Thermal and Reactive Oxygen Species Dual-Responsive OEGylated Polysulfides with Oxidation-Tunable Lower Critical Solution Temperatures.

In this work, two monomethoxy oligo(ethylene glycol) (OEG)-substituted episulfides are prepared and a series of polysulfides are synthesized with subsequent ring-opening polymerization. The OEGylated polysulfides exhibit thermal and reactive oxygen species (ROS) dual-responsive behavior. Their lower critical solution temperatures (LCSTs) are close to human body temperature and depend on the degree of polymerization and OEG length. Notably, the LCST of the polysulfide increases linearly with the oxidation degree by H2 O2 , showing a highly tunable change regulated by the ratio between hydrophobic sulfide and hydrophilic sulfoxide/sulfone in the backbone. Further, the OEGylated polysulfide can act as a ROS scavenger to protect red blood cells (RBCs) from oxidative damage in an RBCs aging model in vitro. This work paves a facile way to synthesize LCST-tunable polysulfides, which hold great promise in biological applications.

Molecular Thorium Trihydrido Clusters Stabilized by Cyclopentadienyl Ligands.

Hydrogenolysis of alkyl-substituted cyclopentadienyl (CpR ) ligated thorium tribenzyl complexes [(CpR )Th(p-CH2 -C6 H4 -Me)3 ] (1-6) afforded the first examples of molecular thorium trihydrido complexes [(CpR )Th(µ-H)3 ]n (CpR =C5 H2 (t Bu)3 or C5 H2 (SiMe3 )3 , n=5; C5 Me4 SiMe3 , n=6; C5 Me5 , n=7; C5 Me4 H, n=8; 7-10 and 12) and [(Cp# )12 Th13 H40 ] (Cp# =C5 H4 SiMe3 ; 13). The nuclearity of the metal hydride clusters depends on the steric profile of the cyclopentadienyl ligands. The hydrogenolysis intermediate, tetra-nuclear octahydrido thorium dibenzylidene complex [(Cpttt )Th(µ-H)2 ]4 (µ-p-CH-C6 H4 -Me)2 (Cpttt =C5 H2 (t Bu)3 ) (11) was also isolated. All of the complexes were characterized by NMR spectroscopy and single-crystal X-ray analysis. Hydride positions in [(CpMe4 )Th(µ-H)3 ]8 (CpMe4 =C5 Me4 H) were further precisely confirmed by single-crystal neutron diffraction. DFT calculations strengthen the experimental assignment of the hydride positions in the complexes 7 to 12.

Facile Fabrication of Hierarchically Thermoresponsive Binary Polymer Pattern for Controlled Cell Adhesion.

A versatile platform allowing capture and detection of normal and dysfunctional cells on the same patterned surface is important for accessing the cellular mechanism, developing diagnostic assays, and implementing therapy. Here, an original and effective method for fabricating binary polymer brushes pattern is developed for controlled cell adhesion. The binary polymer brushes pattern, composed of poly(N-isopropylacrylamide) (PNIPAAm) and poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) chains, is simply obtained via a combination of surface-initiated photopolymerization and surface-activated free radical polymerization. This method is unique in that it does not utilize any protecting groups or procedures of backfilling with immobilized initiator. It is demonstrated that the precise and well-defined binary polymer patterns with high resolution are fabricated using this facile method. PNIPAAm chains capture and release cells by thermoresponsiveness, while POEGMA chains possess high capability to capture dysfunctional cells specifically, inducing a switch of normal red blood cells (RBCs) arrays to hemolytic RBCs arrays on the pattern with temperature. This novel platform composed of binary polymer brush pattern is smart and versatile, which opens up pathways to potential applications as microsensors, biochips, and bioassays.

Label electrochemical immunosensor for prostate-specific antigen based on graphene and silver hybridized mesoporous silica.

