Effect of folic acid-linked chitosan-coated PLGA-based curcumin nanoparticles on the redox system of glioblastoma cancer cells.

OBJECTIVES: Oxidative stress is one of the carcinogenic mechanisms underlying the development of glioblastoma multiforme (GBM), a highly aggressive brain tumor type associated with poor prognosis. Curcumin is known to be an efficient antioxidant, anti-inflammatory, and anticancer compound. However, its poor solubility in water, inappropriate pharmacokinetics, and low bioavailability limit its use as an antitumor drug. We prepared PLGA-based curcumin nanoparticles changed with folic acid and chitosan (curcumin-PLGA-CS-FA) and evaluated its effects on GBM tumor cells' redox status. METHODS: The nanoprecipitation method was used to synthesize CU nanoparticles (CU-NPs). The size, morphology, and stability were characterized by DLS, SEM, and zeta potential analysis, respectively. The CU-NPs' toxic properties were studied by MTT assay and measuring the intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations. The study was completed by measuring the gene expression levels and activity of superoxide dismutase, catalase, glutaredoxin, and thioredoxin antioxidant enzymes. RESULTS: The size, polydispersity index, and zeta potential of CU-NPs were 77.27 nm, 0.29, and -22.45 mV, respectively. The encapsulation efficiency was approximately 98%. Intracellular ROS and MDA levels decreased after CU-NP treatment. Meanwhile, the CU-NPs increased gene expression and activity of superoxide dismutase, catalase, glutaredoxin, and thioredoxin antioxidant enzymes. CONCLUSION: CU-NPs might be effective in the prevention and treatment of glioblastoma cancer by modulating the antioxidant-oxidant balance.

The effect of active oxygen-containing toothpaste on Streptococcus mutans and white spot lesions: An in-vivo randomized controlled trial.

INTRODUCTION: Fixed appliances limit patients' ability to clean their teeth, thus making orthodontic patients highly susceptible to developing white spot lesions (WSLs). Using patient compliance would be one of the simplest methods to prevent WSLs. METHODS: A parallel trial design with 34 patients that met the eligibility criteria were randomized to experimental (received Blue M oxygen for health toothpaste) and control (received Colgate Total fluoridated toothpaste) groups. The eligibility criteria were that the patients should be aged 13-30 years, on fixed mechanotherapy, had undergone therapeutic extraction of all first premolars, had completed leveling and aligning, and had satisfactory oral hygiene (assessed using pretreatment and current Simplified Oral Hygiene Index scores). The objectives were to assess the effects of active oxygen-containing toothpaste on Streptococcus mutans (SM) and WSLs in patients undergoing fixed mechanotherapy. The random allocation sequence was generated using the RAND function in Microsoft Excel. The sequence generated was sealed in opaque white envelopes. The investigators and the participants were blinded until allocation. Blinding of the first author (J.A.G.) who dispensed the toothpaste or the participants was not possible. The outcome assessment was blinded by coding the plaque specimens sent for real-time polymerase chain reaction (RT-PCR) to ensure that the final data assessment was blinded. The study setting was the Department of Orthodontics and Dentofacial Orthopedics, Sri Ramachandra Institute of Higher Education and Research (SRIHER) University. The primary outcome was SM counts, which were analyzed using RT-PCR. The secondary outcome was WSL assessment, performed using DIAGNOdent and International Caries Detection and Assessment System (ICDAS) II criteria at baseline and after 4 weeks. The data were subjected to statistical analysis. RESULTS: Thirty-four patients were randomized to 17 per group and analyzed. RT-PCR showed lower SM in the experimental group (Ct = 32.25 ± 10.6) than in the control group (Ct = 30.9 ± 10.49). However, this was not statistically significant (P = 0.70). ICDAS scores remained the same from baseline and after 4 weeks for both groups. The DIAGNOdent values were in tandem with the ICDAS scores and showed minimal change for the 2 groups (P >0.05). A strong positive correlation was observed for DIAGNOdent and ICDAS scores (τb >0.30). No harms or adverse effects were observed or reported by the patients during the experimental period. CONCLUSIONS: The active oxygen-containing toothpaste showed a greater inhibitory effect on SM than the fluoridated toothpaste. However, this effect was minimal. Both kinds of toothpaste showed negligible effects on WSLs. Thus, active oxygen-containing toothpaste is as effective as fluoridated toothpaste. REGISTRATION: The Trial was registered in the Controlled Trials Registry India (CTRI/2021/10/037458). PROTOCOL: The full protocol can be obtained from any of the authors via e-mail. FUNDING: The project was self-funded.

