Multifunctional Polymer Vesicles for Synergistic Antibiotic-Antioxidant Treatment of Bacterial Keratitis.

As an acute ophthalmic infection, bacterial keratitis (BK) can lead to severe visual morbidity, such as corneal perforation, intraocular infection, and permanent corneal opacity, if rapid and effective treatments are not available. In addition to eradicating pathogenic bacteria, protecting corneal tissue from oxidative damage and promoting wound healing by relieving inflammation are equally critical for the efficient treatment of BK. Besides, it is very necessary to improve the bioavailability of drugs by enhancing the ocular surface adhesion and corneal permeability. In this investigation, therefore, a synergistic antibiotic-antioxidant treatment of BK was achieved based on multifunctional block copolymer vesicles, within which ciprofloxacin (CIP) was simultaneously encapsulated during the self-assembly. Due to the phenylboronic acid residues in the corona layer, these vesicles exhibited enhanced muco-adhesion, deep corneal epithelial penetration, and bacteria-targeting, which facilitated the drug delivery to corneal bacterial infection sites. Additionally, the abundant thioether moieties in the hydrophobic membrane enabled the vesicles to both have ROS-scavenging capacity and accelerated CIP release at the inflammatory corneal tissue. In vivo experiments on a mice model demonstrated that the multifunctional polymer vesicles achieved efficient treatment of BK, owing to the enhanced corneal adhesion and penetration, bacteria targeting, ROS-triggered CIP release, and the combined antioxidant-antibiotic therapy. This synergistic strategy holds great potential in the treatment of BK and other diseases associated with bacterial infections.

Thermoresponsive Hydrogel-Enabled Thermostatic Photothermal Therapy for Enhanced Healing of Bacteria-Infected Wounds.

Photothermal therapy (PTT) has emerged as an attractive technique for the treatment of bacterial infections. However, the uncontrolled heat generation in conventional PTT inevitably causes thermal damages to healthy tissues and/or organs. It is thus essential to develop a smart and universal strategy to regulate the photothermal equilibrium temperature to a preset safe threshold. Herein, a thermoresponsive hydrogel-enabled thermostatic PTT system for enhanced healing of bacteria-infected wounds is reported. In this system, the near-infrared (NIR)-triggered heat generation by photothermal nanomaterials is spontaneously transferred to a thermoresponsive hydrogel with a lower critical solution temperature (LCST), leading to its rapid phase transition by forming considerable light-scattering centers to block NIR penetration. Such a dynamic and reversible process automatically regulates the photothermal equilibrium temperature to the phase-transition point of the LCST-type hydrogel. In contrast to temperature-uncontrolled conventional PTT with severe thermal damages, the thermoresponsive hydrogel-enabled thermostatic PTT provides effective protection on healthy tissues and/or organs, which remarkably accelerates wound healing by efficient bacterial eradication. This study establishes a smart, simple and universal PTT platform, holding great promise in the safe and efficient treatment of bacterial skin infections.

Proton-mediated burst of dual-drug loaded liposomes for biofilm dispersal and bacterial killing.

Exposure of infectious biofilms to dispersants induces high bacterial concentrations in blood that may cause sepsis. Preventing sepsis requires simultaneous biofilm dispersal and bacterial killing. Here, self-targeting DCPA(2-(4-((1,5-bis(octadecenoyl)1,5-dioxopentan-2-yl)carbamoyl)pyridin-1-ium-1-yl)acetate) liposomes with complexed water were self-assembled with ciprofloxacin loaded in-membrane and PEGylated as a lipid-membrane component, together with bromelain loaded in-core. Inside biofilms, DCPA-H2O and PEGylated ciprofloxacin became protonated, disturbing the balance in the lipid-membrane to cause liposome-burst and simultaneous release of bromelain and ciprofloxacin. Simultaneous release of bromelain and ciprofloxacin enhanced bacterial killing in Staphylococcus aureus biofilms as compared with free bromelain and/or ciprofloxacin. After tail-vein injection in mice, liposomes accumulated inside intra-abdominal staphylococcal biofilms. Subsequent liposome-burst and simultaneous release of bromelain and ciprofloxacin yielded degradation of the biofilm matrix by bromelain and higher bacterial killing without inducing septic symptoms as obtained by injection of free bromelain and ciprofloxacin. This shows the advantage of simultaneous release from liposomes of bromelain and ciprofloxacin inside a biofilm.

A Smart Photothermal Nanosystem with an Intrinsic Temperature-Control Mechanism for Thermostatic Treatment of Bacterial Infections.