Prostate-specific antigen (PSA), as the specificity of prostate cancer markers, has been widely used in prostate cancer diagnosis and screening. In this study, we fabricated an electrochemical immunosensor for PSA detection using the amino-functionalized graphene sheet-ferrocenecarboxaldehyde composite materials (NH2-GS@FCA) and silver hybridized mesoporous silica nanoparticles (Ag@NH2-MCM48). Under optimal conditions, the fabricated immunosensor showed a wide linear range with PSA concentration (0.01-10.0ng·ml(-1)). Low detection limit (2pg·ml(-1)) proved the high sensitivity. In addition, the immunosensor possessed good stability and reproducibility. Moreover, the application to PSA analysis in serum samples yielded satisfactory results.

H2O2-Responsive Polymeric Micelles of Biodegradable Aliphatic Poly(carbonate)s as Promising Therapeutic Agents for Inflammatory Diseases.

Excessive amounts of reactive oxygen species (ROS) cause various biological damages and are involved in many diseases, such as cancer, inflammatory and thrombotic complications, and neurodegenerative diseases. Thus, ROS-responsive polymers with inherent ROS scavenging activity and biodegradability are extremely needed for the efficient treatment of ROS-related diseases. Here, this work fabricates the amphiphilic diblock copolymer PEG-b-PBC via ring-opening polymerization (ROP) of phenylboronic acid ester conjugated cyclic carbonate monomer. The copolymer easily forms micelles (BCM) and scavenges ROS rapidly. BCM not only releases the delivered drug but degrades to produce the small molecules p-hydroxybenzyl alcohol (HBA) with anti-inflammatory capability in the presence of H2O2. BCM can reduce the oxidative stress of human umbilical vein endothelial cells (HUVEC) and the levels of inflammatory factors secreted by macrophages, showing antioxidative and anti-inflammatory activity. Finally, BCM exerts a significant capability to reduce the complications of inflammation and thrombosis in vivo. The biodegradable aliphatic poly(carbonate)s have the potential to be used for drug delivery systems (DDS) for diseases induced by reactive oxygen species.

ROS-responsive phenylboronic ester-based nanovesicles as multifunctional drug delivery systems for the treatment of inflammatory and thrombotic complications.

Inflammatory and thrombotic complications and a low loading of dual drugs with different hydrophilicities remain challenges to treat thrombosis with drug delivery systems (DDSs). Here, the reactive oxygen species (ROS)-responsive amphiphilic block polymer poly(ethylene glycol)-b-2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)oxy)-ethyl methacrylate (PEG-b-PTBEM) was synthesized and nanovesicles (PPTV) were prepared successfully for the drug delivery platform by controlling the hydrophilic/hydrophobic ratio of molecular chains and molecular self-assembly. The anti-inflammatory drug indomethacin (IDM) was loaded in the wall of nanovesicles and the thrombolytic enzyme nattokinase (NK) was encapsulated in the aqueous cavity of nanovesicles. Both drugs could be rapidly released at the site of thrombosis and/or inflammation with an excessive ROS concentration. The dual drug-loaded nanovesicles not only eliminated ROS, but also alleviated inflammation and dissolved the generated thrombus, showing significant therapeutic efficacy in the in vivo mouse model of carrageenan tail thrombosis. Therefore, drug-delivery nanovesicles play multiple roles in the treatment of inflammation-induced thrombotic disorders, which offer a promising treatment for inflammatory and thrombotic complications.

A dynamic remodeling bio-mimic extracellular matrix to reduce thrombotic and inflammatory complications of vascular implants.

Thrombotic and inflammatory complications induced by vascular implants remain a challenge to treat cardiovascular disease due to the lack of self-adaption and functional integrity of implants. Inspired by the dynamic remodeling of the extracellular matrix (ECM), we constructed a bio-mimic ECM with a dual-layer nano-architecture on the implant surface to render the surface adaptive to inflammatory stimuli and remodelable possessing long-term anti-inflammatory and anti-thrombotic capability. The inner layer consists of PCL-PEG-PCL [triblock copolymer of polyethylene glycol and poly(ε-caprolactone)]/Au-heparin electrospun fibers encapsulated with indomethacin while the outer layer is composed of polyvinyl alcohol (PVA) and ROS-responsive poly(2-(4-((2,6-dimethoxy-4-methylphenoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (PBA) fibers. In response to acute inflammation after vascular injury, the outer layer reduces ROS rapidly by PBA degradation for inflammation suppression. The degraded outer layer facilitates inner layer reconstruction with enhanced hemocompatibility through the H-bond between PVA and PCL-PEG-PCL. Furthermore, chronic inflammation is effectively depressed with the sustained release of indomethacin from the inner layer. The substantial enhancement of the functional integrity of implants and reduction of thrombotic and inflammatory complications with the self-adaptive ECM are demonstrated both in vitro and in vivo. Our work paves a new way to develop long-term anti-thrombotic and anti-inflammatory implants with self-adaption and self-regulation properties.

