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Materials Today. Bio Jun 2024Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to the imbalance between osteogenesis and osteoclastogenesis, making osteoporotic...
Injectable and high-strength PLGA/CPC loaded ALN/MgO bone cement for bone regeneration by facilitating osteogenesis and inhibiting osteoclastogenesis in osteoporotic bone defects.
Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to the imbalance between osteogenesis and osteoclastogenesis, making osteoporotic bone defects healing a significant clinical challenge. Calcium phosphate cement (CPC) is a promising bone substitute material due to its good osteoinductive activity, however, the drawbacks such as fragility, slow degradation rate and incapability to control bone loss restrict its application in osteoporotic bone defects treatment. Currently, we developed the PLGA electrospun nanofiber sheets to carry alendronate (ALN) and magnesium oxide nanoparticle (nMgO) into CPC, therefore, to obtain a high-strength bone cement (C/AM-PL/C). The C/AM-PL/C bone cement had high mechanical strength, anti-washout ability, good injection performance and drug sustained release capacity. More importantly, the C/AM-PL/C cement promoted the osteogenic differentiation of bone marrow mesenchymal stem cells and neovascularization via the release of Mg (from nMgO) and Ca (during the degradation of CPC), and inhibited osteoclastogenesis via the release of ALN . Moreover, the injection of C/AM-PL/C cement significantly improved bone healing in an OP model with femur condyle defects . Altogether, the injectable C/AM-PL/C cement could facilitate osteoporotic bone regeneration, demonstrating its capacity as a promising candidate for treatment of osteoporotic bone defects.
PubMed: 38873105
DOI: 10.1016/j.mtbio.2024.101092 -
Bioactive Materials Sep 2024Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite the development of nationally recognized first-line anti-osteoporosis...
Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite the development of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their low bioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. This calls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybrid structures with bioactive components and stable fluffy topological morphology by cross-linking calcium and phosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequent grafting of -PEG-DAsp ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealed that these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecular mechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that small-dose AL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. results restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as the consequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant with peculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well as bone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies for other bone diseases.
PubMed: 38846529
DOI: 10.1016/j.bioactmat.2024.05.037 -
Hong Kong Medical Journal = Xianggang... Jun 2024
PubMed: 38841765
DOI: 10.12809/hkmj2210652 -
MSphere Jun 2024Superficial infections of the skin, hair, and nails by fungal dermatophytes are the most prevalent of human mycoses, and many infections are refractory to treatment. As...
UNLABELLED
Superficial infections of the skin, hair, and nails by fungal dermatophytes are the most prevalent of human mycoses, and many infections are refractory to treatment. As current treatment options are limited, recent research has explored drug synergy with azoles for dermatophytoses. Bisphosphonates, which are approved to treat osteoporosis, can synergistically enhance the activity of azoles in diverse yeast pathogens but their activity has not been explored in dermatophytes or other molds. Market bisphosphonates risedronate, alendronate, and zoledronate (ZOL) were evaluated for antifungal efficacy and synergy with three azole antifungals: fluconazole (FLC), itraconazole (ITR), and ketoconazole (KET). ZOL was the most active bisphosphonate tested, displaying moderate activity against nine dermatophyte species (MIC range 64-256 µg/mL), and was synergistic with KET in eight of these species. ZOL was also able to synergistically improve the anti-biofilm activity of KET and combining KET and ZOL prevented the development of antifungal resistance. Rescue assays in revealed that the inhibitory effects of ZOL alone and in combination with KET were due to the inhibition of squalene synthesis. Fluorescence microscopy using membrane- and ROS-sensitive probes demonstrated that ZOL and KET:ZOL compromised membrane structure and induced oxidative stress. Antifungal activity and synergy between bisphosphonates and azoles were also observed in other clinically relevant molds, including species of and . These findings indicate that repurposing bisphosphonates as antifungals is a promising strategy for revitalising certain azoles as topical antifungals, and that this combination could be fast-tracked for investigation in clinical trials.
IMPORTANCE
Fungal infections of the skin, hair, and nails, generally grouped together as "tineas" are the most prevalent infectious diseases globally. These infections, caused by fungal species known as dermatophytes, are generally superficial, but can in some cases become aggressive. They are also notoriously difficult to resolve, with few effective treatments and rising levels of drug resistance. Here, we report a potential new treatment that combines azole antifungals with bisphosphonates. Bisphosphonates are approved for the treatment of low bone density diseases, and in fungi they inhibit the biosynthesis of the cell membrane, which is also the target of azoles. Combinations were synergistic across the dermatophyte species and prevented the development of resistance. We extended the study to molds that cause invasive disease, finding synergy in some problematic species. We suggest bisphosphonates could be repurposed as synergents for tinea treatment, and that this combination could be fast-tracked for use in clinical therapy.
