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International Journal of Nanomedicine 2024Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor...
PURPOSE
Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes.
METHODS
A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications.
RESULTS
In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application.
CONCLUSION
CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form.
Topics: Cannabidiol; Animals; Skin Absorption; Transdermal Patch; Biological Availability; Drug Carriers; Administration, Cutaneous; Male; Nanoparticles; Rats; Rats, Sprague-Dawley; Particle Size; Skin; Micelles
PubMed: 38770103
DOI: 10.2147/IJN.S455032 -
RSC Advances May 2024Dynamic hydrogels possessing injectable, degradable and self-healing abilities have attracted considerable attention in the biomedical field in recent years, but it is...
Dynamic hydrogels possessing injectable, degradable and self-healing abilities have attracted considerable attention in the biomedical field in recent years, but it is difficult to tune the mechanical properties and stability of conventional dynamic hydrogels. In this work, we synthesized ABA-triblock copolymers RAFT polymerization, where the A block consisted of thermo-sensitive poly(-isopropylacrylamide--diacetone acrylamide) and the B block was hydrophilic poly(acrylamide). Subsequently, dynamic hydrogels were obtained based on the acylhydrazone bonds between the triblock copolymers and adipic acid dihydrazide (ADH). The obtained hydrogels exhibited injectable and self-healable abilities. In response to the thermal-induced micellization of their temperature-responsive blocks, the mechanical strength of the hydrogels not only increased, but also they exhibited high stability even at pH 2.0. Moreover, the hydrogel in the stable state could be degraded by the fracture of its trithiocarbonate groups. In addition, the hydrogels exhibited good cytocompatibility and controlled release behavior for doxorubicin (DOX). Considering these attractive tunable properties, these dynamic hydrogels show various potential applications in the biomedical field, such as drug carriers and cell or tissue engineering scaffolds.
PubMed: 38769971
DOI: 10.1039/d4ra02480j -
Langmuir : the ACS Journal of Surfaces... Jun 2024The preparation of multifunctional nanomaterials based on inorganic nanoparticles with organic materials has emerged as a promising strategy for the development of new...
The preparation of multifunctional nanomaterials based on inorganic nanoparticles with organic materials has emerged as a promising strategy for the development of new nanomedicines for in vitro and in vivo biomedical applications. Here, we synthesized pH-responsive hybrid inorganic micelles by combining a novel pH-responsive amphiphilic molecule with hydrophobic payloads. This amphiphile was synthesized in a one-pot reaction and self-assembled readily into micelles under acidic pH conditions. In the presence of hydrophobic NP payloads such as AuNPs or IONPs, the amphiphile self-organized around them through hydrophobic interactions, resulting in the formation of colloidally stable hybrid micelles. The size of the hydrophobic NPs determined the pH-response of the inorganic hybrid micelles, which is tuned from pH 7 to 11 for our pH-responsive amphiphilic molecule. This achievement represents a novel approach for the synthesis of tunable pH-responsive hybrid micelles based on inorganic NPs for biomedical imaging, hyperthermia treatment, and also drug delivery nanosystems.
Topics: Gold; Micelles; Hydrogen-Ion Concentration; Metal Nanoparticles; Ferric Compounds; Hydrophobic and Hydrophilic Interactions; Particle Size
PubMed: 38769025
DOI: 10.1021/acs.langmuir.4c01318 -
Journal of the American Chemical Society Jun 2024The sunlight-driven reduction of CO into fuels and platform chemicals is a promising approach to enable a circular economy. However, established optimization approaches...
The sunlight-driven reduction of CO into fuels and platform chemicals is a promising approach to enable a circular economy. However, established optimization approaches are poorly suited to multivariable multimetric photocatalytic systems because they aim to optimize one performance metric while sacrificing the others and thereby limit overall system performance. Herein, we address this multimetric challenge by defining a metric for holistic system performance that takes multiple figures of merit into account, and employ a machine learning algorithm to efficiently guide our experiments through the large parameter matrix to make holistic optimization accessible for human experimentalists. As a test platform, we employ a five-component system that self-assembles into photocatalytic micelles for CO-to-CO reduction, which we experimentally optimized to simultaneously improve yield, quantum yield, turnover number, and frequency while maintaining high selectivity. Leveraging the data set with machine learning algorithms allows quantification of each parameter's effect on overall system performance. The buffer concentration is unexpectedly revealed as the dominating parameter for optimal photocatalytic activity, and is nearly four times more important than the catalyst concentration. The expanded use and standardization of this methodology to define and optimize holistic performance will accelerate progress in different areas of catalysis by providing unprecedented insights into performance bottlenecks, enhancing comparability, and taking results beyond comparison of subjective figures of merit.
