Light-Stimulated Carbon Dot Hydrogel: Targeting and Clearing Infectious Bacteria In Vivo.

Infectious bacteria evolve fast into resistance to conventional antimicrobial agents, whereas treatments for drug resistance bacteria progress more slowly. Here, we report a universally applicable photoactivated antimicrobial modality through light-responsive carbon dot-embedding soft hyaluronic acid hydrogel (CDgel). Because of the innate nature of the infectious bacteria that produce hyaluronidase, applied hyaluronic acid-based CDgel breaks down via bacteria and releases carbon dots (CDs) into the infectious sites. The released CDs possess photodynamic capabilities under light irradiation, inducing 1O2 generation and growth inhibition of the infectious bacteria, S. aureus and E. coli (∼99% and ∼97%, respectively), in vitro. In particular, these photodynamic effects of CDs from CDgel have been shown to accelerate the healing of infected wounds in vivo, showing a higher wound regeneration rate as compared to that of untreated wounds. Our work demonstrates that the biocompatible and shape-controllable CDgel possesses therapeutic potential as a treatment modality for the light-driven control of drug-resistant bacterial infections.

Photomodulating Carbon Dots for Spatiotemporal Suppression of Alzheimer's ß-Amyloid Aggregation.

Extracellular deposition of ß-amyloid (Aß) peptide aggregates is a major characteristic of Alzheimer's disease (AD) brain. Because Aß peptide aggregates aggravate neuropathy and cognitive impairment for AD patients, numerous efforts have been devoted to suppressing Aß self-assembly as a prospective AD treatment option. Here, we report Aß-targeting, red-light-responsive carbon dots (CDs), and their therapeutic functions as a light-powered nanomodulator to spatiotemporally suppress toxic Aß aggregation both in vitro and in vivo. Our aptamer-functionalized carbon dots (Apta@CDs) showed strong targeting ability toward Aß42 species. Moreover, red LED irradiation induced Apta@CDs to irreversibly denature Aß peptides, impeding the formation of ß-sheet-rich Aß aggregates and attenuating Aß-associated cytotoxicity. Consequently, Apta@CDs-mediated photomodualtion modality achieved effective suppression of Aß aggregation in vivo, which significantly reduced the Aß burden at the targeted sites in the brain of 5xFAD mice by ∼40% and ∼25% according to imaging and ELISA analyses, respectively. Our work demonstrates the therapeutic potential of photomodulating CDs for light-driven suppression against Aß self-assembly and related neurotoxicity.

Photonic Carbon Dots as an Emerging Nanoagent for Biomedical and Healthcare Applications.

As a class of carbon-based nanomaterials, carbon dots (CDs) have attracted enormous attention because of their tunable optical and physicochemical properties, such as absorptivity and photoluminescence from ultraviolet to near-infrared, high photostability, biocompatibility, and aqueous dispersity. These characteristics make CDs a promising alternative photonic nanoagent to conventional fluorophores in disease diagnosis, treatment, and healthcare managements. This review describes the fundamental photophysical properties of CDs and highlights their recent applications to bioimaging, photomedicine (e.g., photodynamic/photothermal therapies), biosensors, and healthcare devices. We discuss current challenges and future prospects of photonic CDs to give an insight into developing vibrant fields of CD-based biomedicine and healthcare.

Multifunctional carbon dots as a therapeutic nanoagent for modulating Cu(ii)-mediated ß-amyloid aggregation.

The abnormal self-assembly of cerebral ß-amyloid (Aß) peptides into toxic aggregates is a hallmark of Alzheimer's disease (AD). Here, we report on multifunctional carbon dots that can chelate Cu(ii) ions, suppress Aß aggregation, and photooxygenate Aß peptides. Copper ions have high relevance to AD pathogenesis, causing Cu(ii)-mediated Aß aggregation and oxidative damage to neuronal cells. For effective conjugation with Cu(ii)-bound Aß complexes, we have designed carbon dots that possess nitrogen (N)-containing polyaromatic functionalities on their surface by employing o-phenylenediamine (OPD) as a polymerization precursor. We demonstrate that the polymerized OPD (pOPD)-derived carbon dots exhibit multiple capabilities against Cu(ii)-mediated Aß aggregation. Furthermore, the pOPD-derived carbon dots exhibited dramatically enhanced absorption and fluorescence upon coordination with Cu(ii) ions and effectively photooxygenated Aß peptides. The photodynamically modulated Aß residues lost the propensity to coordinate with Cu(ii) and to assemble into toxic aggregates. This work demonstrates the potential of carbon dots as a multifunctional ß-sheet breaker and provides a promising anti-amyloidogenic strategy for future Aß-targeted AD treatments.

