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STRUCTURE-ACTIVITY ANALYSIS OF SOD-MIMICS AND THEIR ENCAPSULATION IN NANOREACTORS

English title STRUCTURE-ACTIVITY ANALYSIS OF SOD-MIMICS AND THEIR ENCAPSULATION IN NANOREACTORS
Applicant Palivan Cornelia
Number 129968
Funding scheme Project funding
Research institution Physikalische Chemie Departement Chemie Universität Basel
Institution of higher education University of Basel - BS
Main discipline Physical Chemistry
Start/End 01.04.2010 - 31.08.2011
Approved amount 92'959.00
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Keywords (12)

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

Lay Summary (English)

Lead
Lay summary
RESUME: Reactive oxygen species, such as the superoxide radical anion (O2¯), are responsible for oxidative stress in cells, that has been implicated in the pathogenesis of many cardiovascular and pulmonary diseases. We introduced the concept of antioxidant nanoreactors based on encapsulation of Cu/Zn superoxide dismutase in amphiphilic copolymer nanovesicles whose membranes are oxygen permeable.[1,2] Cu/Zn Superoxide dismutase (Cu/Zn-SOD) is one of the metal proteins which act as an antioxidant enzyme by lowering the steady-state concentration of the superoxide radical anion (O2¯), but due to its very low availability can not be administrated directly. Its encapsulation in polymeric nanocontainers those membrane both shield the sensitive protein and selectively let superoxide and dioxygen penetrate to its inner space represent a new direction for developing drug delivery applications.BUT: The present study aims to develop the antioxidant nanoreactors by encapsulation of SOD-mimics, which are small Cu-based complexes with high SOD-like activity in order to improve the encapsulation efficiency, and thus the activity of the nanoreactors. The function of this antioxidant nanoreactor will be tested in various cell lines in order to demonstrate that the SOD-mimic remains active inside the nanovesicles and detoxifies the superoxide radical in situ. Uptake and toxicity studies are planed to assess the biological impact of the SOD-mimics based antioxidant nanoreactors. In addition, we are interested to improve in a quantified way the basic molecular understanding of the role of the metal coordination in Cu/Zn-SOD antioxidant function via active SOD-mimics and to obtain a hybrid system which is expected to provide a significantly higher bioavailability for the protein or mimics.SIGNIFICATION: This study will combine inorganic, and physical chemistry with polymer science in order to develop antioxidant nanoreactors, as a more efficient way to detoxify superoxide anions than the conventional drug release systems. 1. F. Axthelm, O. Casse, W. Koppenol, T. Nauser, W. Meier, C. Palivan, J. Phys. Chem. B, 2008, 112(28), 8211-8217.2. O. Onaca, D.W. Hughes, V. Balasubramanian, M. Grzelakowski, W. Meier, C. G. Palivan, Macromol. Biosci, 2010, 2010, DOI: 10.1002/mabi.200900379.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Structural characterization of a highly active superoxide-dismutase mimic
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.
A surprising system: Polymeric nanoreactors containing a mimic with dual-enzyme activity
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.
Biocompatible Functionalization of Polymersome Surfaces: A new Approach to Surface Immobilization and Cell Targeting using Polymersomes
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.
Can polymeric vesicles that confine enzymatic reactions act as simplified organelles?
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.
Enzymatic Cascade Reactions inside Polymeric Nanocontainers – A Means to Combat Oxidative Stress,
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.
Global Structure-Activity Analysis in Drug Development Illustrated for Active Cu/Zn Superoxide Dismutase Mimics
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.
How to Reduce Superoxide Anion Concentration using Antioxidant Nanoreactors
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.
Proteins delivery: From conventional drug delivery carriers to polymeric nanoreactors
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.
SOD antioxidant nanoreactors: Influence of block copolymer composition on the nanoreactor efficiency
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.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Workshop on Biomolecules and Nanostructures 04.09.2011 Bedlewo, POLAND
36Th FEBS Congress 30.06.2011 Torino, Italy
International Congress NanoBio- Europe 21.06.2011 Cork, ireland
Polycoll 2011 29.04.2011 University of Geneva, Geneva
3rd Swiss Soft Days 20.10.2010 Fribourg, Switzerland
Trends in Nanotechnology Conference 06.09.2010 Braga, Portugal
NanoBio International Conference 24.08.2010 Zurich, Switzerland
Polycoll 2010 21.07.2010 University of Basel, Basel
43rd IUPAC World Polymer Congress, MACRO2010 11.07.2010 Glasgow, UK
2nd Swiss Soft Days 23.06.2010 EPFL Lausanne, Switzerland
6Th International ECNP Conference on Nanostructured polymers and nanocomposites 28.04.2010 Madrid, Spain


Self-organised

Title Date Place
Swiss Soft Days- 5th edition 08.07.2011 University of Basel, Basel

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Syngenta Basel Meeting 22.09.2011 Basel
CUSO summer school: From Structure to Function in Nanomaterials 22.08.2010 Villars, Switzerland


Awards

Title Year
SCS/SCNAT Travel award 2010

Associated projects

Number Title Start Funding scheme
124406 ANTIOXIDANT NANOREACTORS BASED ON CO-ENCAPSULATION OF ENZYMES IN POLYMERIC VESICLES 01.06.2009 Project funding
115956 Structure-activity relationships in Cu/Zn superoxide dismutase (SOD) and SOD-mimics before and after encapsulation in polymeric nanocontainers 01.04.2007 Project funding

Abstract

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.
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