PubMed: 38837382
DOI: 10.1128/msphere.00248-24 -
JGH Open : An Open Access Journal of... Jun 2024Alendronate is used to treat Paget's bone disease, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis because it suppresses osteoclast activity to stop...
BACKGROUND
Alendronate is used to treat Paget's bone disease, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis because it suppresses osteoclast activity to stop bone resorption.
CASE REPORT
We present an exceptional case of esophagitis caused by alendronate. Blood tests and other data were normal when the patient was taken to the hospital, but an endoscopic examination revealed significant esophageal redness, erosion, and ulceration, along with pseudomembrane. The patient was given medicine after receiving a diagnosis of alendronate pill-induced esophagitis based on the pathological findings.
CONCLUSION
This case report is a timely reminder of the importance of thorough pharmacovigilance, patient education, and smart therapeutic decision-making in the context of alendronate use. To properly treat and prevent problems with the esophagus caused by alendronate, additional research is required.
PubMed: 38832136
DOI: 10.1002/jgh3.13080 -
Experimental Biology and Medicine... 2024[This corrects the article DOI: 10.1177/15353702231211977.].
[This corrects the article DOI: 10.1177/15353702231211977.].
PubMed: 38826627
DOI: 10.3389/ebm.2024.10149 -
Molecules (Basel, Switzerland) May 2024Vitamin D, an essential micronutrient crucial for skeletal integrity and various non-skeletal physiological functions, exhibits limited bioavailability and stability in...
Vitamin D, an essential micronutrient crucial for skeletal integrity and various non-skeletal physiological functions, exhibits limited bioavailability and stability in vivo. This study is focused on the development of polyethylene glycol (PEG)-grafted phospholipid micellar nanostructures co-encapsulating vitamin D3 and conjugated with alendronic acid, aimed at active bone targeting. Furthermore, these nanostructures are rendered optically traceable in the UV-visible region of the electromagnetic spectrum via the simultaneous encapsulation of vitamin D3 with carbon dots, a newly emerging class of fluorescents, biocompatible nanoparticles characterized by their resistance to photobleaching and environmental friendliness, which hold promise for future in vitro bioimaging studies. A systematic investigation is conducted to optimize experimental parameters for the preparation of micellar nanostructures with an average hydrodynamic diameter below 200 nm, ensuring colloidal stability in physiological media while preserving the optical luminescent properties of the encapsulated carbon dots. Comprehensive chemical-physical characterization of these micellar nanostructures is performed employing optical and morphological techniques. Furthermore, their binding affinity for the principal inorganic constituent of bone tissue is assessed through a binding assay with hydroxyapatite nanoparticles, indicating significant potential for active bone-targeting. These formulated nanostructures hold promise for novel therapeutic interventions to address skeletal-related complications in cancer affected patients in the future.
Topics: Micelles; Cholecalciferol; Nanostructures; Bone and Bones; Alendronate; Polyethylene Glycols; Humans; Drug Delivery Systems; Luminescence; Nanoparticles; Drug Carriers; Quantum Dots
PubMed: 38792228
DOI: 10.3390/molecules29102367 -
International Journal of Molecular... May 2024In this study, spherical or hexagonal NaYF:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature...
In this study, spherical or hexagonal NaYF:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature coprecipitation and subsequently modified with three kinds of polymers. These included poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide) [P(DMA-AEA)] terminated with an alendronate anchoring group, and poly(methyl vinyl ether-co-maleic acid) (PMVEMA). The internalization of nanoparticles by rat mesenchymal stem cells (rMSCs) and C6 cancer cells (rat glial tumor cell line) was visualized by electron microscopy and the cytotoxicity of the UCNPs and their leaches was measured by the real-time proliferation assay. The comet assay was used to determine the oxidative damage of the UCNPs. An in vivo study on mice determined the elimination route and potential accumulation of UCNPs in the body. The results showed that the L- and S-UCNPs were internalized into cells in the lumen of endosomes. The proliferation assay revealed that the L-UCNPs were less toxic than S-UCNPs. The viability of rMSCs incubated with particles decreased in the order S-UCNP@Ale-(PDMA-AEA) > S-UCNP@Ale-PEG > S-UCNPs > S-UCNP@PMVEMA. Similar results were obtained in C6 cells. The oxidative damage measured by the comet assay showed that neat L-UCNPs caused more oxidative damage to rMSCs than all coated UCNPs while no difference was observed in C6 cells. An in vivo study indicated that L-UCNPs were eliminated from the body via the hepatobiliary route; L-UCNP@Ale-PEG particles were almost eliminated from the liver 96 h after intravenous application. Pilot fluorescence imaging confirmed the limited in vivo detection capabilities of the nanoparticles.