Photosensitizing materials and platforms for light-triggered modulation of Alzheimer's ß-amyloid self-assembly.

The abnormal aggregation of ß-amyloid (Aß) peptides is a hallmark of Alzheimer's disease (AD) that affects more than 10% of the people over the age 60 world-wide. While the exact mechanism of neuronal loss and cognitive decline has not been elucidated yet, the amyloid hypothesis about the causative role of Aß aggregation in AD pathology has been widely supported by the numerous in vivo and in vitro data. In this respect, many efforts have been made to explore therapeutic agents that can modulate the aggregation of Aß, but none of the efforts succeeded in producing effective anti-Aß drugs for treating AD. This article provides an overview of recent attempts that have employed light energy to intervene with the self-assembly process of Aß peptides via the generation of oxidative stress by photosensitizers, such as natural or synthetic dyes, light-responsive nanomaterials, and photoelectrochemical platforms. The underlying mechanism of photodynamic reactions suppressing Aß aggregation and the dilemma in generating long-been-blamed oxidative stress are discussed by addressing the positive role of oxidative stress produced by the photosensitizers in the light-induced suppression of Aß-mediated neurotoxicity. We have summarized current challenges and strategies to advance photo-induced inhibition and modulation of Aß aggregation as a therapeutic option for treating AD in the future.

Light-triggered dissociation of self-assembled ß-amyloid aggregates into small, nontoxic fragments by ruthenium (II) complex.

The self-assembly of ß-amyloid (Aß) peptides into highly stable plaques is a major hallmark of Alzheimer's disease. Here, we report visible light-driven dissociation of ß-sheet-rich Aß aggregates into small, nontoxic fragments using ruthenium (II) complex {[Ru(bpy)3]2+} that functions as a highly sensitive, biocompatible, photoresponsive anti-Aß agent. According to our multiple analyses using thioflavin T, bicinchoninic acid, dynamic light scattering, atomic force microscopy, circular dichroism, and Fourier transform infrared spectroscopy, [Ru(bpy)3]2+ successfully disassembled Aß aggregates by destabilizing the ß-sheet secondary structure under illumination of white light-emitting diode light. We validated that photoexcited [Ru(bpy)3]2+ causes oxidative damages of Aß peptides, resulting in the dissociation of Aß aggregates. The efficacy of [Ru(bpy)3]2+ is attributed to reactive oxygen species, such as singlet oxygen, generated from [Ru(bpy)3]2+ that absorbed photon energy in the visible range. Furthermore, photoexcited [Ru(bpy)3]2+ strongly inhibited the self-assembly of Aß monomers even at concentrations as low as 1 nM and reduced the cytotoxicity of Aß aggregates. STATEMENT OF SIGNIFICANCE: Alzheimer's disease is the most common progressive neurodegenerative disease, affecting more than 13% of the population over age 65. Over the last decades, researchers have focused on understanding the mechanism of amyloid formation, the hallmark of various amyloid diseases including Alzheimer's and Parkinson's. In this paper, we successfully demonstrate the dissociation of ß-Amyloid (Aß) aggregates into small, less-amyloidic fragments by photoexcited [Ru(bpy)3]2+ through destabilization of ß-sheet secondary structure. We validated the light-triggered dissociation of amyloid structure using multiple analytical tools. Furthermore, we confirmed that photoexcited [Ru(bpy)3]2+ reduces cytotoxicity of Aß aggregates. Our work should open a new horizon in the study of Alzheimer's amyloid aggregation by showing the potential of photoexcited dye molecules as an alternative therapeutic strategy for treating Alzheimer's disease in future.

Shedding Light on Alzheimer's ß-Amyloidosis: Photosensitized Methylene Blue Inhibits Self-Assembly of ß-Amyloid Peptides and Disintegrates Their Aggregates.

Abnormal aggregation of ß-amyloid (Aß) peptides is a major hallmark of Alzheimer's disease (AD). In spite of numerous attempts to prevent the ß-amyloidosis, no effective drugs for treating AD have been developed to date. Among many candidate chemicals, methylene blue (MB) has proved its therapeutic potential for AD in a number of in vitro and in vivo studies; but the result of recent clinical trials performed with MB and its derivative was negative. Here, with the aid of multiple photochemical analyses, we first report that photoexcited MB molecules can block Aß42 aggregation in vitro. Furthermore, our in vivo study using Drosophila AD model demonstrates that photoexcited MB is highly effective in suppressing synaptic toxicity, resulting in a reduced damage to the neuromuscular junction (NMJ), an enhanced locomotion, and decreased vacuole in the brain. The hindrance effect is attributed to Aß42 oxidation by singlet oxygen (1O2) generated from photoexcited MB. Finally, we show that photoexcited MB possess a capability to disaggregate the pre-existing Aß42 aggregates and reduce Aß-induced cytotoxicity. Our work suggests that light illumination can provide an opportunity to boost the efficacies of MB toward photodynamic therapy of AD in future.

