On the biodegradability of polyethylene glycol, polypeptoids and poly(2-oxazoline)s.

Despite being the gold standard of hydrophilic biomaterials and well known sensitivity of polyethylene glycol (PEG) against oxidative degradation, very little information on the decomposition of PEG under biological oxidative stress can be found in the literature. Poly(2-oxazoline)s (POx) and polypeptoids (POI), two pseudo-polypeptides, have attracted some attention for the use as biomaterials and alternative to PEG with an altered stability against oxidative degradation. All three polymer families are supposedly non-biodegradable, which could be seen as one of their main disadvantages. Here, we present evidence that PEG, POx and POI are degradable by oxidative degradation under biologically relevant conditions. Transition metal catalysed generation of reactive oxygen species (ROS) leads to a pronounced time and concentration dependent degradation of all polymers investigated. While we do not envision oxidative degradation to be of relevance in the short-term usage of these polymers, mid- and long-term biodegradability in vivo appears feasible. Moreover, influence in ROS mediated signalling cascades may be one mechanism how synthetic polymers influence complex cellular processes.

[1]  Gunnar Almkvist,et al.  Degradation of polyethylene glycol and hemicellulose in the Vasa , 2007 .

[2]  R. Dixon,et al.  Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis , 1990, Nature.

[3]  P. Dalton,et al.  Degradable polyester scaffolds with controlled surface chemistry combining minimal protein adsorption with specific bioactivation. , 2011, Nature materials.

[4]  J. Groll,et al.  Einbau aktiver Proteine und lebender Zellen in redoxsensitive Hydrogele und Nanogele durch enzymatische Vernetzung , 2013 .

[5]  Lucas H. Hofmeister,et al.  Physiologically relevant oxidative degradation of oligo(proline) cross-linked polymeric scaffolds. , 2011, Biomacromolecules.

[6]  Ivo Feussner,et al.  The lipoxygenase pathway. , 2003, Annual review of plant biology.

[7]  R. Luxenhofer,et al.  Doubly amphiphilic poly(2-oxazoline)s as high-capacity delivery systems for hydrophobic drugs. , 2010, Biomaterials.

[8]  Sébastien Lecommandoux,et al.  Biocompatible and biodegradable poly(trimethylene carbonate)-b-poly(L-glutamic acid) polymersomes: size control and stability. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[9]  J. Hubbell,et al.  Interfacial reactivity of block copolymers: understanding the amphiphile-to-hydrophile transition. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[10]  D. Dempsey,et al.  Comparative analysis of in vitro oxidative degradation of poly(carbonate urethanes) for biostability screening. , 2014, Journal of biomedical materials research. Part A.

[11]  W. Banks,et al.  Conjugates of superoxide dismutase 1 with amphiphilic poly(2-oxazoline) block copolymers for enhanced brain delivery: synthesis, characterization and evaluation in vitro and in vivo. , 2013, Molecular pharmaceutics.

[12]  Sung Hyun Park,et al.  Surface-grafted polysarcosine as a peptoid antifouling polymer brush. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[13]  W. Hennink,et al.  Enzymatic degradation of liposome-grafted poly(hydroxyethyl L-glutamine). , 2005, Bioconjugate chemistry.

[14]  M. Textor,et al.  Polyoxazolines for nonfouling surface coatings--a direct comparison to the gold standard PEG. , 2012, Macromolecular rapid communications.

[15]  Lili He,et al.  In vitro evaluation of the genotoxicity of a family of novel MeO-PEG-poly(D,L-lactic-co-glycolic acid)-PEG-OMe triblock copolymer and PLGA nanoparticles , 2009, Nanotechnology.

[16]  Sung Hyun Park,et al.  An experimental-theoretical analysis of protein adsorption on peptidomimetic polymer brushes. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[17]  S. Rankin,et al.  Neutrophil kinetics in health and disease , 2010, Trends in immunology.

