The gut hormone glucagon-like peptide-1 (GLP-1) is proposed for treatment of Type II diabetes mellitus. However, the short half life of GLP-1 in vivo is a major limitation for its application due to the frequent invasive administrations. To provide a optimal formulation to overcome this limitation, we developed a GLP-1 entrapped microspheres to achieve sustained release GLP-1 for 4-week. GLP-1 was stabilized by GLP-1-zinc complexation with zinc carbonate and encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) with S/O/O solvent extraction to obtain GLP-1 loaded PLGA microspheres (MS). The characteristics of MS were evaluated as follows: The surface morphyology was assessed by scanning electron microscopy (SEM); The drug encapsulation efficiency and GLP-1 controlled release profile was tested by HPLC; The sustained release of GLP-1 MS in vivo and pharmacological efficacy were studied in normal mice and streptozotocin (STZ)-induced diabetic mice model after subcutaneous administration of GLP-1 MS. GLP-1-zinc complexation significantly reduced initial burst release from 37.2 to 7.5%. The controlled release bioactive GLP-1 in vitro was achieved for 4-week period by zinc complexation and addition of ZnCO3. The optimal and complete cumulative release of GLP-1 from MS was increased from 23 to 63% in 28 d by using low MW PLGA (MW 14000). The in vivo testing in normal mice and diabetic mice suggest that this zinc-stabilized technique combined with S/O/O method in the presence of water insoluble antacid additive ZnCO3 preserve the biological activity of GLP-1. GLP-1 MS formulation achieved controlled released in vivo for 28 d and exhibit sustained long term pharmacological efficacy to decrease blood glucose level in diabetic mice. This GLP-1 MS formulation provides a practical formulation for long-term sustained delivery of GLP-1 to treat Type II diabetes.

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival. The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect. To improve the treatment efficacy, we developed Pluronic P123 (P123)-based polymeric micelles dually decorated with alendronate (ALN) and cancer-specific phage protein DMPGTVLP (DP-8) for targeted drug delivery to breast cancer bone metastases. Doxorubicin (DOX) was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity (3.44%). The DOX-loaded polymeric micelles were spherical, 123 nm in diameter on average, and exhibited a narrow size distribution. The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release. The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells. Rapid binding of the micelles to hydroxyapatite (HA) microparticles indicated their high affinity for bone. P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model. In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity. In conclusion, our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Organophosphorus compounds (OPs) is a serious threat to human health and life safety, but because of the existence of blood-brain barrier, most of the therapeutic drugs cannot enter the center, reactivate centrally located toxic acetylcholinesterase (AChE), it is urgent to find an efficient treatment method. The c(RGDyK) cyclic peptide modified HI-6-loaded brain targeting liposomes [c(RGDyK)-PEG₂₀₀₀HI-6-lipo] were prepared by ammonium sulfate gradient method. The in vitro blood-brain barrier (BBB) model was established, and the function of the liposomes was evaluated. The animal model of DDVP poisoning was established, and the central toxic enzyme reactivation ability of c(RGDyK)-PEG₂₀₀₀HI-6-lipo by both the intravenous and nasal administration route was verified. The HI-6-loaded liposomes with brain targeting function were successfully synthesized and prepared with high encapsulation efficiency (70.23 ± 2.18%), drug loading (2.86 ± 0.07)%, average particle size 242.9 nm (polydispersion index 0.149), and ζ potential -16.2 mV. Combined with the in vitro and in vivo studies, the c(RGDyK)-PEG₂₀₀₀HI-6-lipo has better ability to cross the BBB. In addition, compared with intravenous injection, nasal administration was proved to be more effective against organophosphorus poisoning, and the reactivation rate of brain acetylcholinesterase reached (26.19 ± 7.70)%. The prepared c(RGDyK)-PEG₂₀₀₀HI-6-lipo has a better ability to cross BBB. Nasal administration, as a way to bypass the BBB and directly deliver drugs into the brain, effectively improves the bioavailability of HI-6 in the brain. This study holds promise by providing a non-invasive approach to deliver water-soluble oxime antidote into the brain and reactivate central acetylcholinesterase via the naso-brain route.