Carbon Nanodot-Sensitized Modulation of Alzheimer's ß-Amyloid Self-Assembly, Disassembly, and Toxicity.

The self-assembly of amyloidogenic peptides into ß-sheet-rich aggregates is a general feature of many neurodegenerative diseases, including Alzheimer's disease, which signifies the need for the effective attenuation of amyloid aggregation toward alleviating amyloid-associated neurotoxicity. This study reports that photoluminescent carbon nanodots (CDs) can effectively suppress Alzheimer's ß-amyloid (Aß) self-assembly and function as a ß-sheet breaker disintegrating preformed Aß aggregates. This study synthesizes CDs using ammonium citrate through one-pot hydrothermal treatment and passivates their surface with branched polyethylenimine (bPEI). The bPEI-coated CDs (bPEI@CDs) exhibit hydrophilic and cationic surface characteristics, which interact with the negatively charged residues of Aß peptides, suppressing the aggregation of Aß peptides. Under light illumination, bPEI@CDs display a more pronounced effect on Aß aggregation and on the dissociation of ß-sheet-rich assemblies through the generation of reactive oxygen species from photoactivated bPEI@CDs. The light-triggered attenuation effect of Aß aggregation using a series of experiments, including photochemical and microscopic analysis, is verified. Furthermore, the cell viability test confirms the ability of photoactivated bPEI@CDs for the suppression of Aß-mediated cytotoxicity, indicating bPEI@CDs' potency as an effective anti-Aß neurotoxin agent.

Hematite-Based Photoelectrode Materials for Photoelectrocatalytic Inhibition of Alzheimer's ß-Amyloid Self-Assembly.

A visible light-active, hematite-based photoelectrode platform for suppressing ß-amyloid (Aß) self-assembly in vitro is reported. Upon illumination of a light-emitting diode with an anodic bias, the hematite photoanode generates reactive radical species, such as superoxide ions and hydroxyl radicals, via photoelectrocatalytic process. According to our analyses, the hematite photoanode exhibited a strong inhibitory effect on Aß aggregation under visible light illumination and anodic bias. We found that hole-derived radicals played a significant role of oxidizing Aß peptides, which effectively blocked further aggregation. The efficacy of photoelectrocatalytic inhibition on Aß aggregation was enhanced by introducing cobalt phosphate (Co-Pi) as a co-catalyst on the hematite photoanode, which facilitated the separation of electron-hole pairs. We verified that both bare and Co-Pi@hematite photoanodes are biocompatible and effective in reducing Aß aggregation-induced cytotoxicity.

Photoactive g-C3 N4 Nanosheets for Light-Induced Suppression of Alzheimer's ß-Amyloid Aggregation and Toxicity.

Graphitic carbon nitride (g-C3 N4 ) has a suppressive capability toward Alzheimer's Aß aggregation under light-illumination. Photoinduced electrons of g-C3 N4 generate reactive oxygen resulting in photooxidation of amyloid peptides that blocks Aß aggregation. Fe doping of g-C3 N4 frameworks results in enhanced optical properties and even stronger inhibition of Aß aggregation.

Mucoadhesive microparticles with a nanostructured surface for enhanced bioavailability of glaucoma drug.

Topical drug administration to the eye is limited by low drug bioavailability due to its rapid clearance from the preocular surface. Thus, multiple daily administrations are often needed, but patient compliance is low, hence a high chance of unsatisfactory treatment of ocular diseases. To resolve this, we propose mucoadhesive microparticles with a nanostructured surface as potential carriers for delivery of brimonidine, an ocular drug for glaucoma treatment. For sustained drug delivery, the microparticles were composed mainly of a diffusion-wall material, poly(lactic-co-glycolic acid) and a mucoadhesive polymer, polyethylene glycol, was used as an additive. Due to their nanostructured surface, the microparticles with a mucoadhesive material exhibited a 13-fold increase in specific surface area and could thus adhere better to the mucous layer on the eye, as compared with the conventional spherical microparticles. When loaded with brimonidine, the mucoadhesive microparticles with a nanostructured surface increased both drug bioavailability and its activity period by a factor of more than 2 over Alphagan P, a marketed eye drop of brimonidine.