PubMed: 38767460
DOI: 10.1021/jacs.4c01305 -
International Journal of Nanomedicine 2024Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for...
INTRODUCTION
Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for RA therapy remain unsatisfactory because of their low efficiency and obvious adverse effects. Therefore, we here established RA microenvironment-responsive targeted micelles that can respond to the increase in reactive oxygen species (ROS) levels in the joint and improve macrophage-specific targeting of loaded drugs.
METHODS
We here prepared ROS-responsive folate-modified curcumin micelles (TK-FA-Cur-Ms) in which thioketal (TK) was used as a ROS-responsive linker for modifying polyethylene glycol 5000 (PEG) on the micellar surface. When micelles were in the ROS-overexpressing inflammatory microenvironment, the PEG hydration layer was shed, and the targeting ligand FA was exposed, thereby enhancing cellular uptake by macrophages through active targeting. The targeting, ROS sensitivity and anti-inflammatory properties of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was utilized to investigate the targeting, expression of serum inflammatory factors and histology change of the articular cartilage by micelles in vivo.
RESULTS
TK-FA-Cur-Ms had a particle size of 90.07 ± 3.44 nm, which decreased to 78.87 ± 2.41 nm after incubation with HO. The micelles exhibited in vitro targeting of RAW264.7 cells and significantly inhibited inflammatory cytokine levels. Pharmacodynamic studies have revealed that TK-FA-Cur-Ms prolonged the drug circulation and exhibited augmented cartilage-protective and anti-inflammatory effects in vivo.
CONCLUSION
The unique ROS-responsive targeted micelles with targeting, ROS sensitivity and anti-inflammatory properties were successfully prepared and may offer an effective therapeutic strategy against RA.
Topics: Animals; Micelles; Curcumin; Reactive Oxygen Species; Rats; Arthritis, Rheumatoid; RAW 264.7 Cells; Mice; Folic Acid; Arthritis, Experimental; Polyethylene Glycols; Drug Carriers; Folate Receptors, GPI-Anchored; Macrophages; Male; Particle Size; Anti-Inflammatory Agents; Disease Models, Animal
PubMed: 38766660
DOI: 10.2147/IJN.S458957 -
BioRxiv : the Preprint Server For... May 2024While they account for a large portion of drug targets, membrane proteins (MPs) present a unique challenge for drug discovery. Peripheral membrane proteins (PMPs), a...
While they account for a large portion of drug targets, membrane proteins (MPs) present a unique challenge for drug discovery. Peripheral membrane proteins (PMPs), a class of proteins that bind reversibly to membranes, are also difficult targets, particularly those that function only while bound to membranes. The protein-membrane interface in PMPs is often where functional interactions and catalysis occur, making it a logical target for inhibition. However, interfaces are underexplored spaces in inhibitor design and there is a need for enhanced methods for small-molecule ligand discovery. In an effort to better initiate drug discovery efforts for PMPs, this study presents a screening methodology using membrane-mimicking reverse micelles (mmRM) and NMR-based fragment screening to assess ligandability in the protein-membrane interface. The proof-of-principle target, glutathione peroxidase 4 (GPx4), is a lipid hydroperoxidase which is essential for the oxidative protection of membranes and thereby the prevention of ferroptosis. GPx4 inhibition is promising for therapy-resistant cancer therapy, but current inhibitors are generally covalent ligands with limited clinical utility. Presented here is the discovery of non-covalent small-molecule ligands for membrane-bound GPx4 revealed through the mmRM fragment screening methodology. The fragments were tested against GPx4 in bulk aqueous conditions and displayed little to no binding to the protein without embedment into the membrane. The 9 hits had varying affinities and partitioning coefficients and revealed properties of fragments that bind within the protein-membrane interface. Additionally, a secondary screen confirmed the potential to progress the fragments by enhancing the affinity from > 200 μM to ~15 μM with the addition of certain hydrophobic groups. This study presents an advancement of screening capabilities for membrane associated proteins, reveals ligandability within the GPx4 protein-membrane interface, and may serve as a starting point for developing non-covalent inhibitors of GPx4.