Cationic micelle: A promising nanocarrier for gene delivery with high transfection efficiency.

Micelles have demonstrated an excellent ability to deliver several different types of therapeutic agents, including chemotherapy drugs, proteins, small-interfering RNA and DNA, into tumor cells. Cationic micelles, comprising self-assemblies of amphiphilic cationic polymers, have exhibited tremendous promise with respect to the delivery of therapy genes and gene transfection. To date, research in the field has focused on achieving an enhanced stability of the micellar assembly, prolonged circulation times and controlled release of the gene. This review focuses on the micelles as a nanosized carrier system for gene delivery, the system-related modifications for cytoplasm release, stability and biocompatibility, and clinic trials. In accordance with the development of synthetic chemistry and self-assembly technology, the structures and functionalities of micelles can be precisely controlled, and hence the synthetic micelles not only efficiently condense DNA, but also facilitate DNA endocytosis, endosomal escape, DNA uptake and nuclear transport, resulting in a comparable gene transfection of virus.

Photocleavable Visible Light-Triggered Anthraquinone-Derived Water-Soluble Block Copolymer for Peroxynitrite Generation in Cancer Therapy.

We report a facile stimuli-responsive strategy to generate reactive oxygen and nitrogen species (ROS and RNS) in the biological milieu from a photocleavable water-soluble block copolymer under visible light irradiation (427 nm, 2.25 mW/cm2). An anthraquinone-based water-soluble polymeric nitric oxide (NO) donor (BCPx-NO) is synthesized, which exhibits NO release in the range of 40-65 µM within 10 h of photoirradiation with a half-life of 30-103 min. Additionally, BCPx-NO produces peroxynitrite (ONOO-) and singlet oxygen (1O2) under photoirradiation. To understand the mechanism of NO release and photolysis of the functional group under blue light, we prepared a small-molecule anthraquinone-based N-nitrosamine (NOD). The cellular investigation of the effect of spatiotemporally controlled ONOO- and 1O2 generation from the NO donor polymeric nanoparticles in a triple negative breast adenocarcinoma (MDA-MB-231) under visible light irradiation (white light, 5.83 mW/cm2; total dose 31.5 J/cm2) showed an IC50 of 0.6 mg/mL. The stimuli-responsive strategy using a photolabile water-soluble block copolymer employed to generate ROS and RNS in a biological setting widens the horizon for their potential in cancer therapy.

ROS-Scavenging Lignin-Based Tolerogenic Nanoparticle Vaccine for Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a demyelinating autoimmune disease, in which the immune system attacks myelin. Although systemic immunosuppressive agents have been used to treat MS, long-term treatment with these drugs causes undesirable side effects such as altered glucose metabolism, insomnia, and hypertension. Herein, we propose a tolerogenic therapeutic vaccine to treat MS based on lignin nanoparticles (LNP) with intrinsic reactive oxygen species (ROS)-scavenging capacity derived from their phenolic moieties. The LNP loaded with autoantigens of MS allowed for inducing tolerogenic DCs with low-level expression of costimulatory molecules while presenting antigenic peptides. Intravenous injection of an LNP-based tolerogenic vaccine into an experimental autoimmune encephalomyelitis (EAE) model led to durable antigen-specific immune tolerance via inducing regulatory T cells (Tregs). Autoreactive T helper type 1 cells, T helper type 17 cells, and inflammatory antigen presentation cells (APCs) were suppressed in the central nervous system (CNS), ameliorating ongoing MS in early and late disease states. Additionally, the incorporation of dexamethasone into an LNP-based tolerogenic nanovaccine could further improve the recovery of EAE mice in the severe chronic stage. As lignin is the most abundant biomass and waste byproduct in the pulping industry, a lignin-based tolerogenic vaccine could be a novel, cost-effective, high-value vaccine platform with potent therapeutic efficiency in treating autoimmune diseases.

A Curcumin-Modified Coordination Polymers with ROS Scavenging and Macrophage Phenotype Regulating Properties for Efficient Ulcerative Colitis Treatment.

Overexpression of classically activated macrophages (M1) subtypes and assessed reactive oxygen species (ROS) levels are often observed in patients with ulcerative colitis. At present, the treatment system of these two problems has yet to be established. Here, the chemotherapy drug curcumin (CCM) is decorated with Prussian blue analogs in a straightforward and cost-saving manner. Modified CCM can be released in inflammatory tissue (acidic environment), eventually causing M1 macrophages to transform into M2 macrophages and inhibiting pro-inflammatory factors. Co(III) and Fe(II) have abundant valence variations, and the lower REDOX potential in CCM-CoFe PBA enables ROS clearance through multi-nanomase activity. In addition, CCM-CoFe PBA effectively alleviated the symptoms of UC mice induced by DSS and inhibited the progression of the disease. Therefore, the present material may be used as a new therapeutic agent for UC.

