Co-Delivery of Loxoprofen and Tofacitinib by Photothermal Microneedles for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is an autoimmune disease of synovial inflammation that affects populations worldwide. Transdermal drug delivery systems for treating RA have increased but remain challenging. We fabricated a dissolving microneedle (MN) system with photothermal (PT) polydopamine (PDA) to co-load the non-steroidal anti-inflammatory drug loxoprofen (Lox) and the Janus kinase inhibitor tofacitinib (Tof), with the aim of co-delivering Lox and Tof directly to the articular cavity, aided by the combination of MN and PT. In vitro and in vivo permeation studies showed that the PT MN significantly promoted drug permeation and retention in the skin. An in vivo visualization of the drug distribution in the articular cavity showed that the PT MN significantly promoted drug retention in the articular cavity. Importantly, compared to the intra-articular injection of Lox and Tof, the application of the PT MN to a carrageenan/kaolin-induced arthritis rat model exhibited superior performance in reducing joint swelling, muscle atrophy, and cartilage destruction. Furthermore, the PT MN downregulated the mRNA expression levels of proinflammatory cytokines, including TNF-α, IL-1ß, iNOS, JAK2, JAK3, and STAT3. The results show that the PT MN transdermal co-delivery of Lox and Tof is a new synergetic therapy with high compliance and good therapeutic efficacy for RA.

Oxymatrine-fatty acid deep eutectic solvents as novel penetration enhancers for transdermal drug delivery: Formation mechanism and enhancing effect.

Transdermal delivery of drugs is commonly limited by low skin permeability. The aim of the study was to synthesize deep eutectic solvents (DESs) based on oxymatrine (OMT) and fatty acids with various alkyl chain lengths (LCFAs) as novel vehicles, to solubilize the water-insoluble drug and enhance percutaneous penetration. Quercetin (QUE) was selected as a model drug. Combining differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and molecular simulations demonstrated that the formation of DESs was mediated by charge-assisted hydrogen bonding. Physicochemical properties including stability, viscosity, and solubilization capacity were also studied. Subsequently, the effect of three stable DESs on drug release and skin permeability was evaluated. The results showed that QUE was solubilized well and presented a different sustained release behavior in DESs. Meanwhile, DESs enhanced the skin permeation of OMT and QUE, which was influenced by alkyl chain lengths of LCFAs, whereas DES consisting of lauric acid (LA) exhibited the highest enhancing effect. FTIR, DSC, and molecular docking further demonstrated consistency between micro molecular mechanism and macro penetration behavior. Additionally, HaCaT cells treated with DESs showed high cell viability, suggesting their good skin safety. Taken together, OMT-LCFA DESs would be a promising penetration enhancer for transdermal drug delivery, which also provides guidance for the design of new DESs.

Twin-tube terahertz fiber for a polarization filter.

A simple polymer twin-tube terahertz (THz) fiber that can be used as a polarization filter is proposed and investigated using the finite element method in this paper. The twin-tube THz fiber consists of two closely spaced identical tubes located symmetrically inside the protecting jacket. The simulation results show that the y-polarization fundamental mode (YPFM) can be well confined between the two tube walls near the fiber center, while the x-polarization fundamental mode (XPFM) has a huge confinement loss due to the coupling with the tube mode. For the fundamental mode (FM), a polarization extinction ratio (PER) of 30 dB can be realized after a 1.3 cm length of the fiber, and the insertion loss of the YPFM is less than 0.5 dB at 1 THz. In addition, higher order modes (HOMs) can be effectively suppressed by further increasing the fiber length. Simulation results indicate that all HOMs have powers being 30 dB lower than that of the supported YPFM after a 7.44 cm length of the fiber, and the insertion loss of the YPFM is less than 2.7 dB at 1 THz. Furthermore, the effects of fiber structure parameters on the loss properties are investigated, proving that the proposed fiber has a good fabrication tolerance. Owing to the simple structure, the proposed fiber polarization filter is easy to be fabricated and low-cost, which makes it a potential application in commercial THz systems.

Chitosan/hyaluronan nanogels co-delivering methotrexate and 5-aminolevulinic acid: A combined chemo-photodynamic therapy for psoriasis.

Psoriasis does not respond adequately to the monotherapy, tailoring combined strategies for synergistical treatment remains challenging. We fabricated chitosan/hyaluronan nanogels to co-load methotrexate (MTX) and 5-aminoleavulinic acid (ALA), i.e., MTX-ALA NGs, for a combined chemo-photodynamic therapy for psoriasis. Compared with MTX-ALA suspension, the NGs enhanced the penetration and retention of MTX and ALA through and into the skin in vitro and in vivo (p < 0.001). NGs enhanced the cellular uptake (p < 0.001), protoporphyrin IX conversion (p < 0.001), and reactive oxygen species generation (3.93-fold), subsequently exerted the synergistical anti-proliferation and apoptosis on lipopolysaccharide-irritated HaCaT cells with the apoptosis rate of 78.6%. MTX-ALA NGs efficiently ameliorated the skin manifestations and down-regulated the proinflammatory cytokines of TNF-α and IL-17A in imiquimod-induced psoriatic mice (p < 0.001). Importantly, MTX-ALA NGs reduced the toxicities of oral MTX to the liver and kidney. The results support that MTX-ALA NG is a convenient, effective, and safe combined chemo-photodynamic strategy for psoriasis treatment.

Stimuli-responsive nanotherapeutics for precision drug delivery and cancer therapy.

Cancer remains one of the world's leading causes of death. However, most conventional chemotherapeutic drugs only show a narrow therapeutic window in patients because of their inability to discriminate cancer cells from healthy cells. Nanoparticle-based therapeutics (termed nanotherapeutics) have emerged as potential solutions to mitigate many obstacles posed by these free drugs. Deep insights into knowledge of the tumor microenvironment and materials science make it possible to construct nanotherapeutics that are able to release cargoes in response to a variety of internal stimuli and external triggers. Therefore, such highly sophisticated nanosystems could help impede the premature release of toxic drugs in the blood circulation or healthy tissues, thus enhancing the safety profiles of encapsulated drugs. In this context, this review offers a comprehensive overview of several specific stimuli, including internal stimuli (e.g., pH, temperature, enzyme, redox, and H2 O2 ) and external stimuli (e.g., magnetic, photo, and ultrasound). We envision that applications of these smart nanotherapeutics can benefit cancer patients and provide a good chance for clinical translation of many nanoparticle formulas. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > in vitro Nanoparticle-Based Sensing.