[18]  N. Tirelli,et al.  Scavenging ROS: superoxide dismutase/catalase mimetics by the use of an oxidation-sensitive nanocarrier/enzyme conjugate. , 2012, Bioconjugate chemistry.

[19]  B. Babior,et al.  The particulate superoxide-forming system from human neutrophils. Properties of the system and further evidence supporting its participation in the respiratory burst. , 1976, The Journal of clinical investigation.

[20]  S. Tannenbaum,et al.  Nitrosation by stimulated macrophages. Inhibitors, enhancers and substrates. , 1989, Carcinogenesis.

[21]  J. Svanvik,et al.  Hepatic excretion and metabolism of polyethylene glycols and mannitol in the cat. , 1993, Journal of hepatology.

[22]  Jeffrey A. Hubbell,et al.  New Synthetic Methodologies for Amphiphilic Multiblock Copolymers of Ethylene Glycol and Propylene Sulfide , 2001 .

[23]  P. Messersmith,et al.  New peptidomimetic polymers for antifouling surfaces. , 2005, Journal of the American Chemical Society.

[24]  S. Han,et al.  Thermal/oxidative degradation and stabilization of polyethylene glycol , 1997 .

[25]  Effect of cytochrome P-450 inhibition and stimulation on intensity of polyethylene degradation in microsomal fraction of mouse and rat livers. , 1990, Biomaterials.

[26]  Degradation of polyethylene exposed in mouse-liver homogenates by oxidation , 1991 .

[27]  M. Essler,et al.  Synthesis, biodistribution and excretion of radiolabeled poly(2-alkyl-2-oxazoline)s. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[28]  K. Uchida,et al.  Oxidative fragmentation of collagen and prolyl peptide by Cu(II)/H2O2. Conversion of proline residue to 2-pyrrolidone. , 1992, The Journal of biological chemistry.

[29]  F. Veronese,et al.  Polyoxazoline: chemistry, properties, and applications in drug delivery. , 2011, Bioconjugate chemistry.

[30]  M. Erard,et al.  ROS production in phagocytes: why, when, and where? , 2013, Journal of leukocyte biology.

[31]  A. Tauber,et al.  Evidence for hydroxyl radical production by human neutrophils. , 1977, The Journal of clinical investigation.

[32]  A. Kabanov,et al.  Effect of Pluronic P85 on ATPase Activity of Drug Efflux Transporters , 2004, Pharmaceutical Research.

[33]  Richard d'Arcy,et al.  Chemical specificity in REDOX-responsive materials: The diverse effects of different Reactive Oxygen Species (ROS) on polysulfide nanoparticles , 2014 .

[34]  A. Kettle,et al.  Modeling the Reactions of Superoxide and Myeloperoxidase in the Neutrophil Phagosome , 2006, Journal of Biological Chemistry.

[35]  Yingchao Han,et al.  Poly(2-oxazoline)s as polymer therapeutics. , 2012, Macromolecular rapid communications.

[36]  P. Messersmith,et al.  Protein, cell and bacterial fouling resistance of polypeptoid-modified surfaces: effect of side-chain chemistry. , 2008, Soft matter.

[37]  Jeffrey A Hubbell,et al.  Oxidation-sensitive polymeric nanoparticles. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[38]  Yoon Yeo,et al.  Recent advances in stealth coating of nanoparticle drug delivery systems. , 2012, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[39]  Alexander V. Kabanov,et al.  Inhibition of Multidrug Resistance-Associated Protein (MRP) Functional Activity with Pluronic Block Copolymers , 1999, Pharmaceutical Research.

[40]  A. Kettle,et al.  Chlorination of Bacterial and Neutrophil Proteins during Phagocytosis and Killing of Staphylococcus aureus * , 2002, The Journal of Biological Chemistry.

[41]  P. Moghe,et al.  Poly(ethylene glycol) as a sensitive regulator of cell survival fate on polymeric biomaterials: the interplay of cell adhesion and pro-oxidant signaling mechanisms , 2010 .

[42]  Gary T. Howard,et al.  Biodegradation of polyurethane: a review , 2002 .