PubMed: 38766018
DOI: 10.1101/2024.05.09.593437 -
Protein Science : a Publication of the... Jun 2024G-protein coupled receptors (GPCRs) are the largest class of membrane proteins encoded in the human genome with high pharmaceutical relevance and implications to human...
G-protein coupled receptors (GPCRs) are the largest class of membrane proteins encoded in the human genome with high pharmaceutical relevance and implications to human health. These receptors share a prevalent architecture of seven transmembrane helices followed by an intracellular, amphipathic helix 8 (H8) and a disordered C-terminal tail (Ctail). Technological advancements have led to over 1000 receptor structures in the last two decades, yet frequently H8 and the Ctail are conformationally heterogeneous or altogether absent. Here we synthesize a peptide comprising the neurotensin receptor 1 (NTS1) H8 and Ctail (H8-Ctail) to investigate its structural stability, conformational dynamics, and orientation in the presence of detergent and phospholipid micelles, which mimic the membrane. Circular dichroism (CD) and nuclear magnetic resonance (NMR) measurements confirm that zwitterionic 1,2-diheptanoyl-sn-glycero-3-phosphocholine is a potent stabilizer of H8 structure, whereas the commonly-used branched detergent lauryl maltose neopentyl glycol (LMNG) is unable to completely stabilize the helix - even at amounts four orders of magnitude greater than its critical micellar concentration. We then used NMR spectroscopy to assign the backbone chemical shifts. A series of temperature and lipid titrations were used to define the H8 boundaries as F376-R392 from chemical shift perturbations, changes in resonance intensity, and chemical-shift-derived phi/psi angles. Finally, the H8 azimuthal and tilt angles, defining the helix orientation relative of the membrane normal were measured using paramagnetic relaxation enhancement NMR. Taken together, our studies reveal the H8-Ctail region is sensitive to membrane physicochemical properties and is capable of more adaptive behavior than previously suggested by static structural techniques.
Topics: Receptors, Neurotensin; Humans; Micelles; Nuclear Magnetic Resonance, Biomolecular; Peptides; Circular Dichroism; Protein Conformation, alpha-Helical; Detergents; Models, Molecular
PubMed: 38757374
DOI: 10.1002/pro.4976 -
Chemical Science May 2024The mechanisms through which environmental conditions affect the expression of interconnected species is a key step to comprehending the principles underlying complex...
The mechanisms through which environmental conditions affect the expression of interconnected species is a key step to comprehending the principles underlying complex chemical processes. In Nature, chemical modifications triggered by the environment have a major impact on the structure and function of biomolecules and regulate different reaction pathways. Yet, minimalistic artificial systems implementing related adaptation behaviours remain barely explored. The hydrolysis of amino acid methyl esters to their corresponding amino acids leads to a drastic change in p ( 7 and 9, respectively) that protonates the free amino group at physiological conditions. Dynamic covalent libraries (DCvLs) based on amino acid methyl esters and aldehydes respond to such hydrolysis and lead to constitutional adaptation. Each of the libraries studied experiences a DCvL conversion allowing for constituent selection due to the silencing of the zwitterionic amino acids towards imine formation. The selective action of different enzymes on the DCvLs results in states with simplified constitutional distributions and transient chirality. When additional components (, scavengers) that are not affected by hydrolysis are introduced into the dynamic libraries, the amino acid methyl ester hydrolysis induces the up-regulation of the constituents made of these scavenging components. In these systems, the constituent distribution is resolved from a scrambled mixture of imines to a state characterized by the predominance of a single aldimine. Remarkably, although the final libraries display higher "simplexity", the different transient states present an increased complexity that allows for the emergence of organized structures [micelle formation] and distributions [up-regulation of two antagonistic constituents]. This reactive site inhibition by a remote chemical modification resembles the scenario found in some enzymes for the regulation of their activity through proximal post-translational modifications.
