3D printing of multi-unit gastro-retentive tablets for the pulsatile release of artesunate.

Pulsatile drug delivery is hardly achieved by conventional gastro-retentive dosage forms. Artesunate as a typical anti-malaria medicine needs oral pulsatile release. Here, artesunate-loaded pulsatile-release multi-unit gastro-retentive tablets (APGTs) were prepared with a semi-solid extrusion three-dimensional (3D) printing method. An APGT was composed of three units: artesunate-loaded immediate and delayed release units and a block unit. The matrix of the immediate/delayed release units consisted of polyvinylpyrrolidone (PVP) K30 and croscarmellose sodium, which improved the rapid release of artesunate when contacting water. The block unit consisted of octadecanol, hydroxypropyl methyl cellulose K15M, PVP K30, and poloxamer F68. APGTs showed multi-phase release in simulated gastric liquids (SGLs). The first immediate release phase continued for 1 h followed by a long block phase for 7 h. The second rapid release phase was initiated when the eroded holes in the block unit extended to the inner delayed release unit, and this phase continued for about 14 h. Low-density APGTs could ensure their long-term floating in the stomach. Oral APGTs remained in the rabbit stomach for about 20 h. 3D printing provides a new strategy for the preparation of oral pulsatile-release tablets.

Oral Curcumin-Thioketal-Inulin Conjugate Micelles against Radiation-Induced Enteritis.

Radiation-induced enteritis is an unavoidable complication associated with pelvic tumor radiotherapy, significantly influencing the prognosis of cancer patients. The limited availability of commercial gastrointestinal radioprotectors in clinical settings poses a substantial challenge in preventing radiation enteritis. Despite the inherent radioprotective characteristics of Cur in vitro, its poor solubility in water, instability, and low bioavailability lead to inferior therapeutic effects in vivo. Herein, we developed novel ROS-responsive micelles (CTI) from inulin and curcumin, aimed at mitigating radiation enteritis. CTI micelles had excellent solubility and stability. Importantly, CTI improved the cytotoxicity and bioavailability of curcumin, thereby showing enhanced effectiveness in neutralizing ROS induced by radiation, safeguarding against DNA damage, and reducing radiation-induced cellular mortality. Moreover, in a radiation enteritis mice model, CTI not only alleviated severe radiation-induced intestinal injury but also improved redox-related indicators and reduced inflammatory cytokine expression. Furthermore, CTI effectively increased gut microbiota abundance and maintained gut homeostasis. In conclusion, CTI could be a promising candidate for the clinical management of radiation enteritis. Our study provides a new perspective for radioprotection using natural antioxidants.

The effects of Lactobacillus reuteri microcapsules on radiation-induced brain injury by regulating the gut microenvironment.

A radiation-induced brain injury (RIBI) is a major adverse event following radiotherapy of malignant tumors. RIBI would affect cognitive function, leading to a series of complications and even death. However, the pathogenesis of RIBI is still unclear, and it still lacks specific therapeutic drugs. The gut-brain bidirectional communication may be mediated by various microbiota and metabolites in the gastrointestinal tract. Probiotics are closely related to physiological health. The theory of the gut-brain axis provides us with a new idea to improve the gut microenvironment by supplementing probiotics against RIBI. Here, Lactobacillus reuteri microcapsules (LMCs) were prepared, which were predominantly irregular spheres with a rough surface under a scanning electron microscope and a narrow size distribution ranging from 20 to 700 µm. The transmission electron microscopy images showed that the structure of microcapsules containing Lactobacillus reuteri (L. reuteri) was a core and shell structure. The survival of L. reuteri in microcapsules was significantly more than that of free L. reuteri in the simulated stomach environment of pH 1.2. 16S rDNA sequencing showed that LMCs observably increased the relative abundance of Lactobacillus in RIBI mice. More importantly, compared with the RIBI model mice, the behavior of RIBI mice treated with LMCs was significantly improved. In addition, LMCs greatly alleviated the pathological damage of the hippocampus and intestines in the mice after irradiation and reduced the level of TNF-α and IL-6 in vivo. Generally, LMCs are a promising oral preparation, which provide new ideas and methods for the treatment of RIBI.

Injectable multifunctional chitosan/dextran-based hydrogel accelerates wound healing in combined radiation and burn injury.

Clinical wound management of combined radiation and burn injury (CRBI) remains a huge challenge due to serious injuries induced by redundant reactive oxygen species (ROS), the accompanying hematopoietic, immunologic suppression and stem cell reduction. Herein, the injectable multifunctional Schiff base cross-linked with gallic acid modified chitosan (CSGA)/oxidized dextran (ODex) hydrogels were rationally designed to accelerate wound healing through elimination of ROS in CRBI. CSGA/ODex hydrogels, fabricated by mixing solutions of CSGA and Odex, displayed good self-healing ability, excellent injectability, strong antioxidant activity, and favorable biocompatibility. More importantly, CSGA/ODex hydrogels exhibited excellent antibacterial properties, which is facilitated for wound healing. Furthermore, CSGA/ODex hydrogels significantly suppressed the oxidative damage of L929 cells in an H2O2-induced ROS microenvironment. The recovery of mice with CRBI in mice demonstrated that CSGA/ODex hydrogels significantly reduced the hyperplasia of epithelial cells and the expression of proinflammatory cytokine, and accelerated wound healing which was superior to the treatment with commercial triethanolamine ointment. In conclusion, the CSGA/ODex hydrogels as a wound dressing could accelerate the wound healing and tissue regeneration of CRBI, which provides great potential in clinical treatment of CRBI.

