EGFR is a potential therapeutic target for treating bladder cancer, but has not been approved for clinical use yet. Metformin is a widely used antidiabetic drug and has demonstrated interesting anticancer effects on various cancer models, alone or in combination with chemotherapeutic drugs. The efficacy of gefitinib, a well-known EGFR tyrosine kinase inhibitor, combined with metformin was assessed on bladder cancer and underlying mechanisms were explored. This drug combination induced a strong anti-proliferative and anti-colony forming effect and apoptosis in bladder cancer cell lines. Gefitinib suppressed EGFR signaling and inhibited phosphorylation of ERK and Akt. Metformin amplified this inhibitory effect and enhanced gefitinib-induced activation of AMPK signaling pathway. In vivo intravesical treatment of metformin and gefitinib on syngeneic orthotopic mice confirmed the significant inhibitory effect on bladder tumor growth. These two drugs may be an excellent combination for the treatment of bladder cancer through intravesical instillation.

Infections associated with antibiotic-resistant bacteria have become a threat to the global public health. Antimicrobial polymers, which are synthetic mimics of antimicrobial peptides, have gained increasing attention, as they may have a lower chance of inducing resistance. The cationic−hydrophobic balance and distribution of cationic and hydrophobic moieties of these polymers is known to have a major effect on antimicrobial activity. We studied the properties of a series of facially amphiphilic antimicrobial surfactant-like poly(ester urethane)s with different hydrophobic pendant groups (P1, P2, and P3) and cationic groups distributed uniformly along the polymer chain. These polymers exhibited bactericidal activity against Gram-negative Escherichia coli and Pseudomonas aeruginosa, as well as Gram-positive Staphylococcus aureus and Staphylococcus epidermidis. Microscopy and dye release assays demonstrated that these polymers cause membrane disruption, which is dependent on the cationic−hydrophobic ratio in the polymer. Membrane permeability assays revealed that these polymers can permeabilize the outer membrane of E. coli and damage the cytoplasmic membrane of both E. coli and S. aureus. In addition, our results indicate that the three polymers exhibit a different extent of membrane disruption against E. coli. P1 caused minor damage to the cytoplasmic membrane integrity, but it was able to dissipate the cytoplasmic membrane potential, leading to cell death. P2 and P3 depolarized the cytoplasmic membrane and also caused significant damage to the cytoplasmic membrane. Overall, we showed a new class of broad-spectrum bactericidal polymers whose membrane disrupting ability against E. coli correlates with the structural differences of the hydrophobic pendant groups.

We report the design of a series of polyesters containing pendant secondary amide groups to probe the cumulative effects of hydrogen bonding and chain flexibility on their thermal, mechanical, and rheological properties. Reported studies on polymers with secondary amide groups have usually focused on the effect of hydrogen bonding interactions on the mechanical, selfassembly, or self-healing properties, whereas the effect of chain flexibility has often been overlooked. In an effort to probe the cumulative effects of hydrogen bonding and chain flexibility, in this work polyesters were designed with either one or two pendant secondary amide-propyl groups and compared to a control polyester with one pendant ester-propyl group. The results show that hydrogen bonding increases glass transition temperature (T g ), Young's modulus, and polymer brittleness. But at higher temperature (T g + 50 °C), rheometry shows that the polyester containing two amide groups has the shortest chain relaxation time and the lowest zero-shear rate viscosity (η 0 ). These results are counterintuitive, since the polymer with two hydrogen bonding amide groups was expected to relax more slowly and have higher viscosity. Our results demonstrate the opposing effects of side-chain flexibility and hydrogen bonding interactions can be used as a strategy to design materials with desired rheological properties.

Clinically used bio-based tissue sealants bring in the risk of animal-borne infections, non-degradability, allergic reactions, tissue compression, tissue necrosis, and poor wet adhesion. Motivated by these unsatisfactory properties of existing tissue sealants, herein, we designed a library of solvent-and initiator-free hydrophobic musselinspired degradable tissue adhesives that can stick and seal the epidermis, pericardium, and Glisson's capsule under physiologically relevant wet conditions. By varying the molar ratio of the functional groups, we obtained polyester adhesive sealants with similar surface energy and varying viscosity. The careful examination of the wetting behavior of these polyester adhesive sealants on tissue surfaces showed that the polyester adhesive sealant with lower viscosity has higher intrinsic work of adhesion, which allowed them to adhere to strongly hydrated surfaces such as pericardium and Glisson's capsule. Because of the lower intrinsic work of adhesion, the polyester adhesive sealant with higher viscosity only adhered to the relatively hydrophobic surface (epidermis). The strong wet adhesion to tissue surfaces, cell-compatibility, hydrolytic degradability, and radical scavenging nature of these polyester adhesive sealants make them potential candidates for wound closure procedures.

