Synthesis And Self-Assembly Of Redox-Responsive Polymers For Biomedical Applications

Redox reactions play a crucial role in various physiological processes such as metabolism and signaling.The disruption of the balance between oxidation and reduction can cause oxidative stress,leading to a series of inflammation-related diseases.Among them,chronic or acute kidney injury is one of the oxidative stress-related diseases with the largest patient population,causing vast mortality and treatment costs.At present,there are still several important scientific problems in the therapeutic drugs and methods: 1.How to reduce the risk of contrast iduced nephropathy during the angiography in patients with renal insufficiency? 2.How to improve the bioavailability,biocompatibility and broad-spectrum antioxidant activity of antioxidant materials? 3.How to improve the renal accumulation of antioxidant materials and enrich their functions to cope with the complex pathology of renal injury? These questions are all about the prevention and treatment of kidney injury,aiming to explore and solve the key scientific problems in the field of kidney injury treatment through enhancing antioxidant properties,increasing bioavailability and enriching material functions.To solve the above problems,we designed a variety of the redox-responsive polymersomes.A series of functional polymersomes were synthesized by introducing antioxidative moieties,optimizing polymer chains and loading drugs.The main results include the following three aspects:1.A novel biodegradable contrast agent capable of preventing contrast iduced nephropathy was designed for CT angiography.This contrast agent consists of polymersomes that were self-assembled from poly(ethylene oxide)-block-poly(triiodobenzoic chloride-conjugated polylysine-stat-phenylboronic acid pinacol ester-conjugated polylysine)(PEO45-b-P[(Lys-IBC)45-stat-(Lys-PAPE)15]).The hydrophilic PEO block forms the corona and the hydrophobic Lys-IBC and the Lys-PAPE segments form the insoluble membrane;the former repeat units allow CT imaging;the latter repeat units allow ROS scavenging of this polymersome.This renoprotective angiographic polymersome not only has excellent angiographic enhancement effect,but also can relife renal oxidative stress,protect renal function,and significantly reduce the risk of contrast agent nephropathy.In vitro experiments confirmed low cytotoxicity,excellent electrosteric stability and biodegradability,ROS scavenging capability and high CT enhancing efficiency of the polymersome.In vivo experiments revealed that this renoprotective angiographic polymersome has a prolonged circulation time of 30 min.Moerover,the efficient ROS scavenging capability allows RAPs to effectively protect the kidneys from oxidative stress,while no obvious side effects on major organs were observed.2.A biodegradable polypeptide polymersome with broad-spectrum antioxidative activity was designed to solve the limitation of current small molecule antioxidantive peptide and inorganic antioxidants,such as low bioavailability,lack of broad-spectrum antioxidant capacity and biodegradability.The polymersome was first formed by self-assembly of the biodegradable block copolymer PGA9-b-P(Met8-stat-Tyr12).The negatively charged PGA block forms the corona of the polymersome,which can stabilize the polymersome and reduce the chance of combination between polymersome with cells and biological macromolecules to increase the bioavailability of the polymersome;the PMet segement mainly scavenges hydrogen peroxide,while PTyr can scavenge free radicals efficiently.Through combining these two segments,broad-spectrum antioxidant effect can be achieved.In vitro experiments confirmed low cytotoxicity,excellent electrosteric stability,broad-spectrum ROS scavenging capability and oxidative stress relief efficiency of the polymersome.In vivo experiments revealed that these polymersomes can effectively relief renal oxidative stress and protect renal function in mice with acute kidney injury.3.An antioxidative and anti-inflammatory DNA polymersome was designed to solve the limitation of current therapeutic drugs and strategies,such as insufficient accumulation in kidneys and lack of multifunction.The DNA polyermsome was self–assembled from the block copolymer PCL40-b-d T5.Avacopan,a C5 a receptor inhibitor was encapsulated into the lumen of the DNA polymersome during self-assembly to afford the antioxidative-anti-inflammatory DNA polymersome.The corona of this polymersome is composed of d T nucleotide blocks,which can stabilize the polymersome,scavenge reactive oxygen species,and increase the accumulation of polymersomes in the kidney.The hydrophobic PCL block forms the membrane of the polymersome.In vitro experiments confirmed low cytotoxicity,excellent electrosteric stability,effective ROS scavenging capability and oxidative stress relief efficiency of the polymersome.In vivo experiments revealed that these polymersomes can effectively relife renal oxidative stress and inflammation,and protect renal function in mice with acute kidney injury.In summary,we have designed and synthesized various redox-responsive polymersomes,and applied these polymersomes to the prevention and treatment of oxidative stress-related diseases,including preventing contrast induced nephropathy through endowing the materials with ROS scavenging capability,treating acute kidney injury efficiently through increasing the antioxidative activity and bioavailability of the materials,and treating acute kidney injury with complex pathology through enhancing kidney enrichment of the materials and endowing materials with dual functions.In each work,the design and application of materials are further optimized based on the former one.These materials and strategies solved a series of scientific problems in the therapeutic methods of kidney injury,and may be extended for other oxidative stress-related diseases and is promising in terms of bioapplication.