Topics: Animals; Mice; Rats; Mesenchymal Stem Cells; Nanoparticles; Cell Line, Tumor; Polyethylene Glycols; Cell Survival; Particle Size; Male; Oxidative Stress
PubMed: 38791332
DOI: 10.3390/ijms25105294 -
Materials Today. Bio Jun 2024Osteogenic-osteoclast coupling processes play a crucial role in bone regeneration. Recently, strategies that focus on multi-functionalized implant surfaces to enhance...
Osteogenic-osteoclast coupling processes play a crucial role in bone regeneration. Recently, strategies that focus on multi-functionalized implant surfaces to enhance the healing of bone defects through the synergistic regulation of osteogenesis and osteoclastogenesis is still a challenging task in the field of bone tissue engineering. The aim of this study was to create a dual-drug release-based core-shell nanofibers with the intent of achieving a time-controlled release to facilitate bone regeneration. We fabricated core-shell P/PCL nanofibers using coaxial electrospinning, where alendronate (ALN) was incorporated into the core layer and hydroxyapatite (HA) into shell. The surface of the nanofiber construct was further modified with mussel-derived polydopamine (PDA) to induce hydrophilicity and enhance cell interactions. Surface characterizations confirmed the successful synthesis of PDA@PHA/PCL-ALN nanofibers endowed with excellent mechanical strength (20.02 ± 0.13 MPa) and hydrophilicity (22.56°), as well as the sustained sequential release of ALN and Ca ions. experiments demonstrated that PDA-functionalized core-shell PHA/PCL-ALN scaffolds possessed excellent cytocompatibility, enhanced cell adhesion and proliferation, alkaline phosphatase activity and osteogenesis-related genes. In addition to osteogenesis, the engineered scaffolds also significantly reduced osteoclastogenesis, such as tartrate-resistant acid phosphatase activity and osteoclastogenesis-related gene expression. After 12-week of implantation, it was observed that PDA@PHA/PCL-ALN nanofiber scaffolds, in a rat cranial defect model, significantly promoted bone repair and regeneration. Microcomputed tomography, histological examination, and immunohistochemical analysis collectively demonstrated that the PDA-functionalized core-shell PHA/PCL-ALN scaffolds exhibited exceptional osteogenesis-inducing and osteoclastogenesis-inhibiting effects. Finally, it may be concluded from our results that the bio-inspired surface-functionalized multifunctional, biomimetic and controlled release core-shell nanofiber provides a promising strategy to facilitate bone healing.
PubMed: 38779556
DOI: 10.1016/j.mtbio.2024.101088 -
Beilstein Journal of Nanotechnology 2024Sodium alendronate (ALN) is a very hydrosoluble and poorly permeable molecule used as an antiresorptive agent and with vascular anticalcifying capacity. Loaded into...
Sodium alendronate (ALN) is a very hydrosoluble and poorly permeable molecule used as an antiresorptive agent and with vascular anticalcifying capacity. Loaded into targeted nanovesicles, its anti-inflammatory activity may be amplified towards extra-osseous and noncalcified target cells, such as severely irritated vascular endothelium. Here cytotoxicity, mitochondrial membrane potential, ATP content, and membrane fluidity of human endothelial venous cells (HUVECs) were determined after endocytosis of ALN-loaded nanoarchaeosomes (nanoARC-Chol(ALN), made of polar lipids from : cholesterol 7:3 w/w, 166 ± 5 nm, 0.16 ± 0.02 PDI, -40.8 ± 5.4 mV potential, 84.7 ± 21 µg/mg ALN/total lipids, TL). The effect of nanoARC-Chol(ALN) was further assessed on severely inflamed HUVECs. To that aim, HUVECs were grown on a porous barrier on top of a basal compartment seeded either with macrophages or human foam cells. One lighter and one more pronounced inflammatory context was modelled by adding lipopolysaccharide (LPS) to the apical or the apical and basal compartments. The endocytosis of nanoARC-Chol(ALN), was observed to partly reduce the endothelial-mesenchymal transition of HUVECs. Besides, while 10 mg/mL dexamethasone, 7.6 mM free ALN and ALN-loaded liposomes failed, 50 μg/mL TL + 2.5 μg/mL ALN (i.e., nanoARC-Chol(ALN)) reduced the IL-6 and IL-8 levels by, respectively, 75% and 65% in the mild and by, respectively, 60% and 40% in the pronounced inflammation model. This is the first report showing that the endocytosis of nanoARC-Chol(ALN) by HUVECs magnifies the anti-inflammatory activity of ALN even under conditions of intense irritation, not only surpassing that of free ALN but also that of dexamethasone.
PubMed: 38774586
DOI: 10.3762/bjnano.15.46