs as per the importance of mitochondria
regulatory roles. The use of the mitochondria-targeted polymers in more complex hybrid
structures could act synergistically to better deliver challenging cargos to such specific
organelle.
RESOLVED