PubMed: 38756812
DOI: 10.1039/d4sc01288g -
Journal of Dairy Science May 2024The casein (CN) composition, salt composition and micelle size varies largely between milk samples of individual animals. In goats, the link between those casein...
The casein (CN) composition, salt composition and micelle size varies largely between milk samples of individual animals. In goats, the link between those casein characteristics are unknown and could provide useful insights into goat casein micelle structure. In this study, the casein- and salt composition of 42 individual Dutch goats from 17 farms was studied and linked to casein micelle size. Micelle size, proportions of individual caseins, and protein content were associated with each other. Milk with smaller casein micelles was higher in protein content, salt content, and proportion of α-CN, but lower in α-CN and β-CN. The higher salt content in milk with small casein micelles was mainly attributed to a higher protein content, but changes in casein composition might additionally contribute to differences in mineralization. The non-sedimentable casein content in goat milk correlated with non-sedimentable fractions of β-CN and κ-CN and was independent of micelle size. Between large and small casein micelles, goat casein micelles showed more differences in casein and salt composition than bovine micelles, indicating differences in internal structure. Nevertheless, the casein mineralization in goat milk was similar to casein mineralization in bovine milk, indicating that mineralization of casein micelles follows a general principle. These results can help to better understand how composition and micelle structure in goat milk are related to each other, which may be useful to improve processing and product properties of goat milk in the future.
PubMed: 38754827
DOI: 10.3168/jds.2023-24548 -
PloS One 2024Chronic rhinosinusitis (CRS) is an inflammatory disease affecting the sinuses or nose. Persistent inflammatory responses can lead to tissue remodeling, which is a...
BACKGROUND
Chronic rhinosinusitis (CRS) is an inflammatory disease affecting the sinuses or nose. Persistent inflammatory responses can lead to tissue remodeling, which is a pathological characteristics of CRS. Activation of fibroblasts in the nasal mucosal stroma, differentiation and collagen deposition, and subepithelial fibrosis have been associated with CRS.
OBJECTIVES
We aimed to assess the inhibitory effects of doxycycline and deoxycholic acid-polyethyleneimine conjugate (DA3-Doxy) on myofibroblast differentiation and extracellular matrix (ECM) production in nasal fibroblasts stimulated with TGF-β1.
METHODS
To enhance efficacy, we prepared DA3-Doxy using a conjugate of low-molecular-weight polyethyleneimine (PEI) (MW 1800) and deoxycholic acid (DA) and Doxy. The synthesis of the DA3-Doxy polymer was confirmed using nuclear magnetic resonance, and the critical micelle concentration required for cationic micelle formation through self-assembly was determined. Subsequently, the Doxy loading efficiency of DA3 was assessed. The cytotoxicity of Doxy, DA3, PEI, and DA-Doxy in nasal fibroblasts was evaluated using the WST-1 assay. The anti-tissue remodeling and anti-inflammatory effects of DA3-Doxy and DA3 were examined using real-time polymerase chain reaction (Real-time PCR), immunocytochemistry, western blot, and Sircol assay.
RESULTS
Both DA3 and DA3-Doxy exhibited cytotoxicity at 10 μg/ml in nasal fibroblasts. Doxy partially inhibited α-smooth muscle actin, collagen types I and III, and fibronectin. However, DA3-Doxy significantly inhibited α-SMA, collagen types I and III, and fibronectin at 5 μg/ml. DA3-Doxy also modulated TGF-β1-induced changes in the expression of MMP 1, 2, and 9. Nonetheless, TGF-β1-induced expression of MMP3 was further increased by DA3-Doxy. The expression of TIMP 1 and 2 was partially reduced with 5 μg/ml DA3-Doxy.
CONCLUSIONS
Although initially developed for the delivery of genetic materials or drugs, DA3 exhibits inhibitory effects on myofibroblast differentiation and ECM production. Therefore, it holds therapeutic potential for CRS, and a synergistic effect can be expected when loaded with CRS treatment drugs.
Topics: Humans; Polyethyleneimine; Deoxycholic Acid; Fibroblasts; Cell Differentiation; Doxycycline; Extracellular Matrix; Transforming Growth Factor beta1; Myofibroblasts; Nasal Mucosa; Actins
PubMed: 38753593
DOI: 10.1371/journal.pone.0285655