Ultra-Small Platinum Nanoparticle-Enabled Catalysis and Corrosion Susceptibility Reverse Tumor Hypoxia for Cancer Chemoimmunotherapy.

A major challenge in the use of chemotherapy and immunotherapy is hypoxia-induced progression of tumor cells. We aim to curb hypoxia using metal-based O2-producing nanomedicine. The key focus is therapeutic targeting of hypoxia-inducible factor 1α (HIF-1α), a major reactive oxygen species (ROS)-activated player that drives hypoxia-dependent tumor progression. Inhibition of tumor growth by blocking both HIF-1α and immune checkpoint molecules via ROS removal is a promising new strategy to avoid ROS-induced hypoxia signaling and boost antitumor immunity. Here, we investigated the synergistic effect of ultra-small platinum nanoparticles (Pt-nano) with dual functions of enzyme-mimicking catalysis and corrosion susceptibility to block hypoxia signaling of tumors. Ultra-small Pt-nano with highly corrosive susceptibility can efficiently catalyze ROS scavenging and promote oxygen accumulation for hypoxia reversal, leading to reduced HIF-1α expression. The unique corrosion susceptibility allows ultra-small Pt-nano to effectively exert platinum cytotoxicity, induce reversal of hypoxia-mediated immune suppression by promoting cytotoxic T-cell infiltration of tumors, and reduce the levels of tumoral immune checkpoint molecules and immunosuppressive cytokines. In combination with immune checkpoint blockade using monoclonal antibodies, nanoparticle-enabled enzyme-mimicking is a promising strategy for the enhancement of chemoimmunotherapeutic efficacy through the reversal of tumor hypoxia.

The Bioactive Core and Corona Synergism of Quantized Gold Enables Slowed Inflammation and Increased Tissue Regeneration in Wound Hypoxia.

The progress of wound regeneration relies on inflammation management, while neovascular angiogenesis is a critical aspect of wound healing. In this study, the bioactive core and corona synergism of quantized gold (QG) were developed to simultaneously address these complicated issues, combining the abilities to eliminate endotoxins and provide oxygen. The QG was constructed from ultrasmall nanogold and a loosely packed amine-based corona via a simple process, but it could nonetheless eliminate endotoxins (a vital factor in inflammation also called lipopolysaccharides) and provide oxygen in situ for the remodeling of wound sites. Even while capturing endotoxins through electrostatic interactions, the catalytic active sites inside the nanogold could maintain its surface accessibility to automatically transform the overexpressed hydrogen peroxide in hypoxic wound regions into oxygen. Since the inflammatory stage is an essential stage of wound healing, the provision of endotoxin clearance by the outer organic corona of the QG could slow inflammation in a way that subsequently promoted two other important stages of wound bed healing, namely proliferation and remodeling. Relatedly, the efficacy of two forms of the QG, a liquid form and a dressing form, was demonstrated at wound sites in this study, with both forms promoting the development of granulation, including angiogenesis and collagen deposition. Thus, the simply fabricated dual function nanocomposite presented herein not only offers reduced batch-to-batch variation but also increased options for homecare treatments.

Bio-inert interfaces via biomimetic anchoring of a zwitterionic copolymer on versatile substrates.

Bio-inert biomaterial design is vital for fields like biosensors, medical implants, and drug delivery systems. Bio-inert materials are generally hydrophilic and electrical neutral. One limitation faced in the design of bio-inert materials is that most of the modifiers used are specific to their substrate. In this work, we synthesized a novel zwitterionic copolymer containing a catechol group, a non-substrate dependent biomimetic anchoring segment, that can form a stable coating on various materials. No previous study was conducted using a grafting-to approach and determined the critical amount of catechol groups needed to effectively modify a material. The synthesized copolymers of sulfobetaine acrylamide (SBAA) and dopamine methacrylamide (DMA) in this work contains varying numbers of catechol groups, in which the critical number of catechol groups that had effectively modified substrates to have the bio-inert property was determined. The bio-inert property and capability to do coating on versatile substrates were evaluated in contact with human blood by coating different material groups such as ceramic, metallic, and polymeric groups. The novel structure and the simple grafting-to approach provides bio-inert property on various materials, giving them non-specific adsorption and attachment of biomolecules such as plasma proteins, erythrocytes, thrombocytes, bacteria, and tissue cells (85-95% reduction).