Photothermal therapy (PTT) has attracted extensive attention in disease treatments. However, conventional photothermal systems do not possess a temperature-control mechanism, which poses a serious risk to healthy tissues and/or organs due to inevitable thermal damage. Herein, a smart photothermal nanosystem with an intrinsic temperature-control mechanism for thermostatic treatment of bacterial infections is reported. The smart photothermal nanosystem is constructed by loading a thermochromic material into a hollow-structured silica nanocarrier, in which the thermochromic material is composed of naturally occurring phase-change materials (PCMs), a proton-responsive spirolactone, and a proton source. The resulting nanosystem shows strong near-infrared (NIR) absorption and efficient photothermal conversion in solid PCMs but becomes NIR-transparent when PCMs are melted upon NIR irradiation. Such an attractive feature can precisely regulate the photothermal equilibrium temperature to the melting point of PCMs, regardless of the variation in external experimental parameters. In contrast to conventional PTT with severe thermal damage, the reported smart photothermal nanosystem provides an internal protection mechanism on healthy tissues and/or organs, which remarkably accelerates the recovery of bacteria-infected wounds. The smart photothermal nanosystem is a versatile PTT platform, holding great promise in the safe and efficient treatment of bacterial infections and multimodality synergistic therapy.

A near-infrared light-excitable immunomodulating nano-photosensitizer for effective photoimmunotherapy.

Photodynamic therapy has great potential for tumor ablation and the activation of antitumor immune responses. However, its overall therapeutic efficiency is often limited by the immunosuppressive tumor microenvironment. We developed a near-infrared light-excitable immunomodulating nano-photosensitizer (NeINP) that can improve reactive oxygen species production and regulate the immunosuppressive TME to improve photoimmunotherapy. The NeINP is composed of a photosensitive core and a pH-responsive polymer shell, which allows for NeINP loading and delivery of small-molecular immunomodulators to tumor sites for regulation of the immunosuppressive TME and effective photoimmunotherapy. Through the co-delivery of celecoxib and the NIR-triggered photodynamic core to tumors, the NeINP was shown to regulate the immunosuppressive TME and enhance antitumor immunity, leading to the elimination of residual tumor and reduction of metastasis and recurrence. The NeINP can be optimized to co-deliver other immunomodulators, and thus has potential as a universal platform for efficient, precise photoimmunotherapy.

Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance.

Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance.

Synthesis, biodistribution, and imaging of PEGylated-acetylated polyamidoamine dendrimers.

Polyamidoamine (PAMAM) dendrimers have been widely used as drug carriers, non-viral gene vectors and imaging agents. However, the use of dendrimers in biological system is constrained because of inherent toxicity and organ accumulation. In this study, the strategy of acetylation and PEGylation-acetylation was used to minimize PAMAM dendrimers toxicities and to improve their biodistribution and pharmacokinetics for medical application. PEGylated-acetylated PAMAM (G4-Ac-PEG) dendrimers were synthesized by PEGylation of acetylated PAMAM dendrimer of generation 4 (G4) with acetic anhydride and polyethylene glycol (PEG) 3.4 k. To investigate the cytotoxicity and in vivo biodistribution of the conjugates, in vitro cell viability analysis, Iodine-125 (125I) imaging, tissue distribution and hematoxylin-eosin (HE) staining were performed. We find that acetylation and PEGylation-acetylation essentially eliminates the inherent dendrimer cytotoxicity in vitro. Planar gamma (gamma) camera imaging revealed that all the conjugates were slowly eliminated from the body, and higher abdominal accumulation of acetylation PAMAM dendrimer was observed. Tissue distribution analysis showed that PEGylated-acetylated dendrimers have longer blood retention and lower accumulation in organs such as the kidney and liver than the non-PEGylated-acetylated dendrimers, but acetylation only can significantly increase the accumulation of G4 in the kidney and decrease the concentration in blood. Histology results reveal that no obvious damage was observed in all groups after high dose administration. This study indicates that PEGylation-acetylation could improve the blood retention, decrease organ accumulation, and improve pharmacokinetic profile, which suggests that PEGylation-acetylation provides an alternative method for PAMAM dendrimers modification.

Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication.

Organisms have sophisticated subcellular compartments containing enzymes that function in tandem. These confined compartments ensure effective chemical transformation and transport of molecules, and the elimination of toxic metabolic wastes. Creating functional enzyme complexes that are confined in a similar way remains challenging. Here we show that two or more enzymes with complementary functions can be assembled and encapsulated within a thin polymer shell to form enzyme nanocomplexes. These nanocomplexes exhibit improved catalytic efficiency and enhanced stability when compared with free enzymes. Furthermore, the co-localized enzymes display complementary functions, whereby toxic intermediates generated by one enzyme can be promptly eliminated by another enzyme. We show that nanocomplexes containing alcohol oxidase and catalase could reduce blood alcohol levels in intoxicated mice, offering an alternative antidote and prophylactic for alcohol intoxication.