The Baylis–Hillman reaction, which is a carbon–carbon bond forming reaction between an aldehyde and an activated alkene, was utilized to prepare densely functionalized monomers suitable for chain and step polymerization. By reacting formaldehyde with various alkyl acrylates, a series of alkyl α-hydroxymethyl acrylate monomers were synthesized. These monomers efficiently underwent RAFT polymerization to provide α-hydroxymethyl-substituted polyacrylates with well controlled molecular weight and low polydispersity. The resulting homopolymers were also efficient macro-chain transfer agents for further RAFT polymerization. The Baylis–Hillman reaction was also utilized to synthesize alkene functionalized diols which underwent step-growth polymerization to provide polyesters and poly(ester urethane)s. Furthermore, it was demonstrated that the alkene group can be quantitatively functionalized by thiol–ene click chemistry to provide a series of polymers with diverse physical properties.

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In spite of the rapid adoption of three-dimensional (3D) printed scaffolds in biomedical applications, there is a paucity of low-modulus 3D printable biodegradable polymers available for fabrication of tissue-mimetic scaffolds. Extrusion-based direct-write 3D printing (EDP) enables printing and customization of lowmodulus materials that match the modulus of the native tissue. However, the poor printability and low shape fidelity of such materials are significant limitations of soft materials. Herein, we demonstrate that these limitations can be overcome by the introduction of hydrogen bonds into 3D printable low-modulus polyester inks. We show that the hydrogen bonds serve as physical cross-links, which improve the printability and shape fidelity of 3D printed scaffolds without sacrificing the low modulus of the polyester. A 3D printable polyester ink comprising an unsaturated aliphatic side chain, a UV-curable coumarin pendant group, and a secondary amide group-containing side chain was designed. The long aliphatic side chains increase the flowability and allow 3D printing at room temperature. Coumarin groups function as crosslinking sites when irradiated with UV light, which help the scaffold maintain its shape after printing. The hydrogen bonds from the secondary amide groups impede the deformation of filament dimensions after extrusion and result in higher shape fidelity. Most significantly, introduction of hydrogen bonds does not compromise the softness of the polymer, which facilitates room-temperature printing and maintains the low-modulus nature of the polymer post printing.

Rheumatoid arthritis (RA) is a systemic autoimmune disease underlying a cascade of chronic inflammatory processes. Over the past decades, the response rate of effective RA treatments has remained scarce despite numerous advancements in the current therapeutic interventions, owing largely to the associated off-target adverse events and poor accumulation in the inflamed joints. Recently, there is a high interest in the development of targeted drug delivery system by using nanotechnology, as it can provide a handle to improve the therapy efficacy of RA. Here, multifunctional HA@RFM@PB@ SE nanoparticles (HRPS NPs) are developed by loading schisanlactone E (SE, also called with xuetongsu), an anti-RA compound isolated from Tujia ethnomedicine xuetong, into Prussian blue nanoparticles (PB NPs) and further camouflage of RBC-RAFLS hybrid membrane with HA modification onto PB@SE NPs (PS NPs). We demonstrated that the modification of RFM makes PB NPs ideal decoys for targeting inflammatory mediators of arthritis due to the homing effects of the parental cells. Moreover, the encapsulation of RFM on the PB@SE NPs extended the blood circulation time and improved its targeting ability, which accordingly achieved optimal accumulation of SE in arthritic rat paws. In vitro and in vivo assay demonstrated the outstanding performance of HRPS NPs for synergistic chemo-/photothermal therapy of RA without side effects to healthy tissues. Molecular mechanism exploration indicated that the ultrastrong inhibition of synovial hyperplasia and bone destruction was partly via suppressing NF-κB signaling pathway and the expression of matrix metalloproteinases. In summary, the nanodrug delivery system showed controllable release behavior, targeted accumulation at arthritic sites and systemic regulation of immunity, hence improved therapeutic efficacy and clinical outcomes of the disease without attenuating safety.