ROS/Electro Dual-Reactive Nanogel for Targeting Epileptic Foci to Remodel Aberrant Circuits and Inflammatory Microenvironment.

Medicinal treatment against epilepsy is faced with intractable problems, especially epileptogenesis that cannot be blocked by clinical antiepileptic drugs (AEDs) during the latency of epilepsy. Abnormal circuits of neurons interact with the inflammatory microenvironment of glial cells in epileptic foci, resulting in recurrent seizures and refractory epilepsy. Herein, we have selected phenytoin (PHT) as a model drug to derive a ROS-responsive and consuming prodrug, which is combined with an electro-responsive group (sulfonate sodium, SS) and an epileptic focus-recognizing group (α-methyl-l-tryptophan, AMT) to form hydrogel nanoparticles (i.e., a nanogel). The nanogel will target epileptic foci, release PHT in response to a high concentration of reactive oxygen species (ROS) in the microenvironment, and inhibit overexcited circuits. Meanwhile, with the clearance of ROS, the nanogel can also reduce oxidative stress and alleviate microenvironment inflammation. Thus, a synergistic regulation of epileptic lesions will be achieved. Our nanogel is expected to provide a more comprehensive strategy for antiepileptic treatment.

Cryo-Shocked Platelet Coupled with ROS-Responsive Nanomedicine for Targeted Treatment of Thromboembolic Disease.

Thrombolysis with tissue plasminogen activator (tPA) provides the most common therapy for ischemic stroke onset within the past 4.5 h. However, enhanced neutrophil infiltration and secondary blood-brain barrier injury caused by tPA administration have limited its therapeutic application, and tPA treatment is often accompanied by hemorrhagic transformation. To overcome the limitations of thrombolysis by tPA, maximize the therapeutic efficacy, and improve the safety, herein, we report a cryo-shocked platelet-based cell-hitchhiking drug delivery system, which consists of cryo-shocked platelet (CsPLT) and reactive oxygen species (ROS)-responsive liposomes loaded with thrombolytic tPA and anti-inflammation drug aspirin (ASA). CsPLT and liposomes were facilely conjugated via host-guest interactions. Under the guidance of CsPLT, it selectively accumulated in the thrombus site and quickly released the therapeutic payloads in response to the high ROS. tPA subsequently exhibited localized thrombolytic activity to suppress the expansion of thrombus, while ASA assisted in the inactivation of reactive astrogliosis, microglial/macrophage, and obstruction of neutrophil infiltration. This cryo-shocked platelet-hitchhiking tPA/ASA delivery system not only improves the thrombus-targeting efficiency of the two drugs for highly localized thrombolytic effects and anti-inflammation actions and platelets inactivation but also provides insights to the development of targeted drug delivery systems for thromboembolic disease treatment.

An injectable multifunctional thermo-sensitive chitosan-based hydrogel for periodontitis therapy.

Bacteria are recognized as the driving factors of periodontitis. However, excessive reactive oxygen species (ROS) can harm periodontal tissue while also causing an uncontrolled inflammatory response. Hence, eliminating excessive ROS and blocking ROS-induced abnormal inflammatory response by antioxidants are achieving remarkable results in periodontitis therapy. Moreover, influenced by the deep and irregular periodontal pockets, injectable thermo-sensitive chitosan-based hydrogels have attracted a lot of attention. This study aimed to formulate an antibacterial and antioxidant therapeutic regimen by incorporating antimicrobial peptides (Nal-P-113) and/or antioxidants (polydopamine nanoparticles, PDNPs) into chitosan-based hydrogels. The hydrogel was characterized in vitro and finally examined in rats using the experimental periodontitis model. The release kinetics showed that the hydrogel could stably release Nal-P-113 and PDNPs for up to 13 days. The scavenging activity of the hydrogel against DPPH was about 80 % and the antibacterial ratio against Streptococcus gordonii (S. gordonii), Fusobacterium nucleatum (F. nucleatum) and Porphyromonas gingivalis (P. gingivalis) was about 99 %. Importantly, it was examined that the hydrogel had the ability to prevent periodontal tissue damage. Thus, chitosan-based hydrogels may provide a basis for designing multifunctional local drug delivery biomaterials for the treatment of periodontitis.

