Xiaomei Dai

Block versus Random Amphiphilic Glycopolymer Nanopaticles as Glucose-Responsive Vehicles

To explore the effect of polymer structure on their self-assembled aggregates and their unique characteristics, this study was devoted to developing a series of amphiphilic block and random phenylboronic acid-based glycopolymers by RAFT polymerization. The amphiphilic glycopolymers were successfully self-assembled into spherically shaped nanoparticles with narrow size distribution in aqueous solution. For block and random copolymers with similar monomer compositions, block copolymer nanoparticles exhibited a more regular transmittance change with the increasing glucose level, while a more evident variation of size and quicker decreasing tendency in I/I0 behavior in different glucose media were observed for random copolymer nanoparticles. Cell viability of all the polymer nanoparticles investigated by MTT assay was higher than 80%, indicating that both block and random copolymers had good cytocompatibility. Insulin could be encapsulated into both nanoparticles, and insulin release rate for random glycopolymer was slightly quicker than that for the block ones. We speculate that different chain conformations between block and random glycopolymers play an important role in self-assembled nanoaggregates and underlying glucose-sensitive behavior.

An Acid-Triggered Degradable and Fluorescent Nanoscale Drug Delivery System with Enhanced Cytotoxicity to Cancer Cells.

To reduce side-effects of anticancer drugs, development of nanocarriers with precise biological functions is a critical requirement. In this study, the multifunctional nanoparticles combining imaging and therapy for tumor-targeted delivery of hydrophobic anticancer drugs were prepared via self-assembly of amphiphilic copolymers obtained using RAFT polymerization, specifically, acid-labile ortho ester and galactose. First, boron-dipyrromethene dye-conjugated chain transfer agent provides fluorescent imaging capability for diagnostic application. Second, nanoparticles were stable under physiological conditions but degraded in acidic tumor microenvironment, leading to enhanced anticancer efficacy. Third, the application of biocompatible glycopolymers efficiently increased the target-to-background ratio through carbohydrate-protein interactions. Data from cell viability, cellular internalization, flow cytometry, biodistribution and anticancer efficacy tests showed that the drug-loaded nanoparticles were capable of inhibiting cancer cell proliferation with significantly enhanced capacity. Our newly developed multifunctional nanoparticles may thus facilitate the development of effective drug delivery systems for application in diagnosis and therapy of cancer.

Single Continuous Near-Infrared Laser-Triggered Photodynamic and Photothermal Ablation of Antibiotic-Resistant Bacteria Using Effective Targeted Copper Sulfide Nanoclusters

The emergence of antibiotic-resistant bacterial strains has made conventional antibiotic therapies less efficient. The development of a novel nanoantibiotic approach for efficiently ablating such bacterial infections is becoming crucial. Herein, a collection of poly(5-(2-ethyl acrylate)-4-methylthiazole-g-butyl)/copper sulfide nanoclusters (PATA-C4@CuS) was synthesized for efficient capture and effective ablation of levofloxacin-resistant Gram-negative and Gram-positive bacteria upon tissue-penetrable near-infrared (NIR) laser irradiation. In this work, we took advantage of the excellent photothermal and photodynamic properties of copper sulfide nanoparticles (CuSNPs) upon NIR laser irradiation and thiazole derivative as a membrane-targeting cationic ligand toward bacteria. The conjugated nanoclusters could anchor the bacteria to trigger the bacterial aggregation quickly and efficiently kill them. These conjugated nanoclusters could significantly inhibit levofloxacin-resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Bacillus amyloliquefaciens at 5.5 μg/mL under NIR laser irradiation (980 nm, 1.5 W cm-2, 5 min), which suggested that the heat and reactive oxygen species (ROS) generated from the irradiated CuSNPs attached to bacteria were effective in eliminating and preventing the regrowth of the bacteria. Importantly, the conjugated nanoclusters could promote healing in bacteria-infected rat wounds without nonspecific damage to normal tissue. These findings highlight the promise of the highly versatile multifunctional nanoantibiotics in bacterial infection.