Biomimetic nano-NOS mediated local NO release for inhibiting cancer-associated platelet activation and disrupting tumor vascular barriers.

Platelets attribute to the hypercoagulation of blood and maintenance of the tumor vascular integrity, resulting in limited intratumoral perfusion of nanoparticle into solid tumors. To overcome these adversities, we herein present an antiplatelet strategy based on erythrocyte membrane-enveloped proteinic nanoparticles that biomimic nitric oxide synthase (NOS)with co-loading of l-Arginine (LA) and photosensitizer IR783 for local NO release and inhibition of the activation of tumor-associated platelets specifically, thereby enhancing vascular permeability and accumulation of the nanoparticles in tumors. A cRGD-immobolized membrane structure is constructed to actively target platelets and cancer cells respectively, through overexpressed integrin receptors such as integrin αIIbß3 and αvß3, accelerating the inhibition of platelet activation and endocytosis of nanoparticles by tumor cells. Bio-mimicking the arginine/NO pathway in vivo, synergistical delivery of LA and IR783 enables LA molecules readily oxidize to NO with O2 that is mediated by activated IR783, the resulted NO not only retards the activity of platelets to disrupt the vascular integrity of tumor but also enhances toxicity to cancer cells. In addition, NIR-controlled release localizes the NO spatiotemporally to tumor-associated platelets and prevents undesirable systemic bleeding substantially. The reduction of the hypercoagulable state is further demonstrated by the down-regulation of tissues factor (TF) expression in tumor cells. Our study describes a promising approach to combat cancer, which advances the biomimetic NOS system as the potent therapeutic forces toward clinic applications.

Hydrogen Peroxide and Glutathione Dual Redox-Responsive Nanoparticles for Controlled DOX Release.

Polymer nanoparticulate drug delivery systems that respond to reactive oxygen species (ROS) and glutathione (GSH) simultaneously at biologically relevant levels hold great promise to improve the therapeutic efficacy to cancer cells with reduced side effects of chemo drugs. Herein, a novel redox dual-responsive amphiphilic block copolymer (ABP) that consists of a hydrophilic poly (ethylene oxide) block and a hydrophobic block bearing disulfide linked phenylboronic ester group as pendant is synthesized, and the DOX loaded nanoparticles (BSN-DOX) based on ABPs with varied hydrophobic block length are fabricated for DOX delivery. The self-immolative leaving reaction of phenylboronic ester triggered by extracellular ROS and the cleavage of disulfide linkages induced by intracellular GSH both lead to rapid DOX release from BSN-DOX, resulting in an on-demand DOX release. Moreover, BSN-DOX show better tumor inhibition and lower side effects in vivo compared with free drug.

Inhibition of Inflammation-Associated Thrombosis with ROS-Responsive Heparin-DOCA/PVAX Nanoparticles.

Inflammation-associated thrombosis is a non-negligible source of mortalities and morbidities worldwide. To manipulate inflammation-associated coagulation, nanoparticles that contain anti-inflammatory polymer (copolyoxalate containing vanillyl alcohol, PVAX) and anti-thrombotic heparin derivative deoxycholic acid (Hep-DOCA) are prepared. The strategy takes advantage of the reducted side effects of heparin through heparin conjugation, achievement of long-term anti-inflammation by inflammation-trigged release of anti-inflammatory agents, and formation of PVAX/heparin-DOCA nanoparticles by co-self-assembly. It is demonstrated that the Hep-DOCA conjugate and PVAX are synthesized successfully; PVAX and Hep-DOCA nanodrugs (HDP) are obtained by co-assembly; the HDP nanoparticles effectively reduce the inflammation and coagulation without inducing lethal bleeding both in vivo and in vitro. The method provided here is versatile and effective, which paves new way to develop nanodrugs to treat inflammation-associated thrombosis safely.