Nanoengineered Neutrophils as a Cellular Sonosensitizer for Visual Sonodynamic Therapy of Malignant Tumors.

The rapid evolution of cell-based theranostics has attracted extensive attention due to their unique advantages in biomedical applications. However, the inherent functions of cells alone cannot meet the needs of malignant tumor treatment. Thus endowing original cells with new characteristics to generate multifunctional living cells may hold a tremendous promise. Here, the nanoengineering method is used to combine customized liposomes with neutrophils, generating oxygen-carrying sonosensitizer cells with acoustic functions, which are called Acouscyte/O2 , for the visual diagnosis and treatment of cancer. Specifically, oxygen-carried perfluorocarbon and temoporfin are encapsulated into cRGD peptide modified multilayer liposomes (C-ML/HPT/O2 ), which are then loaded into live neutrophils to obtain Acouscyte/O2 . Acouscyte/O2 can not only carry a large amount of oxygen but also exhibits the ability of long circulation, inflammation-triggered recruitment, and decomposition. Importantly, Acouscyte/O2 can be selectively accumulated in tumors, effectively enhancing tumor oxygen levels, and triggering anticancer sonodynamics in response to ultrasound stimulation, leading to complete obliteration of tumors and efficient extension of the survival time of tumor-bearing mice with minimal systemic adverse effects. Meanwhile, the tumors can be monitored in real time by temoporfin-mediated fluorescence imaging and perfluorocarbon (PFC)-microbubble-enhanced ultrasound imaging. Therefore, the nanoengineered neutrophils, i.e., Acouscyte/O2 , are a new type of multifunctional cellular drug, which provides a new platform for the diagnosis and sonodynamic therapy of solid malignant tumors.

Light activated disinfection: an alternative endodontic disinfection strategy.

BACKGROUND: An improved light activated disinfection technique utilizing a specific photosensitizer formulation, liquid optical-conduit, oxygen-carrier and light energy of appropriate wavelength has been introduced recently. This study tested the efficacy of this improved light activated disinfection on ex vivo biofilms of Enterococcus faecalis at two different stages of maturation. METHODS: Eighty-five tooth sections were prepared and endodontic biofilm of E. faecalis were grown within the root canal. In stage 1, conventional light activated disinfection (LAD), chemical disinfectant (sodium hypochlorite) and improved LAD were tested on four-day-old (immature) biofilms. In stage 2, conventional LAD, improved LAD and chemomechanical disinfection (alone and in combination with improved LAD) were tested on four-week-old (mature) biofilms. RESULTS: Sodium hypochlorite and improved LAD showed the ability to significantly inactivate bacteria in four-day-old biofilms when compared to the control and LAD (p < 0.05). Inactivation of bacteria from deeper dentine was higher in improved LAD than sodium hypochlorite. In four-week-old biofilms, a combination of chemomechanical disinfection and improved LAD produced significant bacterial killing compared to either chemomechanical disinfection or improved LAD alone. CONCLUSIONS: This study highlighted the potential of improved LAD to kill bacteria within dentinal tubules. In combination with chemomechanical preparation, the improved LAD significantly inactivated four-week-old biofilm bacteria.

The use of diffuse laser photonic energy and indocyanine green photosensitiser as an adjunct to periodontal therapy.

Light-activated chemical therapy - generally known as photodynamic therapy (PDT) - has been developed within medicine, to allow the use of an applied agent (photosensitiser) that could be activated using laser photonic energy, leading to the destruction of target cellular structures. In clinical dentistry, PDT has been utilised within a wide scope of topical application in endodontic, periodontal and oral epithelial pathology where specifically, anti-bacterial action may prove useful. Underlying the complex and multi-factorial aetiology, periodontal disease remains of essentially-bacterial origin and anti-bacterial PDT (aPDT) has been investigated as an adjunctive to other periodontal treatment therapies. Of several topically-applied photosensitisers, one agent, indocyanine green, may be activated using a diode laser wavelength (810 nm) that is commonly-available in clinical dental practice, to provide generalised bacteriocidal effect. Unlike antibiotics and antibacterial mouthwashes, the mode of action appears to be nonspecific to bacterial species and is linked to cell death through a process of oxidative stress. Additionally, indocyanine green has otherwise low toxicity to non-target host tissue and dental restorative materials. This paper explores the background to this therapy, its position within the broader delivery of periodontal treatment and the specific application of indocyanine green in clinical dental practice.