Superior Bioinert Capability of Zwitterionic Poly(4-vinylpyridine propylsulfobetaine) Withstanding Clinical Sterilization for Extended Medical Applications.

The field of bioinert materials is relatively mature, as unique molecular designs for antifouling have been regularly presented over the past 30 years. However, the effect of steam sterilization, a common procedure in hospitals for sterilizing biomedical devices in clinical uses, on the stability of antifouling and hemocompatible biomaterials remains unexplored. The only available set of data indicates that poly(sulfobetaine methacrylate) (SBMA) is unstable and loses its antifouling properties when exposed to hot humid air, depriving it of its attractiveness. Here, we present zwitterionic biomaterial gels of poly(4-vinylpyridine propylsulfobetaine) (4VPPS) and explore their propensity to biofouling before and after a 1 h steam sterilization at 121 °C. After incubation with erythrocytes, leukocytes, thrombocytes, whole blood, or various bacteria ( Escherichia coli, Stenotrophomonas maltophilia), the antifouling properties of unsterilized 4VPPS gels are comparable to those of SBMA gels. Importantly, they are maintained after steam sterilization, unlike those of SBMA gels, which shows that the structure of 4VPPS and the interactions with water remain unaffected by the humid heat treatment. The antifouling properties of gels coated on materials mimicking surfaces used in biomedical devices including stainless steel (surgical knife), silicon (biochips), or titanium (electrocautery pen) are also maintained after similar sterilization. In addition, repeated sterilizations do not affect the antifouling properties of 4VPPS. Therefore, these results provide a substantial advance over the current knowledge on antifouling materials for repeated usage in actual conditions that often involve, in a biomedical environment, steam sterilization.

Epoxylated Zwitterionic Triblock Copolymers Grafted onto Metallic Surfaces for General Biofouling Mitigation.

Titanium and stainless steel materials are widely used in numerous devices or in custom parts for their excellent mechanical properties. However, their lack of biocompatibility seriously limits their usage in the biomedical field. This study focuses on the grafting of triblock copolymers on titanium and stainless steel metal susbtrates for improving their general biofouling resistance. The series of copolymers that we designed is composed of two blocks of zwitterionic sulfobetaine (SBMA) monomers and one block of glycidyl methacrylate (GMA). The number of repeat units forming each block, n, was finely tuned and controlled to 25, 50, 75, or 100, permitting regulation of the grafting thickness, the morphology, and the dependent properties such as the surface hydrophilicity and biofouling resistance. It was shown that the copolymer possessing n = 50 repeat units in each block, corresponding to a molecular weight of about 15.2 kDa, led to the best nonfouling properties, assessed using plasma proteins, blood cells, fibroblasts cells, and various bacteria. This was explained by an optimized grafting degree and chain organization of the copolymer. Lower value (n = 25) and higher values (n = 75, 100) led to low surface coverage and the formation of aggregates, respectively. The best copolymer was grafted onto scalpels (steel) and dental roots (titanium), and antifouling properties demonstrated using Escherichia coli and HT1080 cells. Results of this work show that this unique triblock copolymer holds promise as a potential material for surface modification of biomedical metallic devices, provided a fine-tuning of the blocks organization and length.

Surface charge-bias impact of amine-contained pseudozwitterionic biointerfaces on the human blood compatibility.