Multiple microarrays of non-adherent cells on a single 3D stimuli-responsive binary polymer-brush pattern.

We have developed a 3D smart binary polymer-brush pattern on the polymer substrate for inducing multiple cell microarrays aided by a lectin and temperature. The binary polymer-brush pattern composed of poly(N-isopropylacrylamide) (PNIPAM) and poly(d-gluconamidoethyl methacrylate) (PGAMA) brushes is fabricated by combining the photolithography technique with a surface-initiated photo-polymerization (SIPP) method. We demonstrate that well-defined binary polymer-brush patterns with high resolution are fabricated using this facile method. The patterned hierarchical PNIPAM brushes exhibit reversible switching to the adhesion of red blood cells (RBCs) induced by thermo-responsiveness. The PGAMA brush domains resist adhesion of RBCs but bind specifically with concanavalin A (Con A), forming a lectin pattern to capture RBCs in a site-specific manner. Therefore, multiple cell microarrays on a single platform are generated with the aid of Con A and temperature. This novel platform composed of a smart binary polymer-brush pattern is versatile and specific, which opens up pathways to potential applications such as microsensors, biochips and bioassays.

Cell-inspired biointerfaces constructed from patterned smart hydrogels for immunoassays in whole blood.

Immunoassays have shown great advances in the fields of biomedical diagnosis. However, successful immunoassays in blood plasma or whole blood based on the designed biointerfaces are still rare. Here, a newly cell-inspired biointerface for immunoassays in blood is demonstrated. Inspired by the high resistance to protein and cell adhesion and extraordinary biological recognition of stem cells, the biointerfaces are constructed by patterning smart hydrogels (PNIPAAm-co-PNaAc) on hydrophilic layers (PEG), followed by immobilization of antibodies on the patterned hydrogels. The hierarchical biointerfaces are hydrophilic to resist blood plasma and blood cell adhesion, but exhibit high affinity to the target antigens. As a result, successful immunoassays in blood are achieved. In addition, the detection signal is further enhanced by the manipulation of the phase transition of the smart hydrogels with temperature, and the sensitivity is higher than that of the widely-used poly(acrylic acid)/(polyacrylate) platform. The biointerface is versatile and effective in antibody-antigen recognition, which offers a potential new approach for developing highly sensitive immunoassays in blood.

Bioinspired Antioxidant Defense System Constructed by Antioxidants-Eluting Electrospun F127-Based Fibers.

Cells were continuously exposed to oxidative damage by overproduction of reactive oxygen species (ROS) when they contacted implanted biomaterials. The strategy to prevent cells from oxidative injures remains a challenge. Inspired by the antioxidant defense system of cells, we constructed a biocompatible and ROS-responsive architecture on the substrate of styrene-b-(ethylene-co-butylene)-b-styrene elastomer (SEBS). The strategy was based on fabrication of architectures through reactive electrospinning of mixture including SEBS, acylated Pluronic F127, copolymer of poly(ethylene glycol) diacrylate and 1,2-ethanedithiol (PEGDA-EDT), and antioxidants (AA-2G) and ROS-triggered release of AA-2G from microfibers to detoxify the excess ROS. We demonstrated that the stable and hydrophilic architecture was constructed by phase separation of SEBS/F127 components and cross-linking between polymer chains during electrospinning; the ROS-responsive fibers controlled the release of AA-2G and the interaction of AA-2G with ROS reduced the oxidative damage to cells. The bioinspired architecture not only reduced mechanical and oxidative damage to cells but also maintained normal ROS level for physiological hemostasis. This work provides basic principles to design and develop antioxidative biomaterials for implantation in vivo.

Guided protein/cell patterning on superhydrophilic polymer brushes functionalized with mussel-inspired polydopamine coatings.

A simple approach for preparing bicomponent polymer patterns was developed by coating polydopamine (PDA) on superhydrophilic poly(2-acryl-amido-2-methylpropane sulfonic acid) (PAMPS) brushes. Well-defined and versatile arrays of proteins and cells were achieved without harm to proteins and cells.