[43]  R. Luxenhofer,et al.  Polypeptoids: A perfect match for molecular definition and macromolecular engineering? , 2013 .

[44]  J. A. Hubbell,et al.  Cell‐Responsive Synthetic Hydrogels , 2003 .

[45]  Alexander V Kabanov,et al.  Polymer genomics: an insight into pharmacology and toxicology of nanomedicines. , 2006, Advanced drug delivery reviews.

[46]  John K. Jackson,et al.  Development of amphiphilic diblock copolymers as micellar carriers of taxol , 1996 .

[47]  R. Luxenhofer,et al.  Thermal Properties of Aliphatic Polypeptoids , 2013 .

[48]  D. Yan,et al.  Therapeutic nanocarriers with hydrogen peroxide-triggered drug release for cancer treatment. , 2013, Biomacromolecules.

[49]  Yingchao Han,et al.  Synergistic combinations of multiple chemotherapeutic agents in high capacity poly(2-oxazoline) micelles. , 2012, Molecular pharmaceutics.

[50]  A. Kettle,et al.  Reactions of superoxide with myeloperoxidase and its products. , 2004, Japanese journal of infectious diseases.

[51]  Alexander V. Kabanov,et al.  Relationship between pluronic block copolymer structure, critical micellization concentration and partitioning coefficients of low molecular mass solutes , 2000 .

[52]  A. Kettle,et al.  Myeloperoxidase: a front‐line defender against phagocytosed microorganisms , 2013, Journal of leukocyte biology.

[53]  E. Stadtman,et al.  Protein Oxidation in Aging, Disease, and Oxidative Stress* , 1997, The Journal of Biological Chemistry.

[54]  E. Mahmoud,et al.  Biocompatible polymeric nanoparticles degrade and release cargo in response to biologically relevant levels of hydrogen peroxide. , 2012, Journal of the American Chemical Society.

[55]  S. Klebanoff Myeloperoxidase: friend and foe , 2005, Journal of leukocyte biology.

[56]  Alexander V. Kabanov,et al.  Pluronic P85 Increases Permeability of a Broad Spectrum of Drugs in Polarized BBMEC and Caco-2 Cell Monolayers , 1999, Pharmaceutical Research.

[57]  P. Messersmith,et al.  The present and future of biologically inspired adhesive interfaces and materials. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[58]  E. Stadtman,et al.  Free radical-mediated oxidation of free amino acids and amino acid residues in proteins , 2003, Amino Acids.

[59]  Nicola Tirelli,et al.  Oxidant‐Dependent REDOX Responsiveness of Polysulfides , 2012 .

[60]  C. Nathan,et al.  Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[61]  E. Pamer,et al.  Monocyte recruitment during infection and inflammation , 2011, Nature Reviews Immunology.

[62]  A. Segal,et al.  How neutrophils kill microbes. , 2005, Annual review of immunology.

[63]  R. van Furth,et al.  THE ORIGIN AND KINETICS OF MONONUCLEAR PHAGOCYTES , 1968, The Journal of experimental medicine.

[64]  E. Kandel,et al.  Lipoxygenase metabolites of arachidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells , 1987, Nature.

[65]  M. Woodle,et al.  New amphipatic polymer-lipid conjugates forming long-circulating reticuloendothelial system-evading liposomes. , 1994, Bioconjugate chemistry.

[66]  R. Luxenhofer,et al.  Neuronal uptake and intracellular superoxide scavenging of a fullerene (C60)-poly(2-oxazoline)s nanoformulation. , 2011, Biomaterials.

[67]  D. Liang,et al.  Oxidation-Accelerated Hydrolysis of the Ortho Ester-Containing Acid-Labile Polymers. , 2013, ACS macro letters.

[68]  J. Santerre,et al.  Biodegradation evaluation of polyether and polyester-urethanes with oxidative and hydrolytic enzymes. , 1994, Journal of biomedical materials research.

[69]  Manuel T. Silva,et al.  Neutrophils and Macrophages: the Main Partners of Phagocyte Cell Systems , 2012, Front. Immun..