Cannabidiol-loaded biomimetic macrophage membrane vesicles against post-traumatic stress disorder assisted by ultrasound.

Post-traumatic stress disorder (PTSD), which normally follows psychological trauma, has been increasingly studied as a brain disease. However, the blood-brain barrier (BBB) prevents conventional drugs for PTSD from entering the brain. Our previous studies proved the effectiveness of cannabidiol (CBD) against PTSD, but low water solubility, low brain targeting efficiency and poor bioavailability restricted its applications. Here, a bionic delivery system, camouflage CBD-loaded macrophage-membrane nanovesicles (CMNVs), was constructed via co-extrusion of CBD with macrophage membranes, which had inflammatory and immune escape properties. In vitro anti-inflammatory, cellular uptake and pharmacokinetic experiments respectively verified the anti-inflammatory, inflammatory targeting and immune escape properties of CMNVs. Brain targeting and excellent anti-PTSD effects of CMNVs had been validated in vivo by imaging and pharmacodynamics studies. In our study, the potential of ultrasound to open BBBs and improve the brain-targeted delivery of CBD was evaluated. In conclusion, this cell membrane bionic delivery system assisted with ultrasound had good therapeutic effect against PTSD mice, which is expected to help convey CBD to inflammatory areas within the brain and alleviate the symptoms of PTSD.

Advances in applications of head mounted devices (HMDs): Physical techniques for drug delivery and neuromodulation.

Head-mounted medical devices (HMDs) are disruptive inventions representing laboratories and clinical institutions worldwide are climbing the apexes of brain science. These complex devices are inextricably linked with a wide range knowledge containing the Physics, Imaging, Biomedical engineering, Biology and Pharmacology, particularly could be specifically designed for individuals, and finally exerting integrated bio-effect. The salient characteristics of them are non-invasive intervening in human brain's physiological structures, and alterating the biological process, such as thermal ablating the tumor, opening the BBB to deliver drugs and neuromodulating to enhance cognitive performance or manipulate prosthetic. The increasing demand and universally accepted of them have set off a dramatic upsurge in HMDs' studies, seminal applications of them span from clinical use to psychiatric disorders and neurological modulation. With subsequent pre-clinical studies and human trials emerging, the mechanisms of transcranial stimulation methods of them were widely studied, and could be basically came down to three notable approach: magnetic, electrical and ultrasonic stimulation. This review provides a comprehensive overviews of their stimulating mechanisms, and recent advances in clinic and military. We described the potential impact of HMDs on brain science, and current challenges to extensively adopt them as promising alternative treating tools.

Quercetin inclusion complex gels ameliorate radiation-induced brain injury by regulating gut microbiota.

Radiation-induced brain injury (RIBI) is a serious adverse effect of radiotherapy. RIBI has garnered considerable clinical attention owing to its powerful effects on brain function and cognition; however, no effective treatment is available. The microbiota-gut-brain axis theory is a novel concept of treating RIBI by regulating gut microbiota. Quercetin, a particularly common flavonoid compound, has a wide range of biological activities and can regulate gut microbiota; however, it has poor solubility and dispersibility. In the present study, oral gels of inclusion complex comprising quercetin and HP-ß-CD were prepared, which increased quercetin dispersion and extended its release time in the intestinal tract. First, the relative abundance and diversity of gut microbiota in RIBI mice changed after oral administration of quercetin inclusion complex gels (QICG). Second, the spontaneous activity behavior and short-term memory ability as well as anxiety level were improved. Third, changes in physical symptoms were observed, including a decrease in TNF-α and IL-6 levels. H&E staining revealed that gut epithelial injury and intestinal inflammation as well as hippocampal inflammation were ameliorated. Antibiotics treatment (Abx) mice were developed to disrupt the mice's original gut microbiota composition. No significant improvement was observed in behavior or histopathology after oral administration of QICG in Abx mice of RIBI, indicating that the effect of QICG on improving RIBI was regulated by intestinal microbiota. Finally, the QICG preparation is efficient, exerting a protective effect on RIBI by regulating gut microbiota via the microbiota-gut-brain axis, which provides a novel idea for RIBI treatment.

Cinnarizine dissolving microneedles against microwave-induced brain injury.

Microwave is commonly used in the life, manufacturing and military fields, which may induce body injuries. Brain is the major target organ of microwave radiation and microwave-induced brain injury (MIBI) can lead to insomnia, dreaminess, and a decline in learning and memory. However, there is no clinical medications are available currently. Calcium channel blockers may protect the brain tissue from microwave but most of them cannot enter the brain. Here, we selected a calcium channel blocker-cinnarizine to prepare its dissolving microneedles (MNs) for the therapy of MIBI. The cinnarizine MNs was composed of polyvinyl pyrrolidone (PVP) K90 as the tip, the photopolymerized PVP as the base and the drug, which owned high mechanical strength, leading to easily piecing the skin on the neck and high drug release in vivo. The cinnarizine MNs markedly improved the recovery of spatial memory and spontaneous exploratory behavior of the rats after microwave radiation by inhibiting the expression of calcineurin and calpain-1. The dissolving MN technique is a promising method to improve drugs into the body and perform the anti-microwave radiation action.