3-n-butylphthalide (NBP) contains one of the main active ingredients of celery seed. It has a series of pharmacological mechanisms, including reconstitution of microcirculation, protection of mitochondrial function, inhibition of oxidative stress, and inhibition of neuronal apoptosis. Based on the complex multi-targeting of NBP pharmacological mechanisms, the clinical applications of NBP are increasing, and more and more clinical studies and animal experiments have focused on NBP. In this study, we used male Sprague Dawley rats as an animal model to elucidate the intervention effect of butylphthalide on high altitude cerebral edema (HACE), and also compared the effect of butylphthalide and rhodiola rosea on HACE. Firstly, we measured the changes of body weight and brain water content and observed the pathological changes of brain tissues. In addition, the contents of inflammatory factors, oxidative stress and brain neurotransmitters were assessed by enzyme-linked immunoassay kits, and finally, the expression of apoptotic proteins in brain tissues was determined by western blotting. The results showed that NBP reduced brain water content, attenuated brain tissue damage, altered inflammatory factors, oxidative stress indicators, and brain neurotransmitter levels, and in addition NBP inhibited the expression of Caspase-related apoptotic proteins. Therefore, NBP has the potential to treat and prevent HACE.

The inflammatory response of lung tissue and abnormal proliferation of pulmonary artery smooth muscle cells are involved in the pathogenesis of high-altitude pulmonary hypertension (HAPH). Halofuginone (HF), an active ingredient derivative of Chang Shan (Dichroa febrifuga Lour. [Hydrangeaceae]), has antiproliferative, antihypertrophic, antifibrotic, and other effects, but its protective effects on HAPH remains unclear. In the present study, we evaluated the efficacy of HF on HAPH by establishing a 6000 m HAPH rat model. Male Sprague–Dawley rats were divided into normoxia, normoxia + halofuginone (1 mg/kg), hypoxia, and hypoxia + halofuginone (1 mg/kg) groups. The results showed that HF (1 mg/kg) could prevent hypoxia-induced hemodynamic abnormalities, right ventricular hypertrophy, and pulmonary vascular remodeling in rats. We further detected the expression levels of inflammatory factors interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and proliferative/antiproliferative indicators proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 6 (CDK6), Cyclin D1, p21 in lung tissue, and found that HF could attenuate the lung tissue inflammatory response and proliferative response in HAPH rats. In addition, we also examined the expression levels of transforming growth factor-β1 (TGF-β1), Smad2/3 and p-Smad2/3 in lung tissue, and found that HF exerted therapeutic effects by inhibiting the TGF-β1/Smad signaling pathway.

Background: Injectable bone cement is commonly used in clinical orthopaedics to fill bone defects, treat vertebral compression fractures, and fix joint prostheses during joint replacement surgery. Poly(propylene fumarate) (PPF) has been proposed as a biodegradable and injectable alternative to polymethylmethacrylate (PMMA) bone cement. Recently, there has been considerable interest in two-dimensional (2D) black phosphorus nanomaterials (BPNSs) in the biomedical field due to their excellent photothermal and osteogenic properties. In this study, we investigated the biological and physicochemical qualities of BPNSs mixed with PPF bone cement created through thermal cross-linking. Methods: PPF was prepared through a two-step process, and BPNSs were prepared via a liquid phase stripping method. BP/PPF was subsequently prepared through thermal cross-linking, and its characteristics were thoroughly analysed. The mechanical properties, cytocompatibility, osteogenic performance, degradation performance, photothermal performance, and in vivo toxicity of BP/PPF were evaluated. Results: BP/PPF exhibited low cytotoxicity levels and mechanical properties similar to that of bone, whereas the inclusion of BPNSs promoted preosteoblast adherence, proliferation, and differentiation on the surface of the bone cement. Furthermore, 200 BP/PPF demonstrated superior cytocompatibility and osteogenic effects, leading to the degradation of PPF bone cement and enabling it to possess photothermal properties. When exposed to an 808-nm laser, the temperature of the bone cement increased to 45–55 °C. Furthermore, haematoxylin and eosin-stained sections from the in vivo toxicity test did not display any anomalous tissue changes. Conclusion: BP/PPF exhibited mechanical properties similar to that of bone: outstanding photothermal properties, cytocompatibility, and osteoinductivity. BP/PPF serves as an effective degradable bone cement and holds great potential in the field of bone regeneration.