[70]  M. Scott,et al.  Comparative efficacy of blood cell immunocamouflage by membrane grafting of methoxypoly(ethylene glycol) and polyethyloxazoline. , 2014, Biomaterials.

[71]  A. Nakano,et al.  Degradation of poly(ethylene oxide) by high‐speed stirring , 1967 .

[72]  R. Luxenhofer,et al.  Polypeptoids from N-Substituted Glycine N-Carboxyanhydrides: Hydrophilic, Hydrophobic, and Amphiphilic Polymers with Poisson Distribution , 2011 .

[73]  C. Colton,et al.  Nitric oxide and redox mechanisms in the immune response , 2011, Journal of leukocyte biology.

[74]  P. Moghe,et al.  Synthetic polymeric substrates as potent pro‐oxidant versus anti‐oxidant regulators of cytoskeletal remodeling and cell apoptosis , 2009, Journal of cellular physiology.

[75]  I. Fridovich Superoxide Anion Radical (O·̄2), Superoxide Dismutases, and Related Matters* , 1997, The Journal of Biological Chemistry.

[76]  K. Krause,et al.  Reactive oxygen species: from health to disease. , 2012, Swiss medical weekly.

[77]  R. Luxenhofer,et al.  Highly defined multiblock copolypeptoids: pushing the limits of living nucleophilic ring-opening polymerization. , 2012, Macromolecular rapid communications.

[78]  J. Tessmar,et al.  Customized PEG-derived copolymers for tissue-engineering applications. , 2007, Macromolecular bioscience.

[79]  D. Kalonia,et al.  Removal of peroxides in polyethylene glycols by vacuum drying: Implications in the stability of biotech and pharmaceutical formulations , 2006, AAPS PharmSciTech.

[80]  Rudolf Zentel,et al.  Overcoming the PEG-addiction: well-defined alternatives to PEG, from structure–property relationships to better defined therapeutics , 2011 .

[81]  Atsushi Harada,et al.  Formation of Polyion Complex Micelles in an Aqueous Milieu from a Pair of Oppositely-Charged Block Copolymers with Poly(ethylene glycol) Segments , 1995 .

[82]  D. Branch,et al.  Long-term stability of grafted polyethylene glycol surfaces for use with microstamped substrates in neuronal cell culture. , 2001, Biomaterials.

[83]  Martin Müller,et al.  Oxidation-responsive polymeric vesicles , 2004, Nature materials.

[84]  P. Starke-Reed,et al.  Protein oxidation and proteolysis during aging and oxidative stress. , 1989, Archives of biochemistry and biophysics.

[85]  R. Luxenhofer,et al.  Living polymerization of N-substituted β-alanine N-carboxyanhydrides: kinetic investigations and preparation of an amphiphilic block copoly-β-peptoid. , 2012, Macromolecular rapid communications.

[86]  Gaurav Sahay,et al.  The utilization of pathogen-like cellular trafficking by single chain block copolymer. , 2010, Biomaterials.

[87]  A. Lendlein,et al.  Surface functionalization of poly(ether imide) membranes with linear, methylated oligoglycerols for reducing thrombogenicity. , 2012, Macromolecular rapid communications.

[88]  Ho-Chul Shin,et al.  Multi-drug loaded polymeric micelles for simultaneous delivery of poorly soluble anticancer drugs. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[89]  Donghui Zhang,et al.  Polypeptoid Materials: Current Status and Future Perspectives , 2012 .

[90]  P. Messersmith,et al.  Experimental and theoretical investigation of chain length and surface coverage on fouling of surface grafted polypeptoids , 2009, Biointerphases.

[91]  Myron S. Cohen,et al.  Free radicals and phagocytic cells , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[92]  B. Freeman,et al.  Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[93]  Marcus Textor,et al.  Comparative Stability Studies of Poly(2-methyl-2-oxazoline) and Poly(ethylene glycol) Brush Coatings , 2012, Biointerphases.