This work discusses the impact of the charge bias and the hydrophilicity on the human blood compatibility of pseudozwitterionic biomaterial gels. Four series of hydrogels were prepared, all containing negatively-charged 3-sulfopropyl methacrylate (SA), and either acrylamide, N-isopropylacrylamide, 2-dimethylaminoethyl methacrylate (DMAEMA) or [2-(methacryloyloxy)ethyl]trimethylammonium (TMA), to form SnAm, SnNm, SnDm or SnTm hydrogels, respectively. An XPS analysis proved that the polymerization was well controlled from the initial monomer ratios. All gels present high surface hydrophilicity, but varying bulk hydration, depending on the nature/content of the comonomer, and on the immersion medium. The most negative interfaces (pure SA, S7A3, S5A5) showed significant fibrinogen adsorption, ascribed to the interactions of the αC domains of the protein with the gels, then correlated to considerable platelet adhesion; but low leukocyte/erythrocyte attachments were measured. Positive gels (excess of DMAEMA or TMA) are not hemocompatible. They mediate protein adsorption and the adhesion of human blood cells, through electrostatic attractive interactions. The neutral interfaces (zeta potential between -10mV and +10mV) are blood-inert only if they present a high surface and bulk hydrophilicity. Overall, this study presents a map of the hemocompatible behavior of hydrogels as a function of their surface charge-bias, essential to the design of blood-contacting devices.

Turning Expanded Poly(tetrafluoroethylene) Membranes into Potential Skin Wound Dressings by Grafting a Bioinert Epoxylated PEGMA Copolymer.

Despite a set of properties ideal to the design of wound dressings, bioinert membranes are seldom applied as wound-healing systems. This work presents a unique series of random copolymers of glycidyl methacrylate (GMA) and poly(ethylene glycol) methacrylate (PEGMA), namely GMA-r-PEGMA, used to surface-modify by grafting onto method polytetrafluorethylene membranes, with the aim of developing wound dressings for quick and efficient wound closure. It is shown that the membrane modified with G50P50 copolymer combines high surface hydrophilicity, high porosity, protein resistance, bacterial resistance, and hemocompatibility, essential properties to wound dressings. Fibrinogen adsorption was measured to be 11.4 ± 3.9% (compared with virgin membrane) correlating with a low water contact angle (14°), whereas the attachment of fluorescent Escherichia coli after 24 h, erythrocytes, leukocytes, thrombocytes, and cells from whole blood was reduced by 85-90%, compared with the virgin membrane. G50P50 membrane was tested as a wound dressing, which outperformed hydrophilic gels of PEGMA in terms of wound-closure kinetic and a commercial dressing in terms of homogeneity of the granulation layer. The facile surface-modification of ePTFE membrane using unique GMA-r-PEGMA copolymer leads to an antibiofouling porous material with improved hemocompatibility combining numerous essential properties of wound dressings and contributing toward the development of the ideal bandage.

Neat poly(ortho-methoxyaniline) electrospun nanofibers for neural stem cell differentiation.

In this manuscript, neat electrospun poly(o-methoxyaniline) (POMA) fibers were applied for the first time in the growth of neural stem cells. POMA was synthesized by chemical oxidative polymerization, followed by dissolving in tetrahydrofuran/dimethylformamide to prepare electrospinning solution. Subsequently, the solution was electrospun to produce polymeric fibers. The structure, transparency and morphology of as-prepared POMA fibers were characterized by Fourier transform infrared spectroscopy, UV-visible spectroscopy and scanning electron microscopy, respectively. It was found to have no adverse effects on the long-term proliferation of the neural stem cells (NSCs), retain the ability to self-renew, and exhibit multipotentiality. Studies on cell-fiber interactions were carried out by culturing NSCs on the POMA substrate and assessing their growth, cell viability, and differentiation. Results of cell viability assay, immunofluorescence staining, quantitative real-time reverse transcription-PCR and calcium image studies confirmed that POMA electrospun fibers not only showed better NSCs attachment, but also enhanced and accelerated differentiation.