Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double-blind, placebo-controlled phase 3a clinical trial.

AIM: To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. MATERIALS AND METHODS: In a multicentred, randomized, double-blinded, placebo-controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%-10.5%, fasting plasma glucose <13.9 mmol/L) were randomized (1:1:1) for weekly subcutaneous injections: placebo, PEX168/100 µg or PEX168/200 µg. The 24-week treatment was followed by a 28-week extension, during which placebo-treated patients were randomly assigned to PEX168/100 µg or PEX168/200 µg. The primary efficacy endpoint was the HbA1c change from baseline to week 24. RESULTS: The three groups had similar demographics and baseline characteristics. The HbA1c least-square mean (95% CI) change from baseline to week 24 was greater for PEX168/100 µg (-1.02% [-1.21%, -0.83%]) and PEX168/200 µg (-1.34% [-1.54%, -1.15%]) than for placebo (-0.17% [-0.36%, 0.02%]); (superiority: P < .0001). The proportions of patients with less than 7% HbA1c in the placebo, PEX168/100 µg and PEX168/200 µg groups were 15.7%, 34.7% and 46.6%, respectively. Common gastrointestinal adverse events (AEs) were nausea (5.6%, 10.0% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively) and vomiting (2.4%, 8.3% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively). Six (1.6%) patients (PEX168/100 µg: N = 2 [1.6%], PEX168/200 µg: N = 3 [2.5%] and placebo: N = 1 [0.8%]) discontinued treatment because of AEs. Four (1.2%) patients (PEX168/100 µg: N = 3 [2.5%] and PEX168/200 µg: N = 1 [0.9%]) developed PEX168 antidrug antibodies. CONCLUSION: PEX168 monotherapy significantly improved glycaemic control in T2D patients with a safety profile resembling that of other glucagon-like peptide-1 receptor agonists.

Near-Infrared Light-Switched MoS2 Nanoflakes@Gelatin Bioplatform for Capture, Detection, and Nondestructive Release of Circulating Tumor Cells.

The integrative bioplatform for capture, detection and release of circulating tumor cells (CTCs) is of great significance in clinical diagnosis and biomedical research. To fulfill this demand, we introduced a near-infrared (NIR) light-switched bioplatform for efficient isolation and downstream analysis of CTCs. The platform was created by first modifying the PEG-MoS2 nanoflakes (NFs)@gelatin nanocomposite on the ITO surface, and then introducing the MUC1 aptamer as a specific recognition element via coupling reaction between aptamer and gelatin to achieve the specific capture for CTCs. Subsequently, the captured cells are released under a NIR light irradiation (808 nm) by using MoS2 NFs as the NIR-regulated control element. Significantly, this platform could capture and release of CTCs with an excellent capture/release efficiency of 89.5% and 92.5%, respectively. Furthermore, the electrochemical bioplatform exhibited a wide linear range for the detection of CTCs from 50 to 1 × 106 cells mL-1 with a detection limit of 15 cells mL-1. After 5 days of reculture, the released cells still maintain good cell shape and proliferation capacity. Moreover, the bioplatfrom is a simple, versatile, and universal system for the recognition, capture, release, and detection of different types of CTCs. Therefore, this bioplatform shows potential applications on the early diagnosis of cancers.

Management of Meige syndrome with bilateral trigeminal and facial nerves combing.

Objective: Meige syndrome (MS) is an adult-onset segmental dystonia for which no satisfactory remedy currently exists. Our team developed a novel surgical approach called bilateral trigeminal/facial nerve combing (BTFC). This study aimed to evaluate the outcomes of patients who underwent BFTC (Clinical Trial Registry Number: ChiCTR2000033481). Method: We assigned 22 patients with MS to undergo BTFC. The primary outcome was assessed using the movement subscale of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-M) at 12 months postoperatively. The second outcome was evaluated using the Medical Outcome Study (MOS) 36-item Short Form Health Survey (SF-36), the dysfunction subscale of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-D), and the sub-item scores of the BFMDRS-M. Safety outcomes included the House-Brackmann (HB) functional grading score and the visual analog scale (VAS) for facial numbness. Results: At the final follow-up at 12 months, the BFMDRS-M showed a mean improvement of 70.7% from baseline. Mean scores of the BFMDRS-M sub-motor (including the eyes, mouth, and speech/swallowing) improved by 65.6, 81.00, and 60%, respectively. The median score of the total BFMDRS-D score was 0.70 ± 1.17 compared with 1.86 ± 2.21 at baseline. There were no serious operative complications in this population. The quality of life of the patients significantly improved (P < 0.05). Conclusion: BFTC has proven to be effective in relieving the symptoms of Meige syndrome. This novel surgical approach offers a new alternative treatment for patients who have failed to respond to medications, botulinum toxin injections, and deep brain stimulation (DBS). Clinical Trial Registration: https://www.chictr.org.cn/bin/project/edit?pid=54567, ChiCTR2000033481.

MPEG-PCL Nanomicelles Platform for Synergistic Metformin and Chrysin Delivery to Breast Cancer in Mice.

