Cu/Zn superoxide dismutase; SOD-mimics; structure-activity analysis; amphiphilic block copolymers; self-assembly; nanoreactors; Electron Paramagnetic Resonance; superoxide dismutase mimics; polymeric nanoreactors; antioxidant activity; superoxide anions; Cu(II) superoxide dismutase mimics
Balasubramanian Vimalkumar, Ezhevskaya Maria, Moons Hans, Neuburger Markus, Cristescu Carol, Van Doorslaer Sabine, Palivan Cornelia (2009), Structural characterization of a highly active superoxide-dismutase mimic, in Phys. Chem. Chem. Phys
, 11, 6778- 6787.
Balasubramanian Vimalkumar, Onaca Ozana, Ezhevskaya Maria, Van Doorslaer Sabine, Sivasankaran Balasubramanian, Paliva Cornelia, A surprising system: Polymeric nanoreactors containing a mimic with dual-enzyme activity, in SoftMatter
, 7, 5595-5603.
Egli Stefan, Nussbaumer Martin, Balasubramanian Vimalkumar, Chami Mohamed, Bruns Nico, Palivan Cornelia, Meier Wolfgang, Biocompatible Functionalization of Polymersome Surfaces: A new Approach to Surface Immobilization and Cell Targeting using Polymersomes, in JACS
, 133(12), 4476-4483.
Tanner Pascal, Egli Stefan, Balasubramanian Vimalkumar, Onaca Ozana, Palivan Coenelia, Meier Wolfgang, Can polymeric vesicles that confine enzymatic reactions act as simplified organelles?, in FEBS letters
, 11(585), 1699-1706.
Tanner Pascal, Onaca Ozana, Balasubramanian Vimalkumar, Meier Wolfgang, Palivan Cornelia, Enzymatic Cascade Reactions inside Polymeric Nanocontainers – A Means to Combat Oxidative Stress,, in Chem. Eur. J.
, 17, 4552-4560.
Palivan Cornelia, Balasubramanian Vimalkumar, Goodman Bernard, Global Structure-Activity Analysis in Drug Development Illustrated for Active Cu/Zn Superoxide Dismutase Mimics, in Eur. J. Inorg. Chem.
, 31, 4634-4639.
Balasubramanian Vimalkumar, Onaca Ozana, Axthelm Fabian, Hughes David, Grzelakowski Mariuz, Meier Wolfgang, Palivan Cornelia, How to Reduce Superoxide Anion Concentration using Antioxidant Nanoreactors, in Journal of Optoelectronics and Advanced Material-symposia
, 1(6), 1083-1087.
Balasubramanian Vimalkumar, Onaca Ozana, Enea Ramona, Hughes David, Palivan Cornelia, Proteins delivery: From conventional drug delivery carriers to polymeric nanoreactors, in Expert. Opin. Drug Delivery
, 7(1), 63-78.
Onaca Ozana, Hughes David, Balasubramanian Vimalkumar, Grzelakowski Mariusz, Meier Wolfgang, Palivan Cornelia, SOD antioxidant nanoreactors: Influence of block copolymer composition on the nanoreactor efficiency, in Macromol. Biosci.
, 10(5), 531-538.
1. SUMMARYThe detailed physical-chemical characterisation of the environment of the metal centre in many metal proteins, and the synthesis of small molecular weight metal complexes mimicking it, represent approaches to obtaining information about its role in the protein behaviour, and the basis for developing new hybrid active systems in combination with various polymers. Cu/Zn Superoxide dismutase (SOD) is one of a family of metallo-proteins which act as antioxidant enzymes by lowering the steady-state concentration of the superoxide radical anion (O2¯), one of the reduced oxygen species responsible for oxidative stress in cells. However, due to its low biodiavailability, SOD provides rather modest protection, if any, when administered. As the copper binding region represents its active site, one approach to overcome this problem is based on the synthesis of low-mass metal complexes that act as SOD-mimics. In this project, we plan to combine inorganic, and physical chemistry with polymer science in order to obtain a better understanding of the structural conformation of highly active SOD-mimics, and to develop efficient antioxidant nanoreactors by encapsulating them in nanovesicles formed by self-assembly of amphiphilic block copolymers.The first objective involves the synthesis and detailed characterisation in various physical states of copper complexes proposed as SOD-mimics, in order to serve as model compounds for their biological activity. We will investigate the extent to which there is a structural model or models for highly active SOD-mimics based on the structure-activity analysis of all reported classes of SOD-mimics. This will then be compared with the metal binding region of SOD to develop a better understanding of how far geometry and composition can be connected with the biological activity of the protein. As SOD has been extensively studied, the available spectroscopic and electrochemical data provide the background we will use both for comparison with the new synthesised SOD-mimics as well as to validate the global structure-activity analysis.The second objective of the project is based on development of efficient antioxidant nanoreactors by encapsulation of the best SOD-mimics in polymeric nanocontainers produced by the self-assembly of block copolymers. Here it will be particularly interesting to evaluate the effects of systematically varying the chemical constitution of the polymers, and the thickness of the hydrophobic part of the membranes, as well as the functionalisation with specific ligands for a targeting approach. In situ activity assay together with structural characterisation of the metal coordination sphere will provide information as to whether there are changes when these antioxidant compounds are encapsulated. The nanocontainers, whose membranes are oxygen permeable, serve as shields for the encapsulated compounds so that they can act inside their inner aqueous cavity.Our overall aim is thus both to improve the basic molecular understanding of the role of the metal coordination in SOD antioxidant function via highly active SOD-mimics, and to obtain antioxidant nanoreactors by encapsulating SOD-mimics in polymeric vesicles, thereby enhancing their effectiveness for further biological applications associated with oxidative stress.