Structure–Activity Relationship of Membrane-Targeting Cationic Ligands on a Silver Nanoparticle Surface in an Antibiotic-Resistant Antibacterial and Antibiofilm Activity Assay

To explore the structure-activity relationship of membrane-targeting cationic ligands on a silver nanoparticle surface in an antibiotic-resistant antibacterial and antibiofilm activity assay, a series of functionalized silver nanocomposites were synthesized. Tuning the structural configuration, molecular weight, and side-chain length of the cationic ligands on the nanoparticle surface provided silver nanocomposites with effective antibacterial activity against both antibiotic-resistant Gram-negative and Gram-positive bacteria, including bacterial biofilms. These silver nanocomposites did not trigger hemolytic activity. Significantly, the bacteria did not develop resistance to the obtained nanocomposites even after 30 generations. A study of the antibacterial mechanism confirmed that these nanocomposites could irreversibly disrupt the membrane structure of bacteria and effectively inhibit intracellular enzyme activity, ultimately leading to bacterial death. The silver nanocomposites (64 μg/mL) could eradicate 80% of an established antibiotic-resistant bacterial biofilm. The strong structure-activity relationship toward antibacterial and antibiofilm activity suggests that variations in the conformational property of the functional ligand could be valuable in the discovery of new nano-antibacterial agents for treating pathogenic bacterial infections.

A biodegradable and fluorescent nanovehicle with enhanced selective uptake by tumor cells

To improve the pharmacokinetic and pharmacodynamic profiles of clinical anticancer drugs for cancer therapy, the development of effective drug delivery systems with precise biological functions is critically required. In the current study, we developed a PEGylated and core-cross-linked polymeric nanovehicle, LA-pDAGEA/pPEGA-b-p(DMDEA-co-BADS), with reduction- and pH-dependent degradation and fluorescence imaging function for tumor-targeted delivery of hydrophobic drugs. The multifunctional copolymers were synthesized using RAFT polymerization. By utilizing the intrinsic fluorescence of nanovehicles resulting from the boron–dipyrromethene dye-conjugated chain transfer agent (BODIPY), the cellular internalization process was exhibited. Cellular uptake and the competition inhibition assay show that the nanovehicles could be internalized into HepG2 cells via receptor-mediated endocytosis. Moreover, the drug-loaded nanovehicles were capable of significantly inhibiting cancer cell proliferation. Our newly developed multifunctional nanovehicles may thus facilitate the development of efficient drug delivery systems for application in diagnosis and therapy of cancer.

Antibacterial amphiphiles based on ε-polylysine: synthesis, mechanism of action, and cytotoxicity

The development of antibacterial materials is recently more and more important and urgent due to the emergence of antibiotic-resistant bacteria. To address the problem, series of new amphiphiles based on e-polylysine (e-PL) were synthesized by alkylation reaction with alkyl bromide, and concurrently their antibacterial activity and cytotoxicity were evaluated. The amphiphiles with a large concentration of positive charges and lipid chain promoted their adsorption to bacterial membranes through electrostatic interaction and hydrophobic interaction, subsequently killed both Gram-positive (S. aureus and B. amyloliquefaciens) and Gram-negative (E. coli and P. aeruginosa) bacteria. Morphology observed using SEM shows that these derivatives could cause leakage of intracellular contents. Analysis of the antimicrobial mechanism displays that these derivatives against the bacteria started with disruption of the bacterial membrane, which caused the leakage of cytoplasm, and killed the bacteria. Among the amphiphiles, e-PL-g-butyl2 presented the most effective antibacterial activity and its minimum inhibitory concentration as low as 3.9 μg mL−1. Importantly, the effective antibacterial concentration of e-PL-g-butyl2 displayed no cytotoxicity against human cells. This work not only highlights the great promise of using e-PL-g-butyl2 as a highly effective antibacterial agent but also provides the important tool for understanding the interactions between the microorganisms and amphiphiles-based e-PL.

Thiazolium-derivative functionalized silver nanocomposites for suppressing bacterial resistance and eradicating biofilms

Commercial antibiotic therapies are becoming less efficient due to the emergence of bacterial resistance and the formation of bacterial biofilms. The design and development of novel antibacterial agents with efficient anti-biofilm/antibacterial activity and without bacterial resistance is becoming crucial. Herein, a series of poly(5-(2-ethyl acrylate)-4-methylthiazole-g-butyl) functionalized silver nanocomposites (PATA-C4@AgNPs) was synthesized, and their antimicrobial/anti-biofilm activity and biocompatibility were systematically evaluated. The multivalent cationic nanocomposites possessed strong antibacterial activity against both Gram-negative and Gram-positive bacteria without the emergence of bacterial resistance. The PATA-C4@AgNPs were found to disrupt the bacterial membrane and inhibit enzymatic activity. Importantly, these nanocomposites effectively eradicated over 60% of Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) biofilms at a low concentration of 16.7 μg mL−1. Furthermore, these nanocomposites showed selectivity for eliminating bacteria over human cells, thus avoiding cytotoxicity. The results demonstrated that these simple synthetic nanocomposites have great promise for applications in preventing bacterial infections.

An Antifouling Hydrogel Containing Silver Nanoparticles for Modulating the Therapeutic Immune Response in Chronic Wound Healing

Patients with diabetic wounds have deficient local and systemic cellular immunity. Herein, a new silver nanoparticle-containing hydrogel with antifouling properties was developed for enhancing the immune response in diabetic wound healing. The antifouling property was obtained by adjusting the composition of cationic chitosan and anionic dextran to approach zero charge. Furthermore, this hybrid hydrogel showed long-lasting and broad-spectrum antibacterial activity. Rapid wound contraction was observed after the treatment with the hydrogel, which suggested its superior healing activity to promote fibroblast migration, granulation tissue formation, and angiogenesis. The upregulation of CD68+ and CD3+ expression levels demonstrated that the hydrogel could trigger immune responses in the treatment of wound healing. These results show that this antifouling hybrid hydrogel as a wound dressing provided a promising strategy for the treatment of diabetic ulcers.

A Water-Soluble Galactose-Decorated Cationic Photodynamic Therapy Agent Based on BODIPY to Selectively Eliminate Biofilm

A multitude of serious chronic infections are involved in bacterial biofilms that are difficult to eradicate. Here, a water-soluble galactose-functionalized cationic 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based photodynamic therapy agent was synthesized for selectively eliminating the bacterial biofilm. These conjugates can capture bacteria to form aggregations through electrostatic interaction and then generate a large number of reactive oxygen species (ROS) under visible light irradiation to kill the bacteria without the emergence of bacterial resistance. Simultaneously, this agent could effectively inhibit and eradicate both Gram-positive and Gram-negative bacterial biofilms. The in-depth analysis of the antimicrobial mechanism confirmed that the conjugates can quickly bind on the bacterial surface, irreversibly disrupt the bacterial membrane, and distinctly inhibit intracellular enzyme activity, ultimately leading to the bacterial death. Importantly, these conjugates are highly selective toward bacterial cells over mammalian cells as well as no cytotoxicity to A549 cells and no discernible hemolytic activity. Collectively, this water-soluble galactose-decorated cationic BODIPY-based photodynamic therapy agent design provides promising insights for the development of therapy for antibiotic-resistant bacteria.

Glycomimetic-Conjugated Photosensitizer for Specific Pseudomonas aeruginosa Recognition and Targeted Photodynamic Therapy

Due to the rapid development of bacterial resistance, there is an urgent need to explore new antibacterial agents to substitute for traditional antibiotic therapy. Photodynamic therapy has been identified as a promising bactericidal method to conquer antibiotic-resistant pathogens. To solve the problem of photosensitizer damage to normal tissues in vivo, we developed a boron-dipyrrolemethene (BODIPY)-based glycosylated photosensitizer for ablating Pseudomonas aeruginosa ( P. aeruginosa). This glycosylated photosensitizer exhibited good water solubility and generated 1O2 rapidly in an aqueous solution under light exposure. The photosensitizer did not cause detectable toxicity to human cells in the dark. Importantly, the photosensitizer was able to selectively attach to P. aeruginosa over normal cells, thus resulting in effective pathogen ablation by reactive oxygen species. Moreover, the photosensitizer inhibited over 90% of the biofilm formation produced by P. aeruginosa. The results indicate that the design of the macromolecular photosensitizer-induced bacterial death and inhibited biofilm formation provide a novel strategy for overcoming bacterial infection.