BACKGROUND: Metformin (MET) is a well-known anti-diabetic drug that also has anti-cancer effects. However, high therapeutic doses of MET on cancer cells and the low efficacy of combinatory therapeutic approaches limit its clinical application. Recent studies have shown that chrysin (CHR) can improve the pharmaceutical efficacy of MET by suppressing human telomerase reverse transcriptase (hTERT) and cyclin D1 gene expression. OBJECTIVE: This study aimed to develop different ratios of methoxy poly(ethylene glycol)-b-poly(e-caprolactone) (MPEG-PCL) micelles for breast cancer to co-deliver a synergistic CHR/MET combination. METHODS: CHR/MET drug-loaded micelles were prepared by modified thin-film hydration.Fourier infrared spectrum, gel permeation chromatography, transmission electron microscopy, and high-performance liquid chromatography were used to evaluate the physicochemical properties of nanostructures. Cell proliferation and cell apoptosis were assessed by MTT and Annexin V-FITC/PI double staining method. The gene expression of hTERT and cyclin D1 was measured by real-time PCR assay. A subcutaneous mouse T47D xenograft model was established to evaluate the in vivo efficiency. RESULTS: When the ratio of MPEG-PCL was 1:1.7, the highest drug loading rate and encapsulation efficiency of CHR (11.31±0.37) and MET (12.22±0.44) were observed. Uniform MPEG-PCL micelles of 51.70±1.91 nm allowed MET to incorporate with CHR, which were co-delivered to breast cancer cells. We demonstrated that CHR/MET co-delivery micelles showed a good synergistic effect on inhibiting proliferation in T47D cells (combination index=0.87) by suppressing hTERT and cyclin D1 gene expression. Compared to the free CHR/MET group, the apoptosis rate on T47D cells by CHR/MET nano-micelles significantly improved from 71.33% to 79.25%. The tumour volume and tumour weight of the CHR/MET group increased more slowly than that of the single-drug treatment group (P<0.05). Compared to the CHR/MET group, the tumour volume and tumour weight of the CHR/MET nano-micelle group decreased by 42% and 59%, respectively. CONCLUSION: We demonstrated that ratiometric CHR/MET micelles could provide an effective technique for the treatment of breast cancer.

Natural polyphenol self-assembled pH-responsive nanoparticles loaded into reversible hydrogel to inhibit oral bacterial activity.

Periodontitis is one of the most prevalent chronic inflammatory diseases and Polyphenols isolated from Turkish gall play a major role in the treatment of inflammatory diseases for their antibacterial, anti-inflammatory and antioxidant activities. In this work, Turkish Galls effective constituent (TGEC, T) was prepared into nanoparticles (T-NPs) by principle of oxidative self-polymerization. The pH-sensitive T-NPs was encapsulated into thermosensitive type in-situ hydrogel, and 42.29 ± 1.12% of effective constituent from T-NPs were continuously released within 96 h under the periodontitis environment. In addition, the weakly alkaline oral micro-environment of patients with periodontitis is more conducive to the sustained release of effective constituent, which is 10.83% more than that of healthy periodontal environment. The bacteriostatic test showed that T-NPs had stronger antibacterial activity on oral pathogens than that of TGEC. Compared with TGEC, the minimum inhibitory concentration (MIC) of T-NPs against P. gingivalis and A. viscosus was reduced by 50% and 25%, respectively. Interestingly, T-NPs induced bacteria lysis by promoting the excessive production of ROS without periodontal tissue damage caused by excessive oxidation reaction. In conclusion, a simple method of preparing microspheres with natural polyphenols was developed, which provides beneficial reference for one-step prepared drug carriers from effective components of natural product, likewise the method offers a green and effective solution to synthesis a new adjuvant therapy drugs for treatment of gingivitis associated with periodontal pockets.

IONP-doped nanoparticles for highly effective NIR-controlled drug release and combination tumor therapy.

Despite advances in controlled drug delivery, drug delivery systems (DDSs) with controlled activated drug release and high spatial and temporal resolution are still required. Theranostic nanomedicine is capable of diagnosis, therapy, and monitoring the delivery and distribution of drug molecules and has received growing interest. In this study, a near-infrared light-controlled "off-on" DDS with magnetic resonance imaging and magnetic targeting properties was developed using a hybrid nanoplatform (carbon nanotubes [CNTs]-iron oxide nanoparticle). Doxorubicin (DOX) and distearoyl-sn-glycero-3-phosphoethanolamine-PEG were adsorbed onto CNTs-iron oxide nanoparticle, and then to avoid the unexpected drug release during circulation, 1-myristyl alcohol was used to encapsulate the CNTs-drug complex. Herein, multifunctional DOX-loaded nanoparticles (NPs) with "off-on" state were developed. DOX-NPs showed an obvious "off-on" effect (temperature increase, drug release) controlled by near-infrared light in vitro and in vivo. In the in vivo and in vitro studies, DOX-NPs exhibited excellent magnetic resonance imaging ability, magnetic targeting property, high biosafety, and high antitumor combined therapeutic efficacy (hyperthermia combined with chemotherapy). These results highlight the great potential of DOX-